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    Clinical Trial Results:
    A Prospective, Randomized, Double Blind Comparison of LY900014 to Humalog in Adults with Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion

    Summary
    EudraCT number
    		 2015-005358-36
    Trial protocol
    		 HU   DE   AT   FR   ES   IT  
    Global end of trial date
    06 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jan 2021
    First version publication date
    20 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I8B-MC-ITRO
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03830281
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 16315
    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
    06 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The reason for this study is to compare the study drug LY900014 to insulin lispro (Humalog) when both are used in insulin pump therapy in adults with type 1 diabetes (T1D).
    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
    14 Feb 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Austria: 18
    Country: Number of subjects enrolled
    Hungary: 50
    Country: Number of subjects enrolled
    United States: 198
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Israel: 43
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Spain: 35
    Worldwide total number of subjects
    471
    EEA total number of subjects
    172
    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)
    409
    From 65 to 84 years
    62
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The purpose of the lead-in period was to assess basal rates and bolus calculator settings and adjust if needed prior to randomization. Participants (Pts) were then randomized to insulin lispro (Humalog) or ultra-rapid lispro as both basal and bolus insulin and delivered bolus doses 0 to 2 minutes prior to each meal (pre-meal).

    Period 1
    Period 1 title
    Lead-in Period (2 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 Insulin Lispro (Humalog)
    Arm description
    		 Participants received individual dose of 100 units per milliliter (U/mL) insulin lispro (Humalog) by continuous subcutaneous insulin infusion (CSII); where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Lispro
    Investigational medicinal product code
    LY275585
    Other name
    Humalog
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received individual dose of 100 U/mL insulin lispro (Humalog) by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Number of subjects in period 1
    		Insulin Lispro (Humalog)
    Started
    471
    Completed
    432
    Not completed
    39
         Physician decision
    2
         Consent withdrawn by subject
    29
         Adverse event, non-fatal
    2
         Not Met Eligibility Criteria
    6
    Period 2
    Period 2 title
    Treatment Period (16 Weeks)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Insulin Lispro (Humalog)
    Arm description
    		 Participants received individual dose of 100 units per milliliter (U/mL) insulin lispro (Humalog) by continuous subcutaneous insulin infusion (CSII); where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Lispro
    Investigational medicinal product code
    LY275585
    Other name
    Humalog
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received individual dose of 100 U/mL insulin lispro (Humalog) by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Arm title
    		 Ultra-Rapid Lispro
    Arm description
    		 Participants received individual dose of 100 U/mL ultra rapid lispro by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ultra-Rapid Lispro
    Investigational medicinal product code
    LY900014
    Other name
    Insulin lispro
    Pharmaceutical forms
    Infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received individual dose of 100 U/mL ultra rapid lispro by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The Lead-in Period (Period 1) was used to assess basal rates and bolus calculator settings and adjust if needed prior to randomization. Baseline analysis population is based on all randomized participants. Participants were randomized to insulin lispro (Humalog) or ultra-rapid lispro in Period 2.
    Number of subjects in period 2 [2]
    		Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Started
    217
    215
    Completed
    205
    198
    Not completed
    12
    17
         Physician decision
    1
    -
         Consent withdrawn by subject
    5
    6
         Adverse event, non-fatal
    1
    7
         Sponsor Decision
    1
    1
         Lost to follow-up
    4
    3
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Participants who completed lead-in period randomized to either insulin lispro (Humalog) or ultra-rapid lispro in treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin Lispro (Humalog)
    Reporting group description
    		 Participants received individual dose of 100 units per milliliter (U/mL) insulin lispro (Humalog) by continuous subcutaneous insulin infusion (CSII); where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Reporting group title
    Ultra-Rapid Lispro
    Reporting group description
    		 Participants received individual dose of 100 U/mL ultra rapid lispro by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Reporting group values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro Total
    Number of subjects
    		 217 215 432
    Age categorical
    Units: Subjects
    Age continuous
    All randomized participants.
    Units: years
        arithmetic mean (standard deviation)
    		 44.7 ± 14.9 48.2 ± 15.4 -
    Gender categorical
    All randomized participants.
    Units: Subjects
        Female
    		 119 120 239
        Male
    		 98 95 193
    Ethnicity (NIH/OMB)
    All randomized participants.
    Units: Subjects
        Hispanic or Latino
    		 17 18 35
        Not Hispanic or Latino
    		 180 178 358
        Unknown or Not Reported
    		 20 19 39
    Race (NIH/OMB)
    All randomized participants.
    Units: Subjects
        American Indian or Alaska Native
    		 0 2 2
        Asian
    		 0 2 2
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 6 7 13
        White
    		 207 202 409
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 2 2 4
    Region of Enrollment
    All randomized participants.
    Units: Subjects
        Canada
    		 11 11 22
        Puerto Rico
    		 2 3 5
        Austria
    		 8 8 16
        Hungary
    		 24 24 48
        United States
    		 86 84 170
        Italy
    		 9 9 18
        Israel
    		 22 19 41
        Australia
    		 15 15 30
        France
    		 7 7 14
        Germany
    		 17 19 36
        Spain
    		 16 16 32
    Hemoglobin A1c
    All randomized participants.
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    		 7.54 ± 0.58 7.56 ± 0.59 -

