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PRONTO-Peds: A Study Comparing LY900014 to Insulin Lispro (Humalog) in Children and Adolescents With Type 1 Diabetes

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT03740919
Collaborator
(none)
751
Enrollment
111
Locations
3
Arms
26.8
Actual Duration (Months)
6.8
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The reason for this study is to compare the study drug LY900014 to insulin lispro (Humalog) in children and adolescents with type 1 diabetes (T1D).

Condition or Disease Intervention/Treatment Phase
  • Drug: LY900014
  • Drug: Insulin Lispro
  • Drug: Insulin Glargine
  • Drug: Insulin Degludec
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
751 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Humalog With an Open-Label Postprandial LY900014 Treatment Group in Children and Adolescents With Type 1 Diabetes
Actual Study Start Date :
Apr 7, 2019
Actual Primary Completion Date :
Jul 2, 2021
Actual Study Completion Date :
Jul 2, 2021

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Insulin Lispro (Humalog)

Participants received 100 units per milliliter (U/mL) insulin lispro (Humalog) administered subcutaneously (SC), 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.

Drug: Insulin Lispro
Administered SC
Other Names:
  • Humalog
  • LY275585

    • Drug: Insulin Glargine
    Administered SC

    Drug: Insulin Degludec
    Administered SC
    Experimental: LY900014

    Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal.

    Drug: LY900014
    Administered SC
    Other Names:
  • Ultra-Rapid Lispro

    		•
    Experimental: LY900014 Postmeal

    Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.

    Drug: LY900014
    Administered SC
    Other Names:
  • Ultra-Rapid Lispro

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26 [Baseline, Week 26]

      Change from baseline in HbA1c was analyzed using mixed model repeated measures (MMRM) and includes fixed class effects of treatment, strata (pooled country, type of basal insulin, and age group), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. An unstructured covariance structure will be used to model the within-participant errors. The Efficacy estimand included data collected prior to permanent discontinuation of study drug through Week 26.

    Secondary Outcome Measures

    1. Change From Baseline in HbA1c (Postprandial) at Week 26 [Baseline, Week 26]

      Change from baseline in HbA1c postprandial was analyzed using (MMRM and includes fixed class effects of treatment, strata (pooled country, type of basal insulin, and age group), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. An unstructured covariance structure will be used to model the within-participant errors. The Efficacy estimand included data collected prior to permanent discontinuation of study drug through Week 26.

    2. Percentage of Participants With Documented Post-dose Hypoglycemic Events Within 1 and 2 Hours After the Prandial Dose [Baseline through Week 26]

      Documented post-dose hypoglycemia <54 milligrams per deciliter (mg/dL) and ≤ 70 mg/dL that occurred 1 and 2 hours after prandial dose.

    3. Rate of Documented Post-dose Hypoglycemic Events Within 1 and 2 Hours After the Prandial Dose [Baseline through Week 26]

      Documented post-dose hypoglycemia event is an event of blood glucose of < 54 mg/dL and ≤70 mg/dL that occurred within 1 and 2 hours after the prandial dose. The rate of documented hypoglycemia was estimated by a negative binomial regression including treatment and age group as independent variable and number of episodes as dependent variables with log (exposure/365.25 days) as the offset in the model.

    4. Percentage of Participants With Documented Hypoglycemic Events [Baseline through Week 26]

      Documented hypoglycemia is defined as <54 mg/dL and ≤70 mg/dL, respectively.

    5. Rate of Documented Hypoglycemia Events [Week 0 through Week 26]

      Documented hypoglycemia is defined as a hypoglycemic event of blood glucose of ≤70 mg/dL or <54 mg/dL. The rate of documented hypoglycemia was estimated by negative binomial regression including treatment and age group as independent variables and number of episodes as dependent variable with log (exposure/365.25 days) as the offset in the model.

    6. Rate of Severe Hypoglycemia [Week 0 through Week 26]

      Severe hypoglycemia: during these episodes, participants have an altered mental status and cannot assist in their own care, may be semiconscious or unconscious, or experience coma with or without seizures, and require assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. The rate of severe hypoglycemia per 100 years was calculated as: 100 times the total number of severe hypoglycemia episodes within the period divided by total exposure (in year) for all participants within the treatment group.

    7. Change From Baseline in Insulin Dose at Week 26 [Baseline, Week 26]

      Change from baseline in insulin dose was analyzed using mixed model repeated measures (MMRM) and includes fixed class effects of treatment, strata (pooled country, type of basal insulin, age group, and HbA1c stratum (≤8.0%, >8.0%)), baseline value, visit and treatment-by-visit interaction. An unstructured covariance structure was used to model the within-participant errors.

    8. Percentage of Participants With HbA1c < 7.0% and <7.5% [Week 26]

      Percentage of participants with HbA1c < 7.0% and <7.5% was analyzed using a longitudinal logistic regression with repeated measurements conducted by a generalized linear mixed model including independent variables of treatment, baseline HbA1c value, visit, baseline HbA1c-by-visit interaction, and treatment-by-visit interaction. An unstructured covariance structure was used.

