A Study Comparing LY900014 to Insulin Lispro (Humalog) in Adults With Type 1 Diabetes Using Insulin Pump Therapy (PRONTO-Pump-2)

A Prospective, Randomized, Double-Blind Comparison of LY900014 to Humalog in Adults With Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion

The reason for this study is to compare the study drug LY900014 to insulin lispro (Humalog) when both are used in insulin pump therapy in adults with type 1 diabetes (T1D).

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Insulin Lispro; Drug: Ultra-Rapid Lispro

• Study Type: Interventional
• Enrollment (Actual): 471
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Merewether, New South Wales, Australia, 2291
      • The Aim Centre
  • South Australia
    • Oaklands Park, South Australia, Australia, 5046
      • GP Plus Marion
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Geelong, Victoria, Australia, 3220
      • Barwon Health - The Geelong Hospital
  • Western Australia
    • Fremantle, Western Australia, Australia, 6160
      • Fremantle Hospital
• Austria
  • Salzburg, Austria, 5020
    • Universitätsklinikum Salzburg
  • Vienna, Austria, 1030
    • KA Rudolfstiftung
  • Steiermark
    • Graz, Steiermark, Austria, 8036
      • Universitätsklinikum Graz
  • Vorarlberg
    • Feldkirch, Vorarlberg, Austria, 6800
      • VIVIT Institut am LKH Feldkirch
• Canada
  • Ontario
    • Barrie, Ontario, Canada, L4N 7L3
      • LMC Endocrinology Centres Ltd.
    • Concord, Ontario, Canada, L4K 4M2
      • LMC Endocrinology Centres Ltd.
    • Oakville, Ontario, Canada, L6M 4H8
      • LMC Endocrinology Centres
    • Toronto, Ontario, Canada, M4G 3E8
      • LMC Endocrinology Centres Ltd.
  • Quebec
    • Montreal, Quebec, Canada, H2W 1R7
      • IRCM
    • Ville St-Laurent, Quebec, Canada, H4T 1Z9
      • LMC Endocrinology Centres Ltd.
• France
  • Le Creusot, France, 71200
    • Clinique Hotel Dieu
  • Montpellier Cedex 5, France, 34295
    • Centre Hospitalier Universitaire Lapeyronie
  • Paris CEDEX 14, France, 75679
    • Hopital Cochin
  • Strasbourg, France, 67098
    • Hôpital de HAUTEPIERRE
  • Venissieux, France, 69200
    • Groupe Hospitalier Mutualiste Les Portes du Sud
  • Cedex 9
    • Toulouse, Cedex 9, France, 31059
      • CHU Toulouse Hopital de Rangueil
• Germany
  • Berlin, Germany, 10409
    • Diabetespraxis Prenzlauer Allee
  • Hamburg, Germany, 21073
    • Diabetologische Schwerpunktpraxis B. Scholz/Dr. B. Paschen
  • Hamburg, Germany, 22607
    • Gemeinschaftspraxis für innere Medizin und Diabetologie
  • Hessen
    • Pohlheim, Hessen, Germany, 35415
      • Arztpraxis Dr. Cornelia Marck
  • Nordrhein-Westfalen
    • Münster, Nordrhein-Westfalen, Germany, 48145
      • Institut für Diabetesforschung Münster GmbH
  • Rheinland-Pfalz
    • Ludwigshafen am Rhein, Rheinland-Pfalz, Germany, 67059
      • Praxis Dr. Kempe - Dr. Stemler
  • Saarland
    • Saint Ingbert-Oberwürzbach, Saarland, Germany, 66386
      • Schwerpunktpraxis Diabetes
  • Schleswig-Holstein
    • Oldenburg, Schleswig-Holstein, Germany, 23758
      • RED-Institut GmbH
• Hungary
  • Budapest, Hungary, 1135
    • UNO Medical Trials Kft.
  • Budapest, Hungary, 1023
    • Budai Irgalmasrendi Korhaz
  • Budapest, Hungary, 1089
    • ClinDiab Kft.
  • Budapest, Hungary, 1213
    • TRANTOR 99 Bt.
• Israel
  • Beer-Sheva, Israel, 8410101
    • Soroka Medical Center - Pediatric Outpatient Clinic
  • Haifa, Israel, 31096
    • Rambam Health Care Campus
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center
  • Petah Tiqva, Israel, 4920235
    • Schneider Medical Center
  • Ramat Gan, Israel, 5266202
    • Sheba Medical Center
• Italy
  • Bergamo, Italy, 24128
    • Azienda Ospedaliera Papa Giovanni XXIII
  • Milano, Italy, 20132
    • IRCCS Ospedale San Raffaele
  • Olbia, Italy, 07026
    • Ospedale San Giovanni di Dio
  • Ravenna, Italy, 48121
    • Ospedale Santa Maria delle Croci
  • Roma, Italy, 00161