    End points

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    End points reporting groups
    Reporting group title
    Insulin Lispro (Humalog)
    Reporting group description
    		 Participants received individual dose of 100 units per milliliter (U/mL) insulin lispro (Humalog) by continuous subcutaneous insulin infusion (CSII); where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.
    Reporting group title
    Insulin Lispro (Humalog)
    Reporting group description
    		 Participants received individual dose of 100 units per milliliter (U/mL) insulin lispro (Humalog) by continuous subcutaneous insulin infusion (CSII); where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Reporting group title
    Ultra-Rapid Lispro
    Reporting group description
    		 Participants received individual dose of 100 U/mL ultra rapid lispro by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Primary: Change from Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 16

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    End point title
    		 Change from Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 16
    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. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Pooled Country + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag + Treatment + Time + Treatment*Time (Type III sum of squares). The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. Analysis population included all randomized participants with baseline and at least one post-baseline HbA1c data.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    207
    191
    Units: Percentage of HbA1c
        least squares mean (standard error)
    -0.09 ± 0.030
    -0.06 ± 0.031
    Statistical analysis title
    		 Statistical Analysis for HbA1c
    Comparison groups
    Ultra-Rapid Lispro v Insulin Lispro (Humalog)
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.565
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.11
    Notes
    [1] - Noninferiority margin = 0.4% for HbA1c.

    Secondary: Change From Baseline in 1-hour Postprandial Glucose (PPG) During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 16

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    End point title
    		 Change From Baseline in 1-hour Postprandial Glucose (PPG) During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 16
    End point description
    A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 1-hour timepoint after the start of meal minus fasting serum glucose. Least Squares (LS) mean was determined by analysis of variance (ANCOVA) model with independent variables: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal CGM/FGM use during study Flag + Treatment (Type III sum of squares).The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. Analysis population included all randomized participants with baseline and at least one post-baseline 1-hour PPG data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    193
    182
    Units: milligrams per deciliter (mg/dL)
        least squares mean (standard error)
    -2.2 ± 5.02
    -26.3 ± 5.33
    Statistical analysis title
    		 Statistical Analysis for 1-hour PPG
    Comparison groups
    Insulin Lispro (Humalog) v Ultra-Rapid Lispro
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -24.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36
         upper limit
    		 -12.2

    Secondary: Change From Baseline in 2-hour PPG During MMTT Efficacy Estimand at Week 16

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    End point title
    		 Change From Baseline in 2-hour PPG During MMTT Efficacy Estimand at Week 16
    End point description
    A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 2-hour timepoint after the start of meal minus fasting serum glucose. Least Squares (LS) mean was determined by analysis of variance (ANCOVA) model with independent variables: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal CGM/FGM use during study Flag + Treatment (Type III sum of squares).The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug. Analysis population included all randomized participants with baseline and at least one post-baseline 2-hour PPG data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    192
    183
    Units: mg/dL
        least squares mean (standard error)
    -4.2 ± 6.27
    -32.0 ± 6.59
    Statistical analysis title
    		 Statistical Analysis for 2-hour PPG
    Comparison groups
    Insulin Lispro (Humalog) v Ultra-Rapid Lispro
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -27.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.6
         upper limit
    		 -13

    Secondary: Percentage of Time with Sensor Glucose Values between 70 and 180 mg/dL Efficacy Estimand at Week 16

