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PRONTO-T1D: A Study of LY900014 in Participants With Type 1 Diabetes

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT03214367
Collaborator
(none)
1,392
Enrollment
172
Locations
6
Arms
25.2
Actual Duration (Months)
8.1
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is to evaluate the efficacy of the study drug LY900014 compared to insulin lispro, both in combination with insulin glargine or insulin degludec, in adults 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 :
1392 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 Insulin Lispro With an Open-Label Postprandial LY900014 Treatment Group, in Combination With Insulin Glargine or Insulin Degludec, in Adults With Type 1 Diabetes PRONTO-T1D
Actual Study Start Date :
Jul 17, 2017
Actual Primary Completion Date :
Sep 6, 2018
Actual Study Completion Date :
Aug 22, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: LY900014

LY900014 given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.

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

    • Drug: Insulin Glargine
    Administered SC

    Drug: Insulin Degludec
    Administered SC
    Active Comparator: Insulin Lispro (Humalog)

    Insulin lispro given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.

    Drug: Insulin Lispro
    Administered SC
    Other Names:
  • Humalog

    • Drug: Insulin Glargine
    Administered SC

    Drug: Insulin Degludec
    Administered SC
    Experimental: LY900014 Postmeal (Open Label)

    LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets.

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

    • Drug: Insulin Glargine
    Administered SC

    Drug: Insulin Degludec
    Administered SC
    Experimental: LY900014 - Maximum Extended Enrollment (MEE)

    LY900014 given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.

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

    • Drug: Insulin Glargine
    Administered SC

    Drug: Insulin Degludec
    Administered SC
    Active Comparator: Insulin Lispro (Humalog)-MEE

    Insulin lispro given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.

    Drug: Insulin Lispro
    Administered SC
    Other Names:
  • Humalog

    • Drug: Insulin Glargine
    Administered SC

    Drug: Insulin Degludec
    Administered SC
    Experimental: LY900014 Postmeal (Open Label)-MEE

    LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets.

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

    • Drug: Insulin Glargine
    Administered SC

    Drug: Insulin Degludec
    Administered SC

    Outcome Measures

    Primary Outcome Measures

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

      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 strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.

    Secondary Outcome Measures

    1. Change From Baseline in 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 26 [Baseline, Week 26]

      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. 1-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.

    2. Change From Baseline in 2-hour PPG Excursion During MMTT Efficacy Estimand at Week 26 [Baseline, Week 26]

      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. 2-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.

    3. Rate of Severe Hypoglycemia at Week 26 [Baseline through Week 26]

      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.

    4. Rate of Documented Symptomatic Hypoglycemia at Week 26 [Baseline through Week 26]

      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.

    5. Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 26 [Baseline, Week 26]

      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, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), 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.

    6. Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26 [Baseline, Week 26]

      SMBG 10-point profiles were measured at fasting, 1-hour post morning meal, 2-hours post morning meal, pre midday meal, 1-hour post midday meal, 2-hours post midday meal, pre evening meal, 1-hour post evening meal, 2-hours post evening meal, and bedtime. LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The efficacy estimand included participant data when baseline and at least one post-baseline measurement prior to permanent discontinuation of study drug.

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

      LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data prior to permanent discontinuation of study drug.

    8. Change From Baseline in Insulin Treatment Satisfaction Questionnaire (ITSQ) Regimen Inconvenience Domain Score at Week 26 [Baseline, Week 26]

      ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the ANCOVA model with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug.

    9. Change From Baseline in ITSQ Lifestyle Flexibility Domain Score at Week 26 [Baseline, Week 26]

      ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the analysis of covariance (ANCOVA) with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug.

    10. Percentage of Participants With HbA1c <7% [Week 26]

      Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.

    11. Change From Baseline in HbA1c at Week 52 [Baseline, Week 52]

      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 MMRM model with variables of baseline, pooled country, type of basal insulin during lead-in, prandial Insulin Dosing Plan, treatment (Type III sum of squares) as fixed factors. The analysis included data prior to permanent discontinuation of study drug.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Have T1D for at least 1 year prior to screening and continuously using insulin for at least 1 year.

    • HbA1c of ≥7.0 and ≤9.5%.

    • Use insulin lispro, insulin aspart, or insulin glulisine as prandial insulin.

    • Use insulin glargine, insulin detemir, insulin degludec, or neutral protamine Hagedorn (NPH) insulin as basal insulin.

    Exclusion Criteria:

    • Have used other antihyperglycemic medications or therapies (inhaled, oral or injectable) within 90-days of screening.

    • Have had more than 1 severe hypoglycemic episode within 6 months of screening.

    • Have had more than 1 hospitalization related to hyperglycemia or diabetic ketoacidosis within 6 months of screening.