    • Dip.to Med. Sperimentale -Polic.Umberto I -Univ. La Sapienza
• Puerto Rico
  • Bayamon, Puerto Rico, 00961
    • Advanced Clinical Research, LLC
  • Lomas Verdes, Puerto Rico, 00956
    • Centro de Endocrinologia Alcantara Gonzalez
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Corporacio Sanitaria Parc Tauli
  • Cataluña
    • Lleida, Cataluña, Spain, 25198
      • Hospital Universitari Arnau de Vilanova
• United States
  • California
    • Concord, California, United States, 94520
      • John Muir Physician Network Clinical Research Center
    • Fresno, California, United States, 93720
      • Valley Research
    • Greenbrae, California, United States, 94904
      • Marin Endocrine Associates
    • La Mesa, California, United States, 91942
      • Diabetes and Endocrine Associates
    • Lancaster, California, United States, 93534
      • First Valley Medical Group
    • Sacramento, California, United States, 95821
      • Center of Excellence in Diabetes & Endocrinology
    • Tustin, California, United States, 92780
      • University Clinical Investigators, Inc.
    • Ventura, California, United States, 93003
      • Coastal Metabolic Research Centre
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Barbara Davis Center for Childhood Diabetes
  • Florida
    • Cooper City, Florida, United States, 33024
      • ALL Medical Research, LLC
    • New Port Richey, Florida, United States, 34652
      • Sun Coast Clinical Research, Inc
    • West Palm Beach, Florida, United States, 33401
      • Metabolic Research Institute Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Atlanta Diabetes Associates
    • Roswell, Georgia, United States, 30076
      • Endocrine Research Solutions, Inc.
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • East West Medical Institute
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Rocky Mountain Diabetes and Osteoporosis Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Feinberg School of Medicine
    • Springfield, Illinois, United States, 62711
      • Prairie Education And Research Cooperative
  • Iowa
    • West Des Moines, Iowa, United States, 50265
      • Iderc, P.L.C.
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Kentucky Diabetes Endocrinology Center
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Endocrine and Metabolic Consultants
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Palm Research Center
    • Las Vegas, Nevada, United States, 89128
      • Palm Research Center
  • New Hampshire
    • Nashua, New Hampshire, United States, 03063
      • Southern New Hampshire Diabetes and Endocrinology
  • North Carolina
    • Greenville, North Carolina, United States, 27843
      • Physicians East
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Texas
    • Austin, Texas, United States, 78749
      • Texas Diabetes and Endocrinology-Austin South
    • Dallas, Texas, United States, 75230
      • Dallas Diabetes Endocrine Center
    • Round Rock, Texas, United States, 78681
      • Texas Diabetes and Endocrinology, P.A.
  • Washington
    • Federal Way, Washington, United States, 98003
      • Private: Dr. Larry Stonesifer
    • Renton, Washington, United States, 98057
      • Rainier Clinical Research Center
    • Tacoma, Washington, United States, 98405
      • Tacoma Center for Arthritis Research, PS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have been diagnosed with T1D and continuously using insulin for at least 1 year
• Have been using CSII therapy for a minimum of 6 months
• Currently treated with <100 Units of one of following rapid-acting analog insulin via CSII for at least the past 30 days: insulin lispro U-100, insulin aspart, fast-acting insulin aspart, insulin glulisine
• Must be using a MiniMed 530G (US), Paradigm Revel (US), or MiniMed 630G (US and Canada), MiniMed 640G or Paradigm Veo (select countries outside the US), insulin pump for at least the past 90 days