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    End point title
    		 Percentage of Time with Sensor Glucose Values between 70 and 180 mg/dL Efficacy Estimand at Week 16
    End point description
    Percentage of time with sensor glucose values between 70 and 180 mg/dL using continuous glucose monitoring (CGM). Least square (LS) mean difference will provided for CGM data normalized to a 24hrs period. Daytime: 0600 hours to midnight (06:00:00-23:59:59 on the 24-hour clock). Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag + Treatment + Time + Treatment*Time (Type III sum of squares). Analysis population included all randomized participants with non-missing baseline value and at least one non-missing post-baseline value.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    181
    172 [2]
    Units: percentage of time
    least squares mean (standard error)
        Daytime
    58.6 ± 0.75
    59.3 ± 0.77
        24-Hour
    57.5 ± 0.76
    57.9 ± 0.79
    Notes
    [2] - 24-Hour: n = 171
    Statistical analysis title
    		 Statistical analysis for glucose values: Day time
    Statistical analysis description
    Statistical analysis during daytime is reported.
    Comparison groups
    Insulin Lispro (Humalog) v Ultra-Rapid Lispro
    Number of subjects included in analysis
    353
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.532
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 2.8
    Notes
    [3] - Statistical analysis during daytime is reported.
    Statistical analysis title
    		 Statistical analysis for glucose values: 24-Hour
    Statistical analysis description
    Statistical analysis during 24-hour period is reported.
    Comparison groups
    Insulin Lispro (Humalog) v Ultra-Rapid Lispro
    Number of subjects included in analysis
    353
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.738
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 2.5
    Notes
    [4] - Statistical analysis during 24-hour period is reported.

    Secondary: Rate of Severe Hypoglycemia at Week 16

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    End point title
    		 Rate of Severe Hypoglycemia at Week 16
    End point description
    Severe hypoglycemia is defined as an event requiring assistance of another person to administer carbohydrate, glucagon, or other resuscitative actions. During these episodes, the participant has an altered mental status and cannot assist in his or her own care, or may be semiconscious or unconscious, or experience coma with or without seizures, and may require parenteral therapy. Rate of severe hypoglycemia events per 100 years during a defined period was calculated by total number of severe hypoglycemia episodes within the period divided by the cumulative days on treatment from all participants within a treatment group *36525. Analysis population included all randomized participants with evaluable hypoglycemic data.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    217
    214
    Units: Events per 100 participant years
        number (not applicable)
    2.95
    6.36
    No statistical analyses for this end point

    Secondary: Rate of Documented Symptomatic Hypoglycemia at Week 16

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    End point title
    		 Rate of Documented Symptomatic Hypoglycemia at Week 16
    End point description
    Documented symptomatic hypoglycemia is an event during which typical symptoms of hypoglycemia are accompanied by blood glucose (BG) of <54 mg/dL [3.0 millimole per liter (mmol/L)]. The rate of documented symptomatic hypoglycemia was estimated by negative binomial model: number of episodes = treatment with log (treatment exposure in days/365.25) as an offset variable. Analysis population included all randomized participants with evaluable hypoglycemic data.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    217
    214
    Units: Events per participant per year
        least squares mean (standard error)
    30.7 ± 2.48
    24.6 ± 1.88
    No statistical analyses for this end point

    Secondary: Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 16

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    End point title
    		 Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 16
    End point description
    1,5-anhydroglucitol (1,5-AG) is a marker of short-term glycemic control especially postprandial hyperglycemia. 1,5-AG accurately predicts rapid changes in glycemia and is tightly associated with glucose fluctuations and postprandial glucose. LS Mean was calculated using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (Pooled Country + Hemoglobin A1C Stratum + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data collected prior to permanent discontinuation of study drug. Analysis population included all randomized participants with baseline and at least one post-baseline 1,5-AG data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    202
    185
    Units: milligram per liter (mg/L)
        least squares mean (standard error)
    0.16 ± 0.116
    0.11 ± 0.121
    No statistical analyses for this end point