    • Have clinically significant gastrointestinal disease.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Internal Medicine Center LLC Mobile Alabama United States 36608
    2 John Muir Physician Network Clinical Research Center Concord California United States 94520
    3 AMCR Institute INC Escondido California United States 92025
    4 Valley Endocrine, Fresno Fresno California United States 93720
    5 Marin Endocrine Associates Greenbrae California United States 94904
    6 Diabetes and Endocrine Associates La Mesa California United States 91942
    7 University Clinical Investigators, Inc. Tustin California United States 92780
    8 Coastal Metabolic Research Centre Ventura California United States 93003
    9 Barbara Davis Center for Childhood Diabetes Aurora Colorado United States 80045
    10 The Center For Diabetes & Endocrine Care Fort Lauderdale Florida United States 33312
    11 East Coast Institute For Research Jacksonville Florida United States 32204
    12 Sun Coast Clinical Research, Inc New Port Richey Florida United States 34652
    13 Metabolic Research Institute Inc. West Palm Beach Florida United States 33401
    14 Atlanta Diabetes Associates Atlanta Georgia United States 30318
    15 East Coast Institute For Research Macon Georgia United States 31210
    16 Endocrine Research Solutions, Inc. Roswell Georgia United States 30076
    17 East West Medical Institute Honolulu Hawaii United States 96814
    18 Northwest Clinical Trials Boise Idaho United States 83704
    19 Rocky Mountain Diabetes and Osteoporosis Center Idaho Falls Idaho United States 83404
    20 Prairie Education and Research Cooperative Springfield Illinois United States 62711
    21 Iderc, P.L.C. West Des Moines Iowa United States 50265
    22 University of Kansas Medical Center Kansas City Kansas United States 66160
    23 Cotton O'Neil Diabetes and Endocrinology Center Topeka Kansas United States 66606
    24 Kentucky Diabetes Endocrinology Center Lexington Kentucky United States 40503
    25 MassResearch Waltham Massachusetts United States 02453
    26 Palm Research Center Las Vegas Nevada United States 89128
    27 Palm Research Center Las Vegas Nevada United States 89148
    28 Southern New Hampshire Diabetes and Endocrinology Nashua New Hampshire United States 03063
    29 Manhattan Medical Research New York New York United States 10016
    30 Physicians East Greenville North Carolina United States 27843
    31 Diabetes & Endocrinology Consultants PC Morehead City North Carolina United States 28557
    32 PMG Research of Wilmington, LLC Wilmington North Carolina United States 28401
    33 Your Diabetes Endocrine Nutrition Group PC Mentor Ohio United States 44060
    34 Lehigh Valley Hospital Allentown Pennsylvania United States 18103
    35 Partners in Nephrology & Endocrinology Pittsburgh Pennsylvania United States 15224
    36 Sudir Bansal M.D. Inc. Warwick Rhode Island United States 02886
    37 University Diabetes and Endocrine Consultants Chattanooga Tennessee United States 37411
    38 Texas Diabetes and Endocrinology Austin Texas United States 78731-4309
    39 Dallas Diabetes Endocrine Center Dallas Texas United States 75230
    40 Texas Diabetes and Endocrinology, P.A. Round Rock Texas United States 78681
    41 Consano Clinical Research Shavano Park Texas United States 78231
    42 Progressive Clinical Research Bountiful Utah United States 84010
    43 Private: Dr. Larry Stonesifer Federal Way Washington United States 98003
    44 Rainier Clinical Research Center Renton Washington United States 98057
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    130 Dr Altagracia Aurora Alcantara Gonzalez Bayamon Puerto Rico 00956
    131 Advanced Clinical Research, LLC Bayamon Puerto Rico 00961
    132 Manati Center for Clinical Research Inc Manati Puerto Rico 00674
    133 Martha Gomez Cuellar M.D. San Juan Puerto Rico 00921
    134 Centro de Endocrinologia del Este Yabucoa Puerto Rico 00767
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    171 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Taipei Taiwan 10507
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    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:
    NCT03214367
    Other Study ID Numbers:
    • 16313
    • I8B-MC-ITRM
    • 2015-005356-99
    First Posted:
    Jul 11, 2017
    Last Update Posted:
    May 1, 2020
    Last Verified:
    Sep 1, 2019
    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
    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 consists of 2 double-blind arms (LY900014 and Insulin Lispro (Humalog)) and one Open-label treatment group (LY900014 Postmeal). Double-blind group: The study included 8-week lead-in period followed by a 52-week treatment period. Open-label treatment group: The treatment period ended after 26 weeks.
    Pre-assignment Detail The purpose of the Lead-in Period was to titrate basal insulin prior to randomization. Participants were then randomized to either LY900014 at mealtime, Insulin Lispro (Humalog) at mealtime, or LY900014 administered 20 minutes after the start of a meal (LY900014 Postmeal) in the treatment period (Period 2).
    Arm/Group Title Insulin Lispro (Humalog) Lead-in Insulin Lispro (Humalog) LY900014 LY900014 Postmeal Insulin Lispro (Humalog) Lead-In Maximum Extended Enrollment Insulin Lispro (Humalog)- Maximum Extended Enrollment (MEE) LY900014-MEE LY900014 Postmeal-MEE
    Arm/Group Description 100 units per milliliter (U/mL) Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets.
    Period Title: Lead-in Period
    STARTED 1316 0 0 0 76 0 0 0
    COMPLETED 1222 0 0 0 74 0 0 0
    NOT COMPLETED 94 0 0 0 2 0 0 0
    Period Title: Lead-in Period
    STARTED 0 442 451 329 0 31 21 22
    COMPLETED 0 408 418 310 0 28 19 21
    NOT COMPLETED 0 34 33 19 0 3 2 1