    9. Change From Baseline in 7-Point Self-Monitored Blood Glucose (SMBG) Values at Week 26 [Baseline, Week 26]

      Change from baseline in 7-point SMBG values were analyzed using MMRM and includes fixed class effects of treatment, strata (pooled country, type of basal insulin, and age group, and HbA1c stratum (≤8.0%, >8.0%)) baseline value, visit, and treatment-by-visit interaction. An unstructured covariance structure was used to model the within-participant errors.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    1 Year to 17 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • T1D for at least 6 months at the screening visit.

    • Have been treated with only one of the following rapid-acting insulin analogs as part of an multiple daily injection regimen for at least the last 90 days prior to the screening visit:

    • insulin lispro U-100, or

    • insulin aspart

    • insulin glulisine or

    • fast acting insulin aspart

    • Have been treated with only one of the following basal insulins for at least the last 90 days prior to the screening visit:

    • insulin glargine U-100 (once a day [QD] or twice a day [BID]), or

    • insulin detemir U-100 (QD or BID), or

    • insulin degludec U-100 (QD)

    • Have a HbA1c value ≤ 9.9% at the screening visit.

    Exclusion Criteria:

    • Have current hypoglycemic unawareness or have had more than 1 episode of severe hypoglycemia within 6 months prior to the screening visit.

    • Have had more than 1 emergency room visit or hospitalization due to poor glucose control within 6 months prior to the screening visit.