    Secondary: Change from Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16

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    End point title
    		 Change from Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16
    End point description
    SMBG 10-point profiles measured at fasting, 1-hour (h) post morning meal,2 h post morning meal,pre midday meal,1 h post midday meal,2 h post midday meal,pre evening meal, 1 h post evening meal,2 hpost evening meal, and bedtime.LS Mean analyzed by MMRM including fixed class effects of treatment,strata (pooled country, HbA1c stratum : less than or equal to (≤)7.5%, greater than (>)7.5% and participant’s personal CGM or FGM use during study),visit,and treatment-by-visit interaction,as well as the continuous,fixed covariates of baseline value. Insulin lispro (Humalog) reporting group - Morning (Mrg),evening (evg) 1-hour (h) Postmeal(poml):n=189;Mrg 2 h Poml: n=192; Midday Premeal(preml):n=195; Midday 1h Poml:n=188; Midday 2 h Poml:n=191; Evg Preml:n=193;Evg 2 h Poml:n=190; Bedtime:n=180 and Ultra-Rapid Lispro reporting group - Mrg 1 h,2 h Poml:n=172; Midday Preml:n=175; Midday 1h Poml:n=166; Midday 2 h Poml and Evg 2 h Poml:n=171; Evg Preml:n=178;Evg 1 h Poml:n=167; Bedtime:n=169
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    195 [5]
    178 [6]
    Units: mg/dL
    least squares mean (standard error)
        Morning Premeal
    0.2 ± 2.76
    0.5 ± 2.89
        Morning 1-hour Postmeal
    -3.1 ± 3.15
    -12.9 ± 3.31
        Morning 2-hour Postmeal
    -2.7 ± 3.04
    -2.9 ± 3.21
        Midday Premeal
    -0.6 ± 2.82
    4.9 ± 2.98
        Midday 1-hour Postmeal
    -4.2 ± 2.85
    -6.3 ± 3.03
        Midday 2-hour Postmeal
    -0.2 ± 3.14
    4.4 ± 3.31
        Evening Premeal
    3.8 ± 3.28
    17.5 ± 3.41
        Evening 1-hour Postmeal
    2.6 ± 3.21
    8.6 ± 3.41
        Evening 2-hour Postmeal
    6.3 ± 3.36
    12.2 ± 3.54
        Bedtime
    8.6 ± 6.37
    19.0 ± 6.58
    Notes
    [5] - All randomized participants with baseline and at least one post-baseline data.
    [6] - All randomized participants with baseline and at least one post-baseline data.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Insulin Dose at Week 16

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    End point title
    		 Change from Baseline in Insulin Dose at Week 16
    End point description
    LS mean was determined by MMRM model with covariates: Baseline + Pooled Country + + Hemoglobin A1C Stratum + Personal CGM or FGM use during study flag + Treatment + Time + Treatment*Time (Type III sum of squares). The analysis included data prior to permanent discontinuation of study drug. Analysis population included all randomized participants with baseline and at least one post-baseline basal insulin dose data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    199 [7]
    186 [8]
    Units: units per day (U/day)
    least squares mean (standard error)
        Daily Basal Insulin Dose
    -0.2 ± 0.43
    -0.1 ± 0.44
        Daily Bolus Insulin Dose
    0.8 ± 0.66
    -1.0 ± 0.68
        Total Daily Insulin Dose
    0.6 ± 0.80
    -1.1 ± 0.82
    Notes
    [7] - Daily Bolus Insulin Dose: n = 197; Total Daily Insulin Dose: n = 195.
    [8] - Daily Bolus Insulin Dose and Total Daily Insulin Dose: n = 183
    No statistical analyses for this end point

    Secondary: Change from Baseline in Bolus/Total Insulin Dose Ratio at Week 16

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    End point title
    		 Change from Baseline in Bolus/Total Insulin Dose Ratio at Week 16
    End point description
    The bolus/total ratio was derived as the bolus dose divided by the total insulin dose at each visit. LS mean was determined by MMRM model with covariates: Baseline + Pooled Country + + Hemoglobin A1C Stratum + Personal CGM or FGM use during study flag + Treatment + Time + Treatment*Time (Type III sum of squares). The analysis included data prior to permanent discontinuation of study drug. Analysis population included all randomized participants with non-missing baseline value and at least one non-missing post-baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    195
    183
    Units: Percentage of bolus/total insulin dose
        least squares mean (standard error)
    0.6 ± 0.66
    -1.3 ± 0.68
    No statistical analyses for this end point

    Secondary: Percentage of Participants with HbA1c <7%

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    End point title
    		 Percentage of Participants with HbA1c <7%
    End point description
    Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Analysis population included all randomized participants with baseline and at least one post-baseline HbA1c <7% data. Missing endpoints were imputed by applying the last observation carried forward (LOCF) method to the post-baseline data.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    207
    191
    Units: Percentage of participants
        number (not applicable)
    20.77
    18.85
    No statistical analyses for this end point