    Baseline Characteristics

    Arm/Group Title Insulin Lispro (Humalog) LY900014 LY900014 Postmeal Insulin Lispro (Humalog)-MEE LY900014-MEE LY900014 Postmeal-MEE Total
    Arm/Group Description 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. Total of all reporting groups
    Overall Participants 442 451 329 31 21 22 1296
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    44.5
    (13.6)
    44.1
    (13.7)
    44.5
    (14.3)
    32.1
    (12.3)
    32.4
    (12.4)
    31.5
    (12.7)
    43.7
    (14.0)
    Sex: Female, Male (Count of Participants)
    Female
    186
    42.1%
    201
    44.6%
    147
    44.7%
    14
    45.2%
    9
    42.9%
    13
    59.1%
    570
    44%
    Male
    256
    57.9%
    250
    55.4%
    182
    55.3%
    17
    54.8%
    12
    57.1%
    9
    40.9%
    726
    56%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    33
    7.5%
    35
    7.8%
    35
    10.6%
    12
    38.7%
    8
    38.1%
    9
    40.9%
    132
    10.2%
    Not Hispanic or Latino
    397
    89.8%
    399
    88.5%
    283
    86%
    18
    58.1%
    12
    57.1%
    12
    54.5%
    1121
    86.5%
    Unknown or Not Reported
    12
    2.7%
    17
    3.8%
    11
    3.3%
    1
    3.2%
    1
    4.8%
    1
    4.5%
    43
    3.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    1
    0.2%
    2
    0.6%
    1
    3.2%
    0
    0%
    1
    4.5%
    5
    0.4%
    Asian
    78
    17.6%
    86
    19.1%
    63
    19.1%
    18
    58.1%
    11
    52.4%
    10
    45.5%
    266
    20.5%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    9
    2%
    7
    1.6%
    5
    1.5%
    0
    0%
    0
    0%
    0
    0%
    21
    1.6%
    White
    344
    77.8%
    346
    76.7%
    254
    77.2%
    12
    38.7%
    9
    42.9%
    11
    50%
    976
    75.3%
    More than one race
    11
    2.5%
    10
    2.2%
    5
    1.5%
    0
    0%
    1
    4.8%
    0
    0%
    27
    2.1%
    Unknown or Not Reported
    0
    0%
    1
    0.2%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.1%
    Region of Enrollment (participants) [Number]
    Argentina
    11
    2.5%
    14
    3.1%
    14
    4.3%
    0
    0%
    0
    0%
    0
    0%
    39
    3%
    Puerto Rico
    2
    0.5%
    3
    0.7%
    2
    0.6%
    0
    0%
    0
    0%
    0
    0%
    7
    0.5%
    Romania
    34
    7.7%
    30
    6.7%
    23
    7%
    0
    0%
    0
    0%
    0
    0%
    87
    6.7%
    United States
    129
    29.2%
    134
    29.7%
    98
    29.8%
    0
    0%
    0
    0%
    0
    0%
    361
    27.9%
    Japan
    59
    13.3%
    62
    13.7%
    46
    14%
    0
    0%
    0
    0%
    0
    0%
    167
    12.9%
    India
    10
    2.3%
    10
    2.2%
    8
    2.4%
    10
    32.3%
    8
    38.1%
    6
    27.3%
    52
    4%
    Russia
    8
    1.8%
    11
    2.4%
    5
    1.5%
    2
    6.5%
    1
    4.8%
    3
    13.6%
    30
    2.3%
    Spain
    25
    5.7%
    30
    6.7%
    20
    6.1%
    0
    0%
    0
    0%
    0
    0%
    75
    5.8%
    Greece
    26
    5.9%
    28
    6.2%
    21
    6.4%
    0
    0%
    0
    0%
    0
    0%
    75
    5.8%
    New Zealand
    10
    2.3%
    11
    2.4%
    3
    0.9%
    0
    0%
    0
    0%
    0
    0%
    24
    1.9%
    Austria
    9
    2%
    6
    1.3%
    7
    2.1%
    0
    0%
    0
    0%
    0
    0%
    22
    1.7%
    Sweden
    5
    1.1%
    2
    0.4%
    3
    0.9%
    0
    0%
    0
    0%
    0
    0%
    10
    0.8%
    Taiwan
    9
    2%
    11
    2.4%
    8
    2.4%
    8
    25.8%
    4
    19%
    4
    18.2%
    44
    3.4%
    Poland
    49
    11.1%
    47
    10.4%
    27
    8.2%
    0
    0%
    0
    0%
    0
    0%
    123
    9.5%
    Italy
    9
    2%
    7
    1.6%
    4
    1.2%
    0
    0%
    0
    0%
    0
    0%
    20
    1.5%
    Mexico
    6
    1.4%
    4
    0.9%
    8
    2.4%
    11
    35.5%
    8
    38.1%
    9
    40.9%
    46
    3.5%
    Slovakia
    6
    1.4%
    6
    1.3%
    4
    1.2%
    0
    0%
    0
    0%
    0
    0%
    16
    1.2%
    Australia
    9
    2%
    10
    2.2%
    7
    2.1%
    0
    0%
    0
    0%
    0
    0%
    26
    2%
    Germany
    26
    5.9%
    25
    5.5%
    21
    6.4%
    0
    0%
    0
    0%
    0
    0%
    72
    5.6%
    Hemoglobin A1c (HbA1c) (Percentage of HbA1c) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Percentage of HbA1c]
    7.33
    (0.67)
    7.34
    (0.65)
    7.36
    (0.64)
    7.52
    (0.99)
    7.28
    (0.67)
    7.60
    (0.62)
    7.35
    (0.66)