    • Have been on a treatment regimen that includes regular human insulin, neutral protamine Hagedorn (NPH), Afrezza® (insulin human) inhalation powder, any premixed insulins or use of diluted insulins within 90 days prior to the screening visit.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama Birmingham Birmingham Alabama United States 35233
    2 University of Arizona Tucson Arizona United States 85724
    3 Children's Hospital Los Angeles - Dept of Endocrinology Los Angeles California United States 90027
    4 Stanford University School of Medicine - Division of Pediatric Endocrinology & Diabetes Palo Alto California United States 94304
    5 Center of Excellence in Diabetes & Endocrinology Sacramento California United States 95821
    6 Rady Childrens Hospital - San Diego San Diego California United States 92123
    7 Barbara Davis Center Aurora Colorado United States 80045
    8 Florida Hospital Orlando Florida United States 32803
    9 Tallahassee Memorial HealthCare Tallahassee Florida United States 32308
    10 University of South Florida Diabetes & Endocrinology Center Tampa Florida United States 33612
    11 VanMeter Pediatric Endocrinology, P.C. Atlanta Georgia United States 30318
    12 St. Luke's Children's Endocrinology Boise Idaho United States 83704
    13 Rocky Mountain Diabetes and Osteoporosis Center Idaho Falls Idaho United States 83404
    14 Indiana University- Riley Children's Hospital Indianapolis Indiana United States 46202
    15 Iowa Diabetes and Endocrinology Research Center West Des Moines Iowa United States 50265
    16 Pennington Biomedical Research Center Baton Rouge Louisiana United States 70808-4124
    17 Barry Reiner Clinic Baltimore Maryland United States 21229
    18 Joslin Diabetes Center Boston Massachusetts United States 02215
    19 Children's Mercy Hospital Kansas City Missouri United States 64108
    20 UBMD Pediatrics Buffalo New York United States 14203
    21 Suny Health Science Center at Syracuse Syracuse New York United States 13210
    22 Endocrinology Services NorthWest Bend Oregon United States 97702
    23 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    24 Texas Diabetes & Endocrinology, P.A. Austin Texas United States 78731-4309
    25 Texas Institute for Kidney and Endocrine Disorders Lufkin Texas United States 75904
    26 Diabetes and Glandular Disease Research Associates PA San Antonio Texas United States 78229
    27 MultiCare Institute for Research & Innovation Tacoma Washington United States 98405
    28 Universitätsklinikum Graz Graz Steiermark Austria 8036
    29 Universitätsklinik Innsbruck Innsbruck Tyrol Austria 6020
    30 Hospital das Clinicas da FMRP Ribeirao Preto SP Brazil 14048-900
    31 CPCLIN São Paulo SP Brazil 01228-200
    32 CPQuali Pesquisa Clínica São Paulo Brazil 01228-000
    33 Children's hospital of Nanjing Nanjing Jiangsu China 210008
    34 Wuxi Children's Hospital Wuxi Jiangsu China
    35 The Fourth Affiliated Hospital of Harbin Medical University Harbin Nangang District China 150001
    36 Children's Hospital Capital Institute of Pediatrics Beijing China 100020
    37 Children's hospital of Fudan University Shanghai China 201102
    38 Zhengzhou Children's Hospital Zhengzhou China 450018
    39 Fakultni Nemocnice v Motole Praha 5 Motole Czechia 150 06
    40 Fakultni nemocnice Hradec Kralove Hradec Kralove Czechia 500 05
    41 Pediatricke odd. Nemocnice Jihlava Jihlava Czechia 58633
    42 Medica Iberia Opava Czechia 74601
    43 FN Ostrava Ostrava-Poruba Czechia 70852
    44 Pardubicka krajska nemocnice Pardubice Czechia 532 03
    45 Herlev and Gentofte Hospital Herlev Denmark 2730
    46 CHRU Lille - Hôpital Jeanne de Flandre Lille France 59037
    47 CHU Hopital d'enfants de la Timone Marseille CEDEX 05 France 13385
    48 Hopital Robert Debre Paris France 75019
    49 Hôpital Universitaire Necker enfants malades Paris France 75743
    50 InnoDiab Forschung Gmbh Essen Nordrhein-Westfalen Germany 45136
    51 Diabetologische Schwerpunktpraxis Dr. Ziegler Münster North Rhine-Westphalia Germany 48155
    52 Medizinisches Versorgungszentrum am Universitätsklinikum Leipzig GmbH Leipzig Sachsen Germany 04103
    53 RED-Institut GmbH Oldenburg in Holstein Schleswig Holstein Germany 23758
    54 Shamir Medical Center (Asaf Harofe)-Pediatric Endocrinology Unit Beer Yaakov Israel 7033001
    55 Soroka Medical Center - Pediatric Outpatient Clinic Beer-Sheva Israel 8410101
    56 Rambam Medical Center - Department of Pediatrics A, Ruth Rappaport Children's Hospital Haifa Israel 3109601
    57 Schneider Children's Medical Center Petah Tikva Israel 4920235
    58 Shiba Medical Center Ramat-gan Israel 5265601
    59 Azienda Ospedaliera Umberto I Ancona Italy 60100
    60 Azienda Ospedaliero Universitaria Meyer Firenze Italy 50139
    61 IRCCS Ospedale San Raffaele Milano Italy 20132
    62 Azienda Ospedaliera Universitaria Federico II Napoli Italy 80131
    63 Ospedale Bambino Gesu Roma Italy 00165
    64 Ospedale Civile Maggiore Borgo Trento Verona Italy 37126
    65 Saitama Children's Medical Center Saitama-shi Saitama Japan 330 8777
    66 Nihon University Hospital Chiyoda-ku Tokyo Japan 101 8309
    67 Tokyo Women's Medical University Hospital Shinjuku-ku Tokyo Japan 162-8666
    68 Hiroshima Prefectural Hospital Hiroshima Japan 734-8530
    69 Niigata University Medical & Dental Hospital Niigata Japan 951-8520
    70 Osaka City University Hospital Osaka Japan 545-8586
    71 Unidad de Investigacion Clinica Cardiometabolica de Occidente Guadalajara Jalisco Mexico 44150
    72 Centro de Inv. Medica de Occidente, SC Zapopan Jalisco Mexico 45116
    73 Hospital Universitario Dr. Jose Eleuterio Gonzalez Monterrey N.l. Mexico 64460
    74 Cli-nica Hospital Cemain Tampico Tamaulipas Mexico 89170
    75 Hospital Angeles Puebla Puebla Mexico 72190
    76 Gdanski Uniwersytet Medyczny Gdansk Poland 80-211
    77 Uniwersytecki Szpital Kliniczny Lodz Poland 91-738
    78 Instytut Diabetologii Sp. z o.o Warsaw Poland 04-376
    79 Pediatric Endocrine Research Associates Rio Piedras Puerto Rico 00927
    80 San Jorge Children and Women's Hospital- Shipping Location San Juan Puerto Rico 00912
    81 Research Institute for Pediatric Endocrinology Moscow Russian Federation 117036
    82 Morozovsky Children's City Clinical Hospital Moscow Russian Federation 119049
    83 Samarskiy Regional Children's Clinical Hospital Samara Russian Federation 443079
    84 Saratov State Medical University Saratov Russian Federation 410054
    85 Smolensk Regional Children's Clinical Hospital Smolensk Russian Federation 214019
    86 St.Petersburg Children's City Polyclinic #44 St.Petersburg Russian Federation 193144
    87 Siberian State Medical University of Roszdrav Tomsk Russian Federation 634055
    88 Tver Children's Clinical Hospital Tver Russian Federation 170023
    89 Voronezh State Medical University Voronezh Russian Federation 394024
    90 Hospital Universitario Central de Asturias Oviedo Asturias Spain 33011
    91 Hospital Virgen del Camino Pamplona Navarra Spain 31008
    92 Hospital Universitari Vall d'Hebron Barcelona Spain 08035
    93 Hospital Universitario HM Monteprincipe Boadilla del Monte Spain 28660
    94 Hospital Sant Joan de Déu Esplugues de Llobregat Spain 08950
    95 CHUS - Hospital Clinico Universitario La Coruña Spain 15706
    96 Clínica nuevas Tecnologías en Diabetes y Endocrinología (NTDE) Sevilla Spain 41003
    97 Hospital Universitario La Fe de Valencia Valencia Spain 46026
    98 Hospital Txagorritxu Vitoria-Gasteiz Spain 01009
    99 Ivano-Frankivsk regional clinical children hospital Ivano-Frankivsk Ukraine 76018
    100 Institute of the Health Care of Children & Adolescents Kharkiv Ukraine 61153
    101 V.P. Komisarenko Institute of Endocrinology and Metabolism of NAMS of Ukraine Kyiv Ukraine 04114
    102 Odesa regional children's clinical hospital Odesa Ukraine 65031
    103 Vinnytsia Regional Clinical Highly Specialized Endocrinology Center Vinnytsia Ukraine 21000
    104 Zaporizhzhia regional clinical children hospital Zaporizhzhia Ukraine 69063
    105 Stepping Hill Hospital Stockport Cheshire United Kingdom SK2 7JE
    106 Norfolk and Norwich Hospital Norwich Norfolk United Kingdom NR4 7UY
    107 King's Mill Hospital Sutton In Ashfield Nottinghamshire United Kingdom NG17 4JL
    108 Worthing Hospital Worthing West Sessex United Kingdom BN11 2DH
    109 St Richards Hospital Chichester West Sussex United Kingdom PO19 6SE
    110 St James's University Hospital Leeds West Yorkshire United Kingdom LS9 7TF
    111 St. George's University Hospitals NHS Foundation Trust London United Kingdom SW17 0QT

    Sponsors and Collaborators

    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT03740919
    Other Study ID Numbers:
    • 16698
    • I8B-MC-ITSB
    • 2018-002371-18
    First Posted:
    Nov 14, 2018
    Last Update Posted:
    Jan 24, 2022
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Eli Lilly and Company
    prandial insulin
    multiple daily injections
    pediatric patients
    postmeal dosing
    Additional relevant MeSH terms:
    Diabetes Mellitus
    Diabetes Mellitus, Type 1
    Insulin
    Insulin, Globin Zinc
    Insulin Glargine
    Insulin Lispro

    Study Results

    Participant Flow

    Recruitment Details The study included a 4-week lead-in period using open-label insulin lispro (Humalog) followed by a 26-week double-blind treatment period (LY900014 and Insulin Lispro) and one Open-label treatment arm (LY900014 Postmeal).
    Pre-assignment Detail The purpose of the lead-in period was to obtain blood glucose (BG) values along with basal and prandial insulin doses to assess basal and mealtime insulin dosing and to determine baseline hypoglycemia rates.
    Arm/Group Title Insulin Lispro (Humalog) Lead-in Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants were switched to open-label insulin lispro (Humalog) administered subcutaneously (SC), using a unit for unit conversion or the dose could have been determined based on investigator's clinical judgement. Participants received 100 units per milliliter (U/mL) insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. Participants received 100 U/mL LY900014 administered SC 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC up to 20 minutes after the start of the meal.
    Period Title: Lead-in Period
    STARTED 751 0 0 0
    Received at Least One Dose of Study Drug 751 0 0 0
    COMPLETED 716 0 0 0
    NOT COMPLETED 35 0 0 0
    Period Title: Lead-in Period
    STARTED 0 298 280 138
    Received at Least One Dose of Study Drug 0 298 280 138
    COMPLETED 0 288 266 135
    NOT COMPLETED 0 10 14 3

    Baseline Characteristics

    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal Total
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal. Total of all reporting groups
    Overall Participants 298 280 138 716
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    12.4
    (3.2)
    12.1
    (3.4)
    12.3
    (3.8)
    12.3
    (3.4)
    Sex: Female, Male (Count of Participants)
    Female
    140
    47%
    144
    51.4%
    65
    47.1%
    349
    48.7%
    Male
    158
    53%
    136
    48.6%
    73
    52.9%
    367
    51.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    6
    2%
    6
    2.1%
    0
    0%
    12
    1.7%
    Asian
    20
    6.7%
    13
    4.6%
    7
    5.1%
    40
    5.6%
    Native Hawaiian or Other Pacific Islander
    2
    0.7%
    0
    0%
    0
    0%
    2
    0.3%
    Black or African American
    7
    2.3%
    3
    1.1%
    1
    0.7%
    11
    1.5%
    White
    256
    85.9%
    256
    91.4%
    126
    91.3%
    638
    89.1%
    More than one race
    4
    1.3%
    0
    0%
    1
    0.7%
    5
    0.7%
    Unknown or Not Reported
    3
    1%
    2
    0.7%
    3
    2.2%
    8
    1.1%
    Region of Enrollment (Count of Participants)
    United States
    51
    17.1%
    55
    19.6%
    25
    18.1%
    131
    18.3%
    Czechia
    26
    8.7%
    23
    8.2%
    11
    8%
    60
    8.4%
    Japan
    7
    2.3%
    3
    1.1%
    2
    1.4%
    12
    1.7%
    Ukraine
    57
    19.1%
    53
    18.9%
    27
    19.6%
    137
    19.1%
    United Kingdom
    3
    1%
    5
    1.8%
    2
    1.4%
    10
    1.4%
    Spain
    21
    7%
    19
    6.8%
    8
    5.8%
    48
    6.7%
    Russia
    23
    7.7%
    21
    7.5%
    12
    8.7%
    56
    7.8%
    Austria
    1
    0.3%
    0
    0%
    0
    0%
    1
    0.1%
    China
    11
    3.7%
    7
    2.5%
    4
    2.9%
    22
    3.1%
    Brazil
    22
    7.4%
    20
    7.1%
    13
    9.4%
    55
    7.7%
    Poland
    14
    4.7%
    13
    4.6%
    6
    4.3%
    33
    4.6%
    Denmark
    0
    0%
    1
    0.4%
    0
    0%
    1
    0.1%
    Italy
    15
    5%
    15
    5.4%
    6
    4.3%
    36
    5%
    Mexico
    25
    8.4%
    22
    7.9%
    11
    8%
    58
    8.1%
    Israel
    15
    5%
    15
    5.4%
    5
    3.6%
    35
    4.9%
    France
    1
    0.3%
    1
    0.4%
    2
    1.4%
    4
    0.6%
    Germany
    6
    2%
    7
    2.5%
    4
    2.9%
    17
    2.4%
    HbA1c at Baseline (percentage of HbA1c) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage of HbA1c]
    7.81
    (0.91)
    7.81
    (0.87)
    7.77
    (0.85)
    7.80
    (0.88)

