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

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

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).

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: LY900014; Drug: Insulin Glargine; Drug: Insulin Degludec; Drug: Insulin Lispro

• Study Type: Interventional
• Enrollment (Actual): 751
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / 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 Glargine; Administered SC; Drug: Insulin Degludec; Administered SC; Drug: Insulin Lispro; Administered SC; Other Names: Humalog; LY275585
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hemoglobin A1c (HbA1c) Efficacy Estimand at 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.	Baseline, Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c (Postprandial) at 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.	Baseline, Week 26
Percentage of Participants With Documented Post-dose Hypoglycemic Events Within 1 and 2 Hours After the Prandial Dose	Documented post-dose hypoglycemia <54 milligrams per deciliter (mg/dL) and ≤ 70 mg/dL that occurred 1 and 2 hours after prandial dose.	Baseline through Week 26
Rate of Documented Post-dose Hypoglycemic Events Within 1 and 2 Hours After the Prandial Dose	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.	Baseline through Week 26
Percentage of Participants With Documented Hypoglycemic Events	Documented hypoglycemia is defined as <54 mg/dL and ≤70 mg/dL, respectively.	Baseline through Week 26
Rate of Documented Hypoglycemia Events	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.	Week 0 through Week 26
Rate of Severe Hypoglycemia	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.	Week 0 through Week 26
Change From Baseline in Insulin Dose at 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.	Baseline, Week 26
Percentage of Participants With HbA1c < 7.0% and <7.5%	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.	Week 26
Change From Baseline in 7-Point Self-Monitored Blood Glucose (SMBG) Values at 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.	Baseline, Week 26

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

Helpful Links

• A Study Comparing LY900014 to Insulin Lispro (Humalog) in Children and Adolescents With Type 1 Diabetes

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2019
• Primary Completion (Actual): July 2, 2021
• Study Completion (Actual): July 2, 2021

Study Registration Dates

• First Submitted: November 12, 2018
• First Submitted That Met QC Criteria: November 12, 2018
• First Posted (Actual): November 14, 2018

Study Record Updates

• Last Update Posted (Actual): January 24, 2022
• Last Update Submitted That Met QC Criteria: December 23, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: pediatric patients; prandial insulin; multiple daily injections; postmeal dosing
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Lispro
• Other Study ID Numbers: 16698; I8B-MC-ITSB (Other Identifier: Eli Lilly and Company); 2018-002371-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• IPD Sharing Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No