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at Week 26
    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 strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and at least one post-baseline HbA1c data. As pre-specified in the analysis plan, outcome measures will not be reported for the Maximum Extended Enrollment (MEE) arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 428 309 417
    Least Squares Mean (Standard Error) [Percentage of HbA1c]
    -0.13
    (0.031)
    0.08
    (0.035)
    -0.05
    (0.031)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LY900014, Insulin Lispro (Humalog)
    Comments
    Type of Statistical Test Non-Inferiority
    Comments Noninferiority margin = 0.4% for HbA1c
    Statistical Test of Hypothesis p-Value 0.060
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.08
    Confidence Interval (2-Sided) 95%
    -0.16 to 0.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection LY900014 Postmeal, Insulin Lispro (Humalog)
    Comments
    Type of Statistical Test Non-Inferiority
    Comments Noninferiority margin = 0.4% for HbA1c
    Statistical Test of Hypothesis p-Value 0.003
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.13
    Confidence Interval (2-Sided) 95%
    0.04 to 0.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline in 1-hour Postprandial Glucose (PPG) Excursion During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 26
    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. 1-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and at least one post-baseline 1-hour PPG excursion data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 403 278 390
    Least Squares Mean (Standard Error) [milligrams per deciliter (mg/dL)]
    -28.6
    (3.33)
    12.5
    (3.74)
    -0.7
    (3.34)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LY900014, Insulin Lispro (Humalog)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -27.9
    Confidence Interval (2-Sided) 95%
    -35.3 to -20.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection LY900014 Postmeal, Insulin Lispro (Humalog)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 13.2
    Confidence Interval (2-Sided) 95%
    5.0 to 21.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Change From Baseline in 2-hour PPG Excursion During MMTT Efficacy Estimand at Week 26
    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. 2-hour PPG excursion during MMTT uses the ANCOVA model with strata (pooled country, type of basal insulin, prandial insulin dosing plan, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate. The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and at least one post-baseline 2-hour PPG excursion data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 401 278 391
    Least Squares Mean (Standard Error) [mg/dL]
    -34.7
    (4.50)
    -10.2
    (5.04)
    -3.5
    (4.51)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LY900014, Insulin Lispro (Humalog)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -31.2
    Confidence Interval (2-Sided) 95%
    -41.1 to -21.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection LY900014 Postmeal, Insulin Lispro (Humalog)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.235
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -6.7
    Confidence Interval (2-Sided) 95%
    -17.6 to 4.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Rate of Severe Hypoglycemia at Week 26
    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.
    Time Frame Baseline through Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with evaluable hypoglycemic data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 451 329 442
    Number [Events per 100 participant years]
    16.50
    13.70
    18.34
    5. Secondary Outcome
    Title Rate of Documented Symptomatic Hypoglycemia at Week 26
    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.
    Time Frame Baseline through Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with evaluable hypoglycemic data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 451 329 442
    Least Squares Mean (Standard Error) [Events per participant per year]
    6.71
    (0.479)
    7.75
    (0.582)
    7.35
    (0.697)
    6. Secondary Outcome
    Title Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 26