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26
    Description Change from baseline in HbA1c was analyzed using mixed model repeated measures (MMRM) and includes fixed class effects of treatment, strata (pooled country, type of basal insulin, and age group), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. An unstructured covariance structure will be used to model the within-participant errors. The Efficacy estimand included data collected prior to permanent discontinuation of study drug through Week 26.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All participants randomly assigned to study drug with baseline and at least one postbaseline measurement available while on study drug, per protocol.
    Arm/Group Title Insulin Lispro (Humalog) LY900014
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal.
    Measure Participants 280 260
    Least Squares Mean (Standard Error) [percentage of HbA1c]
    0.09
    (0.052)
    0.06
    (0.054)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments
    Type of Statistical Test Non-Inferiority
    Comments Noninferiority margin [NIM]=0.4% for HbA1c
    Statistical Test of Hypothesis p-Value 0.783
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter Least Squares (LS) Mean Difference
    Estimated Value -0.02
    Confidence Interval (2-Sided) 95%
    -0.17 to 0.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline in HbA1c (Postprandial) at Week 26
    Description Change from baseline in HbA1c postprandial was analyzed using (MMRM and includes fixed class effects of treatment, strata (pooled country, type of basal insulin, and age group), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. An unstructured covariance structure will be used to model the within-participant errors. The Efficacy estimand included data collected prior to permanent discontinuation of study drug through Week 26.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All participants randomly assigned to study drug with baseline and at least one postbaseline measurement available while on study drug, per protocol.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 280 131
    Least Squares Mean (Standard Error) [percentage of HbA1c]
    0.09
    (0.052)
    0.07
    (0.076)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments
    Type of Statistical Test Non-Inferiority
    Comments NIM of 0.4%
    Statistical Test of Hypothesis p-Value 0.867
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.02
    Confidence Interval (2-Sided) 95%
    -0.20 to 0.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Percentage of Participants With Documented Post-dose Hypoglycemic Events Within 1 and 2 Hours After the Prandial Dose
    Description Documented post-dose hypoglycemia <54 milligrams per deciliter (mg/dL) and ≤ 70 mg/dL that occurred 1 and 2 hours after prandial dose.
    Time Frame Baseline through Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of the randomly assigned study drug with non-missing baseline value and at least one non-missing post-baseline value of the response variable.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 298 280 138
    <54 mg/dL 1 Hour Post Dose
    26.50
    (2.563) 8.9%
    36.79
    (2.891) 13.1%
    29.70
    (3.897) 21.5%
    <54 mg/dL 2 Hour Post Dose
    54.04
    (2.896) 18.1%
    63.61
    (2.883) 22.7%
    57.88
    (4.216) 41.9%
    ≤70 mg/dL 1 Hour Post Dose
    49.67
    (2.901) 16.7%
    63.92
    (2.874) 22.8%
    48.51
    (4.261) 35.2%
    ≤70 mg/dL 2 Hour Post Dose
    77.03
    (2.449) 25.8%
    82.67
    (2.267) 29.5%
    70.29
    (3.912) 50.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments < 54 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.008
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.61
    Confidence Interval (2-Sided) 95%
    1.13 to 2.30
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments < 54 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.487
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.17
    Confidence Interval (2-Sided) 95%
    0.75 to 1.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments < 54 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.153
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.73
    Confidence Interval (2-Sided) 95%
    0.47 to 1.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments < 54 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.020
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.49
    Confidence Interval (2-Sided) 95%
    1.06 to 2.08
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments < 54 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.455
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.17
    Confidence Interval (2-Sided) 95%
    0.78 to 1.76
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments < 54 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.259
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.79
    Confidence Interval (2-Sided) 95%
    0.52 to 1.19
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments ≤ 70 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.79
    Confidence Interval (2-Sided) 95%
    1.29 to 2.51
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments ≤ 70 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.822
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.95
    Confidence Interval (2-Sided) 95%
    0.64 to 1.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments ≤ 70 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.003
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.53
    Confidence Interval (2-Sided) 95%
    0.35 to 0.80
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments ≤ 70 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.092
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.42
    Confidence Interval (2-Sided) 95%
    0.94 to 2.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments ≤ 70 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.133
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.71
    Confidence Interval (2-Sided) 95%
    0.45 to 1.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments ≤ 70 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.004
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.50
    Confidence Interval (2-Sided) 95%
    0.31 to 0.80
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Rate of Documented Post-dose Hypoglycemic Events Within 1 and 2 Hours After the Prandial Dose
    Description Documented post-dose hypoglycemia event is an event of blood glucose of < 54 mg/dL and ≤70 mg/dL that occurred within 1 and 2 hours after the prandial dose. The rate of documented hypoglycemia was estimated by a negative binomial regression including treatment and age group as independent variable and number of episodes as dependent variables with log (exposure/365.25 days) as the offset in the model.
    Time Frame Baseline through Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of the randomly assigned study drug with non-missing baseline value and at least one non-missing post-baseline value of the response variable.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 298 280 138
    < 54mg/dL 1 Hour Post Dose
    1.59
    (0.251)
    2.04
    (0.262)
    1.38
    (0.287)
    < 54 mg/dL 2 Hour Post Dose
    4.48
    (0.454)
    5.95
    (0.510)
    6.17
    (0.816)
    ≤70 mg/dL 1 Hour Post Dose
    6.54
    (1.036)
    8.46
    (0.992)
    5.29
    (1.145)
    ≤70 mg/dL 2 Hour Post Dose
    19.0
    (1.58)
    23.7
    (1.86)
    21.1
    (2.31)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments < 54 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.220
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments < 54 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.599
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments < 54 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.112
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments < 54 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.034
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments < 54 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.055
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments < 54 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.814
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments ≤70 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.194
    Comments
    Method Negative binomial regression
    Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments ≤70 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.428