Exclusion Criteria:

• Have hypoglycemia unawareness
• Have had more than 1 episode of severe hypoglycemia within 6 months prior to screening
• Have had more than 1 emergency room visit or hospitalization due to poor glucose control (hyperglycemia or diabetic ketoacidosis) within 6 months prior to screening

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Insulin Lispro (Humalog); Participants received individual dose of 100 U/mL insulin lispro (Humalog) by CSII; where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.	Drug: Insulin Lispro; Administered SC; Other Names: Humalog; LY275585
Experimental: Ultra-Rapid Lispro; Participants received individual dose of 100 units per milliliter (U/mL) ultra rapid lispro by continuous subcutaneous insulin infusion (CSII); where mealtime boluses were delivered 0 to 2 minutes prior to the start of each meal, with basal infusion rates 24 hours/day, and correction boluses as necessary.	Drug: Ultra-Rapid Lispro; Administered SC; Other Names: LY900014; Insulin 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 16	HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Pooled Country + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag + Treatment + Time + Treatment*Time (Type III sum of squares). The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.	Baseline, Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 1-hour Postprandial Glucose (PPG) During Mixed-Meal Tolerance Test (MMTT) Efficacy Estimand at Week 16	A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 1-hour timepoint after the start of meal minus fasting serum glucose. Least Squares (LS) mean was determined by analysis of variance (ANCOVA) model with independent variables: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal CGM/FGM use during study Flag + Treatment (Type III sum of squares).The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.	Baseline, Week 16
Change From Baseline in 2-hour PPG During MMTT Efficacy Estimand at Week 16	A standardized MMTT was used to characterize postprandial glucose control following administration of the study insulin. Serum glucose measured at 2-hour timepoint after the start of meal minus fasting serum glucose. Least Squares (LS) mean was determined by analysis of variance (ANCOVA) model with independent variables: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal CGM/FGM use during study Flag + Treatment (Type III sum of squares).The efficacy estimand included participant data when baseline and at least one post-baseline measurement were available prior to permanent discontinuation of study drug.	Baseline, Week 16
Percentage of Time With Sensor Glucose Values Between 70 and 180 mg/dL Efficacy Estimand at Week 16	Percentage of time with sensor glucose values between 70 and 180 mg/dL using continuous glucose monitoring (CGM). Least square (LS) mean difference will provided for CGM data normalized to a 24hrs period. Daytime: 0600 hours to midnight (06:00:00-23:59:59 on the 24-hour clock). Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Pooled Country + Hemoglobin A1C Stratum + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag + Treatment + Time + Treatment*Time (Type III sum of squares).	Week 16
Rate of Severe Hypoglycemia at Week 16	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.	Baseline through Week 16
Rate of Documented Symptomatic Hypoglycemia at Week 16	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.	Baseline through Week 16
Change From Baseline in 1,5-Anhydroglucitol (1,5-AG) at Week 16	1,5-anhydroglucitol (1,5-AG) is a marker of short-term glycemic control especially postprandial hyperglycemia. 1,5-AG accurately predicts rapid changes in glycemia and is tightly associated with glucose fluctuations and postprandial glucose. LS Mean was calculated using mixed model repeated measures (MMRM) including fixed class effects of treatment, strata (Pooled Country + Hemoglobin A1C Stratum + Personal continuous glucose Monitor (CGM) or Flash glucose monitor (FGM) use during study flag), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline value. The analysis included data collected prior to permanent discontinuation of study drug.	Baseline, Week 16
Change From Baseline in 10-Point Self-Monitoring Blood Glucose (SMBG) Values at Week 16	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, HbA1c stratum : less than or equal to (≤)7.5%, greater than (>)7.5% and participant's personal CGM or FGM use during the study), 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.	Baseline, Week 16
Change From Baseline in Insulin Dose at Week 16	LS mean was determined by MMRM model with covariates: Baseline + Pooled Country + + Hemoglobin A1C Stratum + Personal CGM or FGM use during study flag + Treatment + Time + Treatment*Time (Type III sum of squares). The analysis included data prior to permanent discontinuation of study drug.	Baseline, Week 16
Change From Baseline in Bolus/Total Insulin Dose Ratio at Week 16	The bolus/total ratio was derived as the bolus dose divided by the total insulin dose at each visit. LS mean was determined by MMRM model with covariates: Baseline + Pooled Country + + Hemoglobin A1C Stratum + Personal CGM or FGM use during study flag + Treatment + Time + Treatment*Time (Type III sum of squares). The analysis included data prior to permanent discontinuation of study drug.	Baseline, Week 16
Percentage of Participants With HbA1c <7%	Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.	Week 16
Percentage of Participants With at Least 1 Pump Occlusion Alarm That Leads to an Unplanned Infusion Set Change	Percentage of participants with at least 1 pump occlusion alarm that leads to an unplanned infusion set change was evaluated.	Baseline through Week 16
Percentage of Participants With at Least 1 Event of Unexplained Hyperglycemia >300 mg/dL Confirmed by SMBG That Leads to an Unplanned Infusion Set Change	Percentage of participants with at least 1 event of unexplained hyperglycemia >300 milligrams per deciliter (mg/dL) confirmed by SMBG that leads to an unplanned infusion set change was evaluated.	Baseline through Week 16

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

Helpful Links

• A Study Comparing LY900014 to Insulin Lispro in Adults With Type 1 Diabetes Using Insulin Pump Therapy

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2019
• Primary Completion (Actual): January 6, 2020
• Study Completion (Actual): January 6, 2020

Study Registration Dates

• First Submitted: February 4, 2019
• First Submitted That Met QC Criteria: February 4, 2019
• First Posted (Actual): February 5, 2019

Study Record Updates

• Last Update Posted (Actual): January 22, 2021
• Last Update Submitted That Met QC Criteria: January 4, 2021
• Last Verified: January 1, 2020

More Information

Terms related to this study

• 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 Lispro
• Other Study ID Numbers: 16315; I8B-MC-ITRO (Other Identifier: Eli Lilly and Company); 2015-005358-36 (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 European Union (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