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

Diabetes Mellitus, Type 1 Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02414958
• Other study ID #: 1245.69
• Secondary ID: 2014-001922-14
• Status: Completed
• Phase: Phase 3
• Start date: June 30, 2015
• Est. completion date: October 23, 2017

Study information

• Verified date: December 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 730
• Est. completion date: October 23, 2017
• Est. primary completion date: April 20, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Drug:
• Empagliflozin

• Empagliflozin

• Placebo

Locations

Country	Name	City	State
Australia	Coffs Endocrine & Diabetes Services	Coffs Harbour	New South Wales
Australia	Royal Brisbane & Women's Hospital-Endocrinology	Herston	Queensland
Australia	AIM Centre	Merewether	New South Wales
Austria	VIVIT Instit.am LKH Feldkirch,Abt.f.Innere Med.u.Kardiologie	Feldkirch
Austria	LKH Steyr, Kardiologie	Steyr
Austria	Hospital Hietzing	Wien
Austria	KH Rudolfstiftung, 1. Med. Abt., Wien	Wien
Belgium	Arlon - HOSP Sud Luxembourg - Vivalia	Arlon
Belgium	Bonheiden - HOSP Imelda	Bonheiden
Belgium	Brussels - UNIV UZ Brussel	Brussel
Belgium	ULB Hopital Erasme	Bruxelles
Belgium	Edegem - UNIV UZ Antwerpen	Edegem
Belgium	UNIV UZ Gent	Gent
Belgium	La Louvière - UNIV CHU Tivoli	La Louvière
Belgium	UZ Leuven	Leuven
Belgium	Centre Hospitalier Universitaire de Liège	Liège
Belgium	Liège - HOSP CHR de la Citadelle	Liège
Belgium	Merksem - HOSP ZNA Jan Palfijn	Merksem
Canada	LMC Endocrinology Centres (Calgary) Ltd.	Calgary	Alberta
Canada	Capital District Health Auth.	Halifax	Nova Scotia
Canada	Kingston General Hospital	Kingston	Ontario
Canada	CHUM - Pavillon R	Montreal	Migration Data
Canada	Royal Victoria Hospital	Montreal	Quebec
Canada	The Bailey Clinic	Red Deer	Alberta
Canada	LMC Thornhill/Vaughan	Thornhill	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Royal Jubilee Hospital	Victoria	British Columbia
Canada	Health Sciences Centre Winnipeg	Winnipeg	Manitoba
Czechia	General Univ.hosp.in Prague (VFN), Diabetes ambulance	Praha 2
Czechia	Diabetology and Internal Practice Dr. Vladimir Lelek	Slany
Czechia	Masaryk Hospital, Internal Department	Usti nad Labem
Denmark	Aalborg Sygehus Syd	Aalborg
Denmark	Aarhus Universitets Hospital	Aarhus C
Denmark	Steno Diabetes Center Copenhagen	Gentofte
Denmark	Nordsjællands Hospital - Hillerød	Hillerød
Denmark	Køge Sygehus	Køge
Finland	IteLasaretti	Kuopio
Finland	Terveystalo Oulu, Diapolis	Oulu
Finland	TYKS	Turku
France	HOP Côte de Nacre	Caen
France	HOP Saint-Louis	La Rochelle Cedex 1
France	HOP de Narbonne, diabéto endo, Narbonne	Narbonne
France	HOP Robert Debré	Reims
France	HOP de Brabois	Vandoeuvre-lès-Nancy
France	HOP les Portes du Sud, Diabéto, Vénissieux	Vénissieux
Germany	Studienzentrum Aschaffenburg	Aschaffenburg
Germany	Gemeinschaftspraxis, Asslar	Asslar
Germany	ikfe - Institut für klinische Forschung und Entwicklung Berlin GmbH	Berlin
Germany	InnoDiab Forschung GmbH	Essen
Germany	Praxis Dr. Kosch, Pirna	Pirna
Germany	Allgemeinmedizinische und Diabetologische Schwerpunktpraxis	Rehlingen-Siersburg
Germany	Praxis Dr. Hirschhäuser	Saarbrücken
Germany	Praxis Dr. Segner, St. Ingbert	Saint Ingbert/Oberwürzbach
Germany	Ambulanzzentrum Schweinfurt	Schweinfurt
Netherlands	Noordwest Ziekenhuisgroep	Alkmaar
Netherlands	Academisch Medisch Centrum (AMC)	Amsterdam
Netherlands	Rijnstate Hospital	Arnhem
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	Bethesda Ziekenhuis Hoