Empagliflozin as Adjunctive to InSulin thErapy Over 52 Weeks in Patients With Type 1 Diabetes Mellitus (EASE-2)

December 12, 2018 updated by: Boehringer Ingelheim

A Phase III, Randomised, Double Blind, Placebo-controlled, Parallel Group, Efficacy, Safety and Tolerability Trial of Once Daily, Oral Doses of Empagliflozin as Adjunctive to inSulin thErapy Over 52 Weeks in Patients With Type 1 Diabetes Mellitus (EASE-2)

Comparison of 2 doses of empagliflozin vs placebo in patients already using either an insulin regimen of multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Randomisation to 3 treatments arms (equal assignment) following a screening period, an optimisation period and a run-in period. 52 week double-blind treatment period, and 3 week follow-up period.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

730

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • New South Wales
      • Coffs Harbour, New South Wales, Australia, 2450
        • Coffs Endocrine & Diabetes Services
      • Merewether, New South Wales, Australia, 2291
        • AIM Centre
    • Queensland
      • Herston, Queensland, Australia, 4006
        • Royal Brisbane & Women's Hospital-Endocrinology
  • Austria
      • Feldkirch, Austria, 6807
        • VIVIT Instit.am LKH Feldkirch,Abt.f.Innere Med.u.Kardiologie
      • Steyr, Austria, 4400
        • LKH Steyr, Kardiologie
      • Wien, Austria, 1030
        • KH Rudolfstiftung, 1. Med. Abt., Wien
      • Wien, Austria, 1130
        • Hospital Hietzing
  • Belgium
      • Arlon, Belgium, 6700
        • Arlon - HOSP Sud Luxembourg - Vivalia
      • Bonheiden, Belgium, 2820
        • Bonheiden - HOSP Imelda
      • Brussel, Belgium, 1090
        • Brussels - UNIV UZ Brussel
      • Bruxelles, Belgium, 1070
        • ULB Hopital Erasme
      • Edegem, Belgium, 2650
        • Edegem - UNIV UZ Antwerpen
      • Gent, Belgium, 9000
        • UNIV UZ Gent
      • La Louvière, Belgium, 7100
        • La Louvière - UNIV CHU Tivoli
      • Leuven, Belgium, 3000
        • UZ Leuven
      • Liège, Belgium, 4000
        • Centre Hospitalier Universitaire de Liège
      • Liège, Belgium, 4000
        • Liège - HOSP CHR de la Citadelle
      • Merksem, Belgium, 2170
        • Merksem - HOSP ZNA Jan Palfijn
  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2H 2G4
        • LMC Endocrinology Centres (Calgary) Ltd.
      • Red Deer, Alberta, Canada, T4N 6V7
        • The Bailey Clinic
    • British Columbia
      • Victoria, British Columbia, Canada, V8R 1J8
        • Royal Jubilee Hospital
    • Manitoba
      • Winnipeg, Manitoba, Canada, R3E 3P4
        • Health Sciences Centre Winnipeg
    • Migration Data
      • Montreal, Migration Data, Canada, Quebec
        • CHUM - Pavillon R
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H 1V7
        • Capital District Health Auth.
    • Ontario
      • Kingston, Ontario, Canada, K7L 2V7
        • Kingston General Hospital
      • Thornhill, Ontario, Canada, L4J 8L7
        • LMC Thornhill/Vaughan
      • Toronto, Ontario, Canada, M5T 3L9
        • Mount Sinai Hospital
    • Quebec
      • Montreal, Quebec, Canada, H3A 1A1
        • Royal Victoria Hospital
  • Czechia
      • Praha 2, Czechia, 128 08
        • General Univ.hosp.in Prague (VFN), Diabetes ambulance
      • Slany, Czechia, 274 01
        • Diabetology and Internal Practice Dr. Vladimir Lelek
      • Usti nad Labem, Czechia, 401 13
        • Masaryk Hospital, Internal Department
  • Denmark
      • Aalborg, Denmark, 9100
        • Aalborg Sygehus Syd
      • Aarhus C, Denmark, 8000
        • Aarhus Universitets Hospital
      • Gentofte, Denmark, 2820
        • Steno Diabetes Center Copenhagen
      • Hillerød, Denmark, 3400
        • Nordsjællands Hospital - Hillerød
      • Køge, Denmark, 4600
        • Køge Sygehus
  • Finland
      • Kuopio, Finland, FI-70100
        • IteLasaretti
      • Oulu, Finland, FI-90100
        • Terveystalo Oulu, Diapolis
      • Turku, Finland, FI-20520
        • TYKS
  • France
      • Caen, France, 14033
        • HOP Côte de Nacre
      • La Rochelle Cedex 1, France, 17000
        • HOP Saint-Louis
      • Narbonne, France, 11100
        • HOP de Narbonne, diabéto endo, Narbonne
      • Reims, France, 51092
        • HOP Robert Debré
      • Vandoeuvre-lès-Nancy, France, 54511
        • HOP de Brabois
      • Vénissieux, France, 69200
        • HOP les Portes du Sud, Diabéto, Vénissieux
  • Germany
      • Aschaffenburg, Germany, 63739
        • Studienzentrum Aschaffenburg
      • Asslar, Germany, 35614
        • Gemeinschaftspraxis, Asslar
      • Berlin, Germany, 10115
        • ikfe - Institut für klinische Forschung und Entwicklung Berlin GmbH
      • Essen, Germany, 45136
        • InnoDiab Forschung GmbH
      • Pirna, Germany, 01796
        • Praxis Dr. Kosch, Pirna
      • Rehlingen-Siersburg, Germany, 66780
        • Allgemeinmedizinische und Diabetologische Schwerpunktpraxis
      • Saarbrücken, Germany, 66121
        • Praxis Dr. Hirschhäuser
      • Saint Ingbert/Oberwürzbach, Germany, 66386
        • Praxis Dr. Segner, St. Ingbert
      • Schweinfurt, Germany, 97421
        • Ambulanzzentrum Schweinfurt
  • Netherlands
      • Alkmaar, Netherlands, 1815 JD
        • Noordwest Ziekenhuisgroep
      • Amsterdam, Netherlands, 1105 AZ
        • Academisch Medisch Centrum (AMC)
      • Arnhem, Netherlands, 6815 AD
        • Rijnstate Hospital
      • Groningen, Netherlands, 9728 NT
        • Martini Ziekenhuis
      • Hoogeveen, Netherlands, 7909 AA
        • Bethesda Ziekenhuis Hoogeveen
      • Rotterdam, Netherlands, 3045 PM
        • Sint Franciscus Gasthuis
      • Zwijndrecht, Netherlands, 3331 LZ
        • Albert Schweitzer Ziekenhuis, Zwijndrecht
  • Norway
      • Hamar, Norway, N-2318
        • Sykehuset Innlandet HF, Avd. Hamar
      • Lørenskog, Norway, N-1478
        • Akershus Universitetssykehus HF
      • Oslo, Norway, N-0424
        • Oslo Universitetssykehus HF, Aker sykehus
      • Ålesund, Norway, N-6026
        • Helse Møre og Romsdal HF, Ålesund sjukehus
  • Poland
      • Bialystok, Poland, 15-276
        • Med Univ Bialystok Clin Dep Endocrinol, Diabetol & Int Dis
      • Bialystok, Poland, 15-435
        • NZOZ Specjalistyczny Ośrodek Internistyczno-Diabetologiczny
      • Krakow, Poland, 31011
        • Dobry Lekarz,Spec.Med.Clinics,Private Prac,Krakow
      • Lublin, Poland, 20-538
        • NZOZ Specialized Ambulance "MEDICA"
      • Poznan, Poland, 60-834
        • Marcinkowski Poznan Univ of Med Sci, Clin Dept Diab, Poznan
      • Radom, Poland, 26610
        • NZOZ Centrum Medyczne AESKULAP,Private Prac, Radom
      • Rzeszow, Poland, 35-055
        • Centrum Medyczne Medyk
      • Warsaw, Poland, 00-465
        • NBR Polska
  • Spain
      • Barcelona, Spain, 08035
        • Hospital Vall d'Hebron
      • Barcelona, Spain, 08025
        • C.A.P. Sardenya
      • Granada, Spain, 18004
        • Hospital de la Inmaculada Concepción
      • Malaga, Spain, 29010
        • Hospital Virgen de la Victoria
      • Segovia, Spain, 40002
        • Hospital General de Segovia
      • Sevilla, Spain, 41071
        • Hospital Virgen Macarena
      • Sevilla, Spain, 41014
        • Hospital Nuestra Señora de Valme
  • Sweden
      • Borås, Sweden, 506 30
        • Ladulaas Kliniska Studier
      • Karlstad, Sweden, 651 85
        • Centralsjukhuset, Karlstad
      • Vällingby, Sweden, 162 68
        • Läkarhuset, Vällingby
  • Taiwan
      • Taichung, Taiwan, 40447
        • China Medical University Hospital
      • Taichung, Taiwan, 402
        • Chung Shan Medical University Hospital
      • Tainan, Taiwan, 710
        • Chi Mei Medical Center
      • Taipei, Taiwan, 100
        • National Taiwan University Hospital
      • Taipei, Taiwan, 11490
        • Tri-Service General Hospital
  • United Kingdom
      • Buckinghamshire, United Kingdom, MK65LD
        • Milton Keynes Hospital
      • Cambridge, United Kingdom, CB2 0QQ
        • Addenbrooke's Hospital
      • Edinburgh, United Kingdom, EH4 2XU
        • Wellcome Trust Clinical Research Facility
      • Leicester, United Kingdom, LE5 4PW
        • Leicester General Hospital
      • London, United Kingdom, E1 1BB
        • Royal London Hospital
      • Nottingham, United Kingdom, NG7 2UH
        • Queen's Medical Centre
      • Nuneaton, United Kingdom, CV10 7DJ
        • George Eliot Hospital
      • Surrey, United Kingdom, RH1 5RH
        • East Surrey Hospital
      • Welwyn Garden City, United Kingdom, AL7 4HQ
        • Queen Elizabeth II Hospital
  • United States
    • California
      • Escondido, California, United States, 92025
        • AMCR Institute, Inc.
      • Huntington Beach, California, United States, 92648
        • Diabetes/Lipid Management and Research Center
      • Los Angeles, California, United States, 90057
        • National Research Institute
      • San Mateo, California, United States, 94401
        • Mills-Peninsula Health Services
      • Tarzana, California, United States, 91356
        • Metabolic Institute of America
      • Tustin, California, United States, 92780
        • University Clinical Investigators, Inc.
    • Colorado
      • Denver, Colorado, United States, 80246
        • Creekside Endocrine Associates, PC
    • Florida
      • Fort Lauderdale, Florida, United States, 33312
        • The Center for Diabetes and Endocrine Care
      • Jacksonville, Florida, United States, 32204
        • East Coast Institute for Research, LLC
      • Miami, Florida, United States, 33156
        • Baptist Diabetes Associates, PA
    • Georgia
      • Lawrenceville, Georgia, United States, 30046
        • Physicians Research Associates, LLC
      • Roswell, Georgia, United States, 30076
        • Endocrine Research Solutions, Inc.
    • Idaho
      • Idaho Falls, Idaho, United States, 83404
        • Rocky Mountain Diabetes and Osteoporosis Center
    • Illinois
      • Arlington Heights, Illinois, United States, 60005
        • Northwest Endo Diabetes Research, LLC
      • Crystal Lake, Illinois, United States, 60012
        • Midwest Endocrinology
    • Iowa
      • West Des Moines, Iowa, United States, 50265
        • Iowa Diabetes and Endocrinology Research Center
    • Nebraska
      • Omaha, Nebraska, United States, 68114
        • Diabetes anddocrine Associates, PC
    • Nevada
      • Henderson, Nevada, United States, 89052
        • Desert Endocrinology Clinical Research Center
      • Las Vegas, Nevada, United States, 89148
        • Palm Research Center
    • New Hampshire
      • Nashua, New Hampshire, United States, 03063
        • Southern New Hampshire Diabetes and Endocrinology
    • New York
      • Albany, New York, United States, 12206
        • Albany Medical Center / Albany Medical College
      • Staten Island, New York, United States, 10301
        • University Physicians Group Research Division
    • North Carolina
      • Morehead City, North Carolina, United States, 28557
        • Diabetes and Endocrinology Consultants, PC
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • The Carl and Edyth Lindner Center for Research & Education at The Christ Hospital
    • Tennessee
      • Nashville, Tennessee, United States, 37212
        • Diabetes and Obesity Clinical Trials Center
    • Texas
      • Dallas, Texas, United States, 75231
        • North Texas Endocrine Center
      • Houston, Texas, United States, 77090
        • Office of Dr. Michelle Zaniewski-Singh
      • Round Rock, Texas, United States, 78681
        • Texas Diabetes and Endocrinology
    • Utah
      • Salt Lake City, Utah, United States, 84102
        • Bateman Horne Center
      • South Ogden, Utah, United States, 84405
        • Advanced Research Institute
    • Washington
      • Federal Way, Washington, United States, 98003
        • Larry D Stonesifer, MD Inc., PS
      • Renton, Washington, United States, 98057
        • Rainier Clinical Research Center, Inc
      • Seattle, Washington, United States, 98104
        • The Polyclinic
      • Tacoma, Washington, United States, 98405
        • Multicare Institute for Research and Innovation

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Male or female patient receiving insulin for the treatment of documented diagnosis of Type 1 Diabetes Mellitus (T1DM) for at least 1 year at the time of Visit 1
  • Fasting C-peptide value of < 0.7 ng/mL (0.23 nmol/L) at Visit 2 measured by the central laboratory

  • Use of, and be willing, based on the Investigator's judgement, to continue throughout the duration of the trial, either:

    • Multiple Daily Injections (MDI) of insulin consisting of at least one basal insulin injection and at least three daily bolus injections OR
    • Continuous Subcutaneous Insulin Infusion (CSII) of any insulin type, with at least 5 months experience of using CSII prior to Visit 1
  • HbA1c >/= 7.5% and </= 10.0% at Visit 5 measured by the central laboratory
  • Age >/= 18 years at Visit 1

Additional inclusion criteria may apply

Exclusion criteria:

  • History of Type 2 Diabetes Mellitus (T2DM), maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis
  • Pancreas, pancreatic islet cells or renal transplant recipient
  • T1DM treatment with any other antihyperglycaemic drug (e.g. metformin, alpha-glucosidase inhibitors, Glucagon-like-peptide 1 (GLP-1) analogues, Sodium-Glucose Co-Transporter (SGLT-2) inhibitors, pramlintide, inhaled insulin, pre-mixed insulins etc.) except subcutaneous basal and bolus insulin within 3 months prior to Visit 1
  • Occurrence of severe hypoglycaemia involving coma/unconsciousness and/or seizure that required hospitalisation or hypoglycaemia-related treatment by an emergency physician or paramedic within 3 months prior to Visit 1 and until randomisation
  • Occurence of Diabetic Ketoacidosis (DKA) within 3 months prior to Visit 1 and until randomisation

Additional exclusion criteria may apply

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Empagliflozin low dose
Empagliflozin tablets once daily
Drug: Empagliflozin
Experimental: Empagliflozin high dose
Empagliflozin tablets once daily
Drug: Empagliflozin
Placebo Comparator: Placebo
Placebo tablets matching empagliflozin once daily
Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26
Time Frame: Baseline to week 26
Change from baseline in glycated haemoglobin (HbA1c) for full analysis set (FAS) (observed cases [OC]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects.
Baseline to week 26
Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD) )
Time Frame: Baseline to week 26
Change from baseline in glycated haemoglobin (HbA1c) for modified intention-to-treat population set (mITT) (observed case - all data [OC-AD]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects.
Baseline to week 26

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG)
Time Frame: Week 5 to Week 26, Week 1 to Week 26
This is a key secondary endpoint. Rate per patient-year of investigator-reported symptomatic hypoglycaemia adverse events (AEs) with confirmed plasma glucose (PG) <54 milligram per deciliter (mg/dL) (<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycaemia AEs (i.e. all investigator-reported AEs that had confirmed PG <54 mg/dL [<3.0 mmol/L] with symptoms reported and all severe hypoglycaemia events that were confirmed by adjudication) is presented for (i) From week 5 to 26 and (ii) From week 1 to 26. Least squares mean is actually an adjusted event rate.
Week 5 to Week 26, Week 1 to Week 26
Change From Baseline in Body Weight at Week 26
Time Frame: Baseline to week 26
Change from baseline in body weight is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline.
Baseline to week 26
Change From Baseline in Percentage of Time Spent in Target Glucose Range From Weeks 23 to 26
Time Frame: Week 23 to 26
Change from baseline in the percentage of time spent in target glucose range of >70 to ≤180 mg/dL (>3.9 to ≤10.0 mmol/L) as determined by continuous glucose monitoring (CGM) is presented in week 23 to 26. Least squares mean is actually an adjusted event rate.
Week 23 to 26
Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 23 to 26
Time Frame: Week 23 to 26
Change from baseline in interstitial glucose variability based on the IQR as determined by CGM is presented for week 23 to 26. Least squares mean is actually an adjusted event rate.
Week 23 to 26
Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26
Time Frame: Baseline to week 26
Change from baseline in TDID is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline.
Baseline to week 26
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26
Time Frame: Baseline to week 26
Change from baseline in SBP and DBP is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline.
Baseline to week 26

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Boehringer Ingelheim

Collaborators

Eli Lilly and Company

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 30, 2015

Primary Completion (Actual)

April 20, 2017

Study Completion (Actual)

October 23, 2017

Study Registration Dates

First Submitted

April 8, 2015

First Submitted That Met QC Criteria

April 8, 2015

First Posted (Estimate)

April 13, 2015

Study Record Updates

Last Update Posted (Actual)

January 3, 2019

Last Update Submitted That Met QC Criteria

December 12, 2018

Last Verified

December 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1245.69
  • 2014-001922-14 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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