    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, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), 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.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and at least one post-baseline 1,5-AG data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 430 307 417
    Least Squares Mean (Standard Error) [milligram per liter (mg/L)]
    0.19
    (0.108)
    -0.38
    (0.124)
    -0.22
    (0.109)
    7. Secondary Outcome
    Title Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 26
    Description SMBG 10-point profiles were measured at fasting, 1-hour post morning meal, 2-hours post morning meal, pre midday meal, 1-hour post midday meal, 2-hours post midday meal, pre evening meal, 1-hour post evening meal, 2-hours post evening meal, and bedtime. LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The efficacy estimand included participant data when baseline and at least one post-baseline measurement prior to permanent discontinuation of study drug.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and at least one post-baseline SMBG data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 314 230 300
    Morning Premeal
    -1.1
    (2.82)
    2.9
    (3.19)
    -3.3
    (2.84)
    Morning 1-hour Postmeal
    -14.8
    (3.30)
    5.4
    (3.71)
    -1.0
    (3.31)
    Morning 2-hour Postmeal
    -10.1
    (3.21)
    -0.2
    (3.63)
    1.4
    (3.22)
    Midday Premeal
    6.6
    (2.80)
    4.0
    (3.17)
    1.9
    (2.83)
    Midday 1-hour Postmeal
    -2.2
    (3.36)
    11.4
    (3.81)
    1.4
    (3.40)
    Midday 2-hour Postmeal
    -5.2
    (3.24)
    0.0
    (3.67)
    -2.7
    (3.28)
    Evening Premeal
    5.2
    (3.21)
    0.4
    (3.64)
    -1.4
    (3.24)
    Evening 1-hour Postmeal
    -7.0
    (3.53)
    15.3
    (3.95)
    -0.9
    (3.57)
    Evening 2-hour Postmeal
    -8.2
    (3.43)
    -1.6
    (3.83)
    -0.6
    (3.45)
    Bedtime
    -6.8
    (3.58)
    -11.0
    (4.08)
    -2.9
    (3.56)
    8. Secondary Outcome
    Title Change From Baseline in Insulin Dose at Week 26
    Description LS Mean was analyzed using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (pooled country, type of basal insulin, HbA1c stratum and number of prandial doses at study entry), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data prior to permanent discontinuation of study drug.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and at least one post-baseline basal insulin dose data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 400 285 379
    Total Daily Insulin Dose
    2.9
    (0.72)
    2.2
    (0.83)
    2.0
    (0.73)
    Daily Basal Insulin Dose
    1.0
    (0.28)
    1.2
    (0.33)
    0.9
    (0.29)
    Daily Prandial Insulin Dose
    1.5
    (0.59)
    1.0
    (0.68)
    0.9
    (0.60)
    9. Secondary Outcome
    Title Change From Baseline in Insulin Treatment Satisfaction Questionnaire (ITSQ) Regimen Inconvenience Domain Score at Week 26
    Description ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the ANCOVA model with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and post-baseline data. Missing endpoints were imputed by applying the Last Observation Carried Forward (LOCF) method to post-baseline data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 432 314 423
    Least Squares Mean (Standard Error) [Units on a scale]
    1.4
    (0.92)
    1.5
    (1.01)
    0.7
    (0.91)
    10. Secondary Outcome
    Title Change From Baseline in ITSQ Lifestyle Flexibility Domain Score at Week 26
    Description ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed overall score on a scale of 0-100, where higher scores indicate better treatment satisfaction. LS Mean was calculated using the analysis of covariance (ANCOVA) with strata (pooled country, type of basal insulin, number of prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as covariate. The analysis included data prior to permanent discontinuation of study drug. The analysis included data prior to permanent discontinuation of study drug.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and post-baseline data. Missing endpoints were imputed by applying the LOCF method to the post-baseline data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 432 314 423
    Least Squares Mean (Standard Error) [Units on a scale]
    2.1
    (1.09)
    3.7
    (1.19)
    1.3
    (1.07)
    11. Secondary Outcome
    Title Percentage of Participants With HbA1c <7%
    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.
    Time Frame Week 26

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and at least one post-baseline HbA1c <7% data. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups.
    Arm/Group Title LY900014 LY900014 Postmeal Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 450 322 442
    Number [Percentage of participants]
    36.00
    8.1%
    24.84
    5.5%
    33.94
    10.3%
    12. Secondary Outcome
    Title Change From Baseline in HbA1c at Week 52
    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 MMRM model with variables of baseline, pooled country, type of basal insulin during lead-in, prandial Insulin Dosing Plan, treatment (Type III sum of squares) as fixed factors. The analysis included data prior to permanent discontinuation of study drug.
    Time Frame Baseline, Week 52

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with baseline and at least one postbaseline observation for HbA1c. As pre-specified in the analysis plan, outcome measures will not be reported for the MEE arms/groups but only for the main global study arms/groups. Only double blind arms analysed for this outcome because open label group ended at week 26.
    Arm/Group Title LY900014 Insulin Lispro (Humalog)
    Arm/Group Description 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets.
    Measure Participants 410 400
    Least Squares Mean (Standard Error) [Percentage of HbA1c]
    0.13
    (0.036)
    0.20
    (0.037)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LY900014, LY900014 Postmeal
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.184
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.06
    Confidence Interval (2-Sided) 95%
    -0.16 to 0.03
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame Up to 56 Weeks
    Adverse Event Reporting 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.
    Arm/Group Title Insulin Lispro (Humalog) Lead-in Insulin Lispro (Humalog) LY900014 LY900014 Postmeal Insulin Lispro (Humalog) Lead-in-MEE Insulin Lispro (Humalog)-MEE LY900014-MEE LY900014 Postmeal-MEE
    Arm/Group Description 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL Insulin lispro given subcutaneously (SC) 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 0-2 minutes before each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Preprandial insulin doses were individualized and titrated according to protocol-defined targets. 100 U/mL LY900014 given SC 20 minutes after the start of each meal with either basal insulin glargine given SC once or twice daily or insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets.
    All Cause Mortality
    Insulin Lispro (Humalog) Lead-in Insulin Lispro (Humalog) LY900014 LY900014 Postmeal Insulin Lispro (Humalog) Lead-in-MEE Insulin Lispro (Humalog)-MEE LY900014-MEE LY900014 Postmeal-MEE
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/1316 (0%) 1/442 (0.2%) 1/451 (0.2%) 1/329 (0.3%) 0/76 (0%) 0/31 (0%) 0/21 (0%) 0/22 (0%)
    Serious Adverse Events
    Insulin Lispro (Humalog) Lead-in Insulin Lispro (Humalog) LY900014 LY900014 Postmeal Insulin Lispro (Humalog) Lead-in-MEE Insulin Lispro (Humalog)-MEE LY900014-MEE LY900014 Postmeal-MEE
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 48/1316 (3.6%) 67/442 (15.2%) 54/451 (12%) 30/329 (9.1%) 0/76 (0%) 9/31 (29%) 3/21 (14.3%) 2/22 (9.1%)
    Cardiac disorders
    Acute myocardial infarction 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Angina pectoris 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Angina unstable 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Bradycardia 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Coronary artery disease 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Myocardial infarction 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Palpitations 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pericardial effusion 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pericarditis 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pulseless electrical activity 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Ear and labyrinth disorders
    Deafness 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 2 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Tinnitus 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 2 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Eye disorders
    Keratitis 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Gastrointestinal disorders
    Impaired gastric emptying 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Oesophagitis 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Vomiting 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    General disorders
    Death 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Non-cardiac chest pain 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pyrexia 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 1/31 (3.2%) 1 0/21 (0%) 0 0/22 (0%) 0
    Immune system disorders
    Drug hypersensitivity 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Infections and infestations
    Appendicitis 1/1316 (0.1%) 1 1/442 (0.2%) 1 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 1/31 (3.2%) 1 0/21 (0%) 0 0/22 (0%) 0
    Cellulitis 1/1316 (0.1%) 1 1/442 (0.2%) 1 0/451 (0%) 0 2/329 (0.6%) 2 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Epididymitis 0/743 (0%) 0 1/256 (0.4%) 1 0/250 (0%) 0 0/182 (0%) 0 0/40 (0%) 0 0/17 (0%) 0 0/12 (0%) 0 0/9 (0%) 0
    Erysipelas 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Gastroenteritis 0/1316 (0%) 0 1/442 (0.2%) 1 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Genital herpes 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Influenza 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Localised infection 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Osteomyelitis 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Peritonsillar abscess 0/1316 (0%) 0 1/442 (0.2%) 1 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pneumonia 0/1316 (0%) 0 1/442 (0.2%) 1 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pneumonia streptococcal 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pyelonephritis 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pyelonephritis acute 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 1/31 (3.2%) 1 0/21 (0%) 0 0/22 (0%) 0
    Urinary tract infection 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Urogenital infection bacterial 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Viral pericarditis 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Injury, poisoning and procedural complications
    Ankle fracture 2/1316 (0.2%) 2 2/442 (0.5%) 2 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Bladder injury 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Brachial plexus injury 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Femoral neck fracture 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Femur fracture 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Foot fracture 1/1316 (0.1%) 1 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Injury 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Joint dislocation 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Ligament rupture 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 1/31 (3.2%) 1 0/21 (0%) 0 0/22 (0%) 0
    Multiple injuries 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pelvic fracture 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Radius fracture 0/1316 (0%) 0 0/442 (0%) 0 2/451 (0.4%) 2 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Rib fracture 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Road traffic accident 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Spinal compression fracture 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Thermal burn 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Upper limb fracture 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Wrist fracture 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Diabetic ketoacidosis 1/1316 (0.1%) 1 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 2/31 (6.5%) 2 0/21 (0%) 0 0/22 (0%) 0
    Hypoglycaemia 33/1316 (2.5%) 38 39/442 (8.8%) 69 33/451 (7.3%) 52 16/329 (4.9%) 23 0/76 (0%) 0 3/31 (9.7%) 5 3/21 (14.3%) 6 2/22 (9.1%) 3
    Ketoacidosis 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Type 1 diabetes mellitus 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 1/31 (3.2%) 1 0/21 (0%) 0 0/22 (0%) 0
    Joint ankylosis 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Rhabdomyolysis 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Ependymoma 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Intraductal proliferative breast lesion 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Lipoma 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Nervous system disorders
    Dizziness 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Dural arteriovenous fistula 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Headache 0/1316 (0%) 0 1/442 (0.2%) 1 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Hemiparesis 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Hypoglycaemic coma 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 2/329 (0.6%) 2 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Hypoglycaemic seizure 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Hypoglycaemic unconsciousness 2/1316 (0.2%) 2 0/442 (0%) 0 2/451 (0.4%) 2 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Ischaemic stroke 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Multiple sclerosis 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Partial seizures 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Syncope 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Transient ischaemic attack 1/1316 (0.1%) 1 2/442 (0.5%) 2 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed 0/573 (0%) 0 0/186 (0%) 0 0/201 (0%) 0 1/147 (0.7%) 1 0/36 (0%) 0 0/14 (0%) 0 0/9 (0%) 0 0/13 (0%) 0