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments ≤70 mg/dL 1 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.057
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments ≤70 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.056
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments ≤70 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.435
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments ≤70 mg/dL 2 hour post-dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.404
    Comments
    Method Negative binomial regression
    Comments Treatment and age group as covariates, log (exposure/365.25 days) as the offset in the model.
    5. Secondary Outcome
    Title Percentage of Participants With Documented Hypoglycemic Events
    Description Documented hypoglycemia is defined as <54 mg/dL and ≤70 mg/dL, respectively.
    Time Frame Baseline through Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of the randomly assigned study drug with non-missing baseline value and at least one non-missing post-baseline value of the response variable.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 298 280 138
    <54 mg/dL
    80.81
    (2.283) 27.1%
    81.37
    (2.329) 29.1%
    74.45
    (3.718) 53.9%
    ≤70 mg/dL
    93.98
    (1.375) 31.5%
    92.55
    (1.569) 33.1%
    87.62
    (2.806) 63.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments <54 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.864
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.04
    Confidence Interval (2-Sided) 95%
    0.68 to 1.57
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments <54 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.132
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.69
    Confidence Interval (2-Sided) 95%
    0.43 to 1.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.104
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.67
    Confidence Interval (2-Sided) 95%
    0.41 to 1.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments ≤70 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.489
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.80
    Confidence Interval (2-Sided) 95%
    0.42 to 1.52
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments ≤70 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.025
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.45
    Confidence Interval (2-Sided) 95%
    0.23 to 0.90
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments ≤70 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.099
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.57
    Confidence Interval (2-Sided) 95%
    0.29 to 1.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Rate of Documented Hypoglycemia Events
    Description Documented hypoglycemia is defined as a hypoglycemic event of blood glucose of ≤70 mg/dL or <54 mg/dL. The rate of documented hypoglycemia was estimated by negative binomial regression including treatment and age group as independent variables and number of episodes as dependent variable with log (exposure/365.25 days) as the offset in the model.
    Time Frame Week 0 through Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of the randomly assigned study drug with non-missing baseline value and at least one non-missing post-baseline value of the response variable.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 298 280 138
    < 54 mg/dL
    16.6
    (1.23)
    16.1
    (1.20)
    17.7
    (1.99)
    ≤70 mg/dL
    78.0
    (4.23)
    75.1
    (4.44)
    76.1
    (6.10)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments < 54 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.732
    Comments
    Method Negative binomial regression
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments < 54 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.638
    Comments
    Method Negative binomial regression
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments <54 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.462
    Comments
    Method Negative binomial regression
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments ≤ 70 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.632
    Comments
    Method Negative binomial regression
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments ≤ 70 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.800
    Comments
    Method Negative binomial regression
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments ≤ 70 mg/dL
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.889
    Comments
    Method Negative binomial regression
    Comments
    7. Secondary Outcome
    Title Rate of Severe Hypoglycemia
    Description Severe hypoglycemia: during these episodes, participants have an altered mental status and cannot assist in their own care, may be semiconscious or unconscious, or experience coma with or without seizures, and require assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. The rate of severe hypoglycemia per 100 years was calculated as: 100 times the total number of severe hypoglycemia episodes within the period divided by total exposure (in year) for all participants within the treatment group.
    Time Frame Week 0 through Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of the randomly assigned study drug with non-missing baseline value and at least one non-missing post-baseline value of the response variable.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 298 280 138
    Number [Events per participant per 100 years]
    2.05
    2.20
    0.00
    8. Secondary Outcome
    Title Change From Baseline in Insulin Dose at Week 26
    Description Change from baseline in insulin dose was analyzed using mixed model repeated measures (MMRM) and includes fixed class effects of treatment, strata (pooled country, type of basal insulin, age group, and HbA1c stratum (≤8.0%, >8.0%)), baseline value, visit and treatment-by-visit interaction. An unstructured covariance structure was used to model the within-participant errors.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All participants randomly assigned to study drug with baseline and at least one postbaseline measurement available while on study drug.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 283 264 132
    Total Daily Basal Insulin Dose
    2.3
    (0.28)
    2.9
    (0.29)
    2.7
    (0.40)
    Total Daily Insulin Dose
    5.3
    (0.66)
    5.8
    (0.69)
    5.0
    (0.96)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments Total Daily Basal Insulin
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.130
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.6
    Confidence Interval (2-Sided) 95%
    -0.2 to 1.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments Total Daily Basal Insulin
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.404
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.4
    Confidence Interval (2-Sided) 95%
    -0.5 to 1.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments Total Daily Basal Insulin
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.693
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.2
    Confidence Interval (2-Sided) 95%
    -1.2 to 0.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments Total Daily Insulin Dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.625
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.5
    Confidence Interval (2-Sided) 95%
    -1.4 to 2.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments Total Daily Insulin Dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.758
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.4
    Confidence Interval (2-Sided) 95%
    -2.6 to 1.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments Total Daily Insulin Dose
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.485
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value -0.8
    Confidence Interval (2-Sided) 95%
    -3.1 to 1.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Percentage of Participants With HbA1c < 7.0% and <7.5%
    Description Percentage of participants with HbA1c < 7.0% and <7.5% was analyzed using a longitudinal logistic regression with repeated measurements conducted by a generalized linear mixed model including independent variables of treatment, baseline HbA1c value, visit, baseline HbA1c-by-visit interaction, and treatment-by-visit interaction. An unstructured covariance structure was used.
    Time Frame Week 26