    Secondary: Percentage of Participants with at Least 1 Pump Occlusion Alarm that Leads to an Unplanned Infusion Set Change

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    End point title
    		 Percentage of Participants with at Least 1 Pump Occlusion Alarm that Leads to an Unplanned Infusion Set Change
    End point description
    Percentage of participants with at least 1 pump occlusion alarm that leads to an unplanned infusion set change was evaluated. Analysis population included all randomized participants with baseline and at least one post-baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    212
    210
    Units: Percentage of participants
        number (not applicable)
    12.7
    14.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants with at Least 1 Event of Unexplained Hyperglycemia >300 mg/dL confirmed by SMBG that Leads to an Unplanned Infusion Set Change

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    End point title
    		 Percentage of Participants with at Least 1 Event of Unexplained Hyperglycemia >300 mg/dL confirmed by SMBG that Leads to an Unplanned Infusion Set Change
    End point description
    Percentage of participants with at least 1 event of unexplained hyperglycemia >300 milligrams per deciliter (mg/dL) confirmed by SMBG that leads to an unplanned infusion set change was evaluated. Analysis population included all randomized participants with baseline and at least one post-baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 16
    End point values
    		 Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Number of subjects analysed
    217
    215
    Units: Percentage of participants
        number (not applicable)
    18.4
    16.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 20 Weeks
    Adverse event reporting additional description
    All randomized participants. There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Insulin Lispro (Humalog) Lead-in
    Reporting group description
    		 Participants received individual dose of 100 units per milliliter (U/mL) insulin lispro (Humalog) by continuous subcutaneous insulin infusion (CSII); where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Reporting group title
    Insulin Lispro (Humalog)
    Reporting group description
    		 Participants received individual dose of 100 U/mL insulin lispro (Humalog) by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Reporting group title
    Ultra-Rapid Lispro
    Reporting group description
    		 Participants received individual dose of 100 U/mL ultra rapid lispro by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.

    Serious adverse events
    		 Insulin Lispro (Humalog) Lead-in Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 471 (0.85%)
    10 / 217 (4.61%)
    17 / 215 (7.91%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    breast cancer
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    malignant melanoma
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    1 / 217 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    intraocular pressure increased
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    1 / 471 (0.21%)
    0 / 217 (0.00%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    fibula fracture
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    foreign body in respiratory tract
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    humerus fracture
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    maternal exposure during pregnancy
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed [1]
    0 / 261 (0.00%)
    1 / 119 (0.84%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    patella fracture
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    1 / 217 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    tibia fracture
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    acute myocardial infarction
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    stress cardiomyopathy
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    cerebrovascular accident
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    facial paralysis
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    1 / 217 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    impaired healing
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    1 / 471 (0.21%)
    0 / 217 (0.00%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    vitreous haemorrhage
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    1 / 471 (0.21%)
    0 / 217 (0.00%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    hiatus hernia
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    1 / 217 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    intestinal dilatation
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    1 / 217 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    1 / 471 (0.21%)
    0 / 217 (0.00%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    respiratory failure
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    1 / 217 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    abscess limb
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    1 / 471 (0.21%)
    0 / 217 (0.00%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis viral
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    1 / 217 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    herpes zoster oticus
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    1 / 217 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    1 / 471 (0.21%)
    0 / 217 (0.00%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    diabetic ketoacidosis
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    3 / 217 (1.38%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypoglycaemia
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    2 / 217 (0.92%)
    5 / 215 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ketosis
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 471 (0.00%)
    0 / 217 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    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: There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Insulin Lispro (Humalog) Lead-in Insulin Lispro (Humalog) Ultra-Rapid Lispro
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 471 (3.18%)
    31 / 217 (14.29%)
    90 / 215 (41.86%)
    General disorders and administration site conditions
    infusion site pain
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    3 / 471 (0.64%)
    6 / 217 (2.76%)
    35 / 215 (16.28%)
         occurrences all number
    3
    6
    41
    infusion site reaction
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    6 / 471 (1.27%)
    16 / 217 (7.37%)
    47 / 215 (21.86%)
         occurrences all number
    6
    16
    60
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    6 / 471 (1.27%)
    13 / 217 (5.99%)
    13 / 215 (6.05%)
         occurrences all number
    6
    14
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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