    Abortion spontaneous 0/573 (0%) 0 0/186 (0%) 0 1/201 (0.5%) 1 1/147 (0.7%) 1 0/36 (0%) 0 0/14 (0%) 0 0/9 (0%) 0 0/13 (0%) 0
    Ectopic pregnancy 0/573 (0%) 0 0/186 (0%) 0 1/201 (0.5%) 1 0/147 (0%) 0 0/36 (0%) 0 0/14 (0%) 0 0/9 (0%) 0 0/13 (0%) 0
    Pre-eclampsia 0/573 (0%) 0 1/186 (0.5%) 1 0/201 (0%) 0 0/147 (0%) 0 0/36 (0%) 0 0/14 (0%) 0 0/9 (0%) 0 0/13 (0%) 0
    Psychiatric disorders
    Depression 0/1316 (0%) 0 1/442 (0.2%) 1 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Sleep disorder 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Renal and urinary disorders
    Nephrolithiasis 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Renal colic 0/1316 (0%) 0 0/442 (0%) 0 0/451 (0%) 0 1/329 (0.3%) 1 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Reproductive system and breast disorders
    Cervical dysplasia 0/573 (0%) 0 1/186 (0.5%) 1 0/201 (0%) 0 0/147 (0%) 0 0/36 (0%) 0 0/14 (0%) 0 0/9 (0%) 0 0/13 (0%) 0
    Uterine polyp 0/573 (0%) 0 0/186 (0%) 0 1/201 (0.5%) 1 0/147 (0%) 0 0/36 (0%) 0 0/14 (0%) 0 0/9 (0%) 0 0/13 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 1/1316 (0.1%) 1 0/442 (0%) 0 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Lung disorder 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Pneumothorax 0/1316 (0%) 0 0/442 (0%) 0 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Vascular disorders
    Aortic stenosis 0/1316 (0%) 0 2/442 (0.5%) 2 0/451 (0%) 0 0/329 (0%) 0 0/76 (0%) 0 0/31 (0%) 0 0/21 (0%) 0 0/22 (0%) 0
    Other (Not Including Serious) Adverse Events
    Insulin Lispro (Humalog) Lead-in Insulin Lispro (Humalog) LY900014 LY900014 Postmeal Insulin Lispro (Humalog) Lead-in-MEE Insulin Lispro (Humalog)-MEE LY900014-MEE LY900014 Postmeal-MEE
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 131/1316 (10%) 147/442 (33.3%) 163/451 (36.1%) 104/329 (31.6%) 5/76 (6.6%) 13/31 (41.9%) 3/21 (14.3%) 4/22 (18.2%)
    General disorders
    Pyrexia 4/1316 (0.3%) 4 2/442 (0.5%) 2 6/451 (1.3%) 7 8/329 (2.4%) 8 2/76 (2.6%) 2 4/31 (12.9%) 4 1/21 (4.8%) 1 0/22 (0%) 0
    Infections and infestations
    Cellulitis 1/1316 (0.1%) 1 2/442 (0.5%) 2 1/451 (0.2%) 1 1/329 (0.3%) 1 0/76 (0%) 0 2/31 (6.5%) 2 0/21 (0%) 0 0/22 (0%) 0
    Influenza 5/1316 (0.4%) 5 24/442 (5.4%) 24 24/451 (5.3%) 25 15/329 (4.6%) 16 1/76 (1.3%) 1 3/31 (9.7%) 4 0/21 (0%) 0 2/22 (9.1%) 2
    Nasopharyngitis 85/1316 (6.5%) 87 88/442 (19.9%) 123 106/451 (23.5%) 161 66/329 (20.1%) 85 1/76 (1.3%) 1 5/31 (16.1%) 7 1/21 (4.8%) 1 2/22 (9.1%) 2
    Pharyngitis 3/1316 (0.2%) 3 4/442 (0.9%) 5 6/451 (1.3%) 6 4/329 (1.2%) 5 0/76 (0%) 0 2/31 (6.5%) 2 1/21 (4.8%) 1 0/22 (0%) 0
    Upper respiratory tract infection 25/1316 (1.9%) 25 33/442 (7.5%) 43 28/451 (6.2%) 34 19/329 (5.8%) 22 1/76 (1.3%) 1 1/31 (3.2%) 1 0/21 (0%) 0 1/22 (4.5%) 1
    Injury, poisoning and procedural complications
    Fall 0/1316 (0%) 0 1/442 (0.2%) 1 1/451 (0.2%) 1 0/329 (0%) 0 0/76 (0%) 0 2/31 (6.5%) 2 1/21 (4.8%) 1 0/22 (0%) 0
    Maternal exposure during pregnancy 2/573 (0.3%) 2 3/186 (1.6%) 3 2/201 (1%) 2 2/147 (1.4%) 2 0/36 (0%) 0 1/14 (7.1%) 1 0/9 (0%) 0 0/13 (0%) 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity 1/1316 (0.1%) 1 5/442 (1.1%) 5 4/451 (0.9%) 5 1/329 (0.3%) 1 1/76 (1.3%) 1 2/31 (6.5%) 2 0/21 (0%) 0 0/22 (0%) 0
    Pregnancy, puerperium and perinatal conditions
    Hyperemesis gravidarum 0/573 (0%) 0 0/186 (0%) 0 0/201 (0%) 0 0/147 (0%) 0 0/36 (0%) 0 1/14 (7.1%) 1 0/9 (0%) 0 0/13 (0%) 0
    Placenta praevia 0/573 (0%) 0 0/186 (0%) 0 0/201 (0%) 0 0/147 (0%) 0 0/36 (0%) 0 1/14 (7.1%) 1 0/9 (0%) 0 0/13 (0%) 0
    Retroplacental haematoma 0/573 (0%) 0 0/186 (0%) 0 0/201 (0%) 0 0/147 (0%) 0 0/36 (0%) 0 1/14 (7.1%) 1 0/9 (0%) 0 0/13 (0%) 0
    Reproductive system and breast disorders
    Vaginal haemorrhage 1/573 (0.2%) 1 0/186 (0%) 0 1/201 (0.5%) 1 0/147 (0%) 0 0/36 (0%) 0 1/14 (7.1%) 1 0/9 (0%) 0 0/13 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 9/1316 (0.7%) 9 4/442 (0.9%) 5 7/451 (1.6%) 7 6/329 (1.8%) 6 0/76 (0%) 0 2/31 (6.5%) 2 0/21 (0%) 0 0/22 (0%) 0
    Surgical and medical procedures
    Vasectomy 0/743 (0%) 0 0/256 (0%) 0 0/250 (0%) 0 0/182 (0%) 0 0/40 (0%) 0 1/17 (5.9%) 1 0/12 (0%) 0 0/9 (0%) 0

    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 800-545-5979
    Email ClinicalTrials.gov@lilly.com
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT03214367
    Other Study ID Numbers:
    • 16313
    • I8B-MC-ITRM
    • 2015-005356-99
    First Posted:
    Jul 11, 2017
    Last Update Posted:
    May 1, 2020
    Last Verified:
    Sep 1, 2019