    Outcome Measure Data

    Analysis Population Description
    All participants who were randomly assigned to study drug and had non-missing baseline value and at least one non-missing post-baseline value of the response variable.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 298 280 138
    HbA1c <7%
    20.00
    6.7%
    21.92
    7.8%
    19.08
    13.8%
    HbA1c < 7.5%
    40.00
    13.4%
    37.31
    13.3%
    32.82
    23.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments HbA1c < 7%
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.396
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.23
    Confidence Interval (2-Sided) 95%
    0.76 to 2.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments HbA1c < 7%
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.814
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.93
    Confidence Interval (2-Sided) 95%
    0.49 to 1.75
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments HbA1c < 7%
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.384
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.75
    Confidence Interval (2-Sided) 95%
    0.39 to 1.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014
    Comments HbA1c < 7.5%
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.400
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.84
    Confidence Interval (2-Sided) 95%
    0.55 to 1.27
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Insulin Lispro (Humalog), LY900014 Postmeal
    Comments HbA1c < 7.5%
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.094
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.62
    Confidence Interval (2-Sided) 95%
    0.36 to 1.08
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments HbA1c < 7.5%
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.306
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.75
    Confidence Interval (2-Sided) 95%
    0.43 to 1.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Change From Baseline in 7-Point Self-Monitored Blood Glucose (SMBG) Values at Week 26
    Description Change from baseline in 7-point SMBG values were analyzed using MMRM and includes fixed class effects of treatment, strata (pooled country, type of basal insulin, and age group, and HbA1c stratum (≤8.0%, >8.0%)) baseline value, visit, and treatment-by-visit interaction. An unstructured covariance structure was used to model the within-participant errors.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All participants randomly assigned to study drug with baseline and at least one postbaseline measurement available while on study drug.
    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal
    Arm/Group Description Participants received 100 U/mL insulin lispro (Humalog) administered SC, 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    Measure Participants 298 280 138
    Morning Premeal - Fasting
    1.0
    (2.78)
    -3.4
    (2.88)
    -5.9
    (4.11)
    Morning 1 hour Postmeal
    -3.2
    (2.92)
    -17.9
    (3.06)
    -9.8
    (4.39)
    Midday Premeal
    -3.1
    (3.06)
    2.5
    (3.17)
    -6.0
    (4.52)
    Midday 1 hour Postmeal
    0.9
    (2.99)
    -5.2
    (3.14)
    -1.5
    (4.43)
    Evening Premeal
    1.0
    (3.18)
    4.6
    (3.29)
    0.3
    (4.69)
    Evening 1 hour Postmeal
    6.9
    (3.22)
    -6.2
    (3.39)
    -3.9
    (4.79)
    Bedtime
    -1.9
    (3.03)
    -2.3
    (3.14)
    -2.7
    (4.53)

    Adverse Events

    Time Frame From Lead-in to Safety Follow-up (up to 32 Weeks)
    Adverse Event Reporting Description All randomized participants who received at least one dose of study drug.
    Arm/Group Title Humalog Lead-in Humalog LY900014 LY900014 Postmeal
    Arm/Group Description Participants received open-label insulin lispro (Humalog) administered subcutaneously (SC), using a unit for unit conversion or the dose was determined based on the investigator's clinical judgement. Participants received 100 U/mL insulin lispro (Humalog) administered subcutaneously (SC), 0 to 2 minutes before each meal with once or twice daily basal insulin. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. Participants received 100 U/mL LY900014 administered SC, 0 to 2 minutes before start of the meal. Participants received 100 U/mL LY900014 administered SC, up to 20 minutes after the start of the meal.
    All Cause Mortality
    Humalog Lead-in Humalog LY900014 LY900014 Postmeal
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/751 (0%) 0/298 (0%) 0/280 (0%) 0/138 (0%)
    Serious Adverse Events
    Humalog Lead-in Humalog LY900014 LY900014 Postmeal
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/751 (0.3%) 12/298 (4%) 6/280 (2.1%) 2/138 (1.4%)
    Congenital, familial and genetic disorders
    Macroglossia 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/751 (0%) 0 0/298 (0%) 0 1/280 (0.4%) 1 0/138 (0%) 0
    Gastritis 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Immune system disorders
    Anaphylactic reaction 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Infections and infestations
    Complicated appendicitis 0/751 (0%) 0 0/298 (0%) 0 0/280 (0%) 0 1/138 (0.7%) 1
    Gastroenteritis 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Pilonidal cyst 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Upper respiratory tract infection 0/751 (0%) 0 0/298 (0%) 0 1/280 (0.4%) 1 0/138 (0%) 0
    Injury, poisoning and procedural complications
    Reactive gastropathy 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Skin laceration 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Spinal fracture 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis 0/751 (0%) 0 0/298 (0%) 0 2/280 (0.7%) 2 1/138 (0.7%) 1
    Hyperglycaemia 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Hypoglycaemia 1/751 (0.1%) 1 2/298 (0.7%) 2 3/280 (1.1%) 3 0/138 (0%) 0
    Nervous system disorders
    Headache 0/751 (0%) 0 0/298 (0%) 0 1/280 (0.4%) 1 0/138 (0%) 0
    Hypoglycaemic coma 0/751 (0%) 0 1/298 (0.3%) 1 0/280 (0%) 0 0/138 (0%) 0
    Psychiatric disorders
    Mental disorder 1/751 (0.1%) 1 0/298 (0%) 0 0/280 (0%) 0 0/138 (0%) 0
    Other (Not Including Serious) Adverse Events
    Humalog Lead-in Humalog LY900014 LY900014 Postmeal
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 39/751 (5.2%) 60/298 (20.1%) 67/280 (23.9%) 21/138 (15.2%)
    Gastrointestinal disorders
    Vomiting 1/751 (0.1%) 1 9/298 (3%) 11 9/280 (3.2%) 10 3/138 (2.2%) 3
    General disorders
    Injection site reaction 1/751 (0.1%) 1 0/298 (0%) 0 11/280 (3.9%) 14 2/138 (1.4%) 2
    Infections and infestations
    Nasopharyngitis 21/751 (2.8%) 21 23/298 (7.7%) 30 28/280 (10%) 37 7/138 (5.1%) 9
    Rhinitis 7/751 (0.9%) 7 10/298 (3.4%) 10 6/280 (2.1%) 6 4/138 (2.9%) 5
    Upper respiratory tract infection 3/751 (0.4%) 3 16/298 (5.4%) 18 15/280 (5.4%) 17 2/138 (1.4%) 3
    Nervous system disorders
    Headache 6/751 (0.8%) 6 13/298 (4.4%) 21 13/280 (4.6%) 22 5/138 (3.6%) 5

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-595-5979
    Email ClinicalTrials.gov@lilly.com
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT03740919
    Other Study ID Numbers:
    • 16698
    • I8B-MC-ITSB
    • 2018-002371-18
    First Posted:
    Nov 14, 2018
    Last Update Posted:
    Jan 24, 2022
    Last Verified:
    Dec 1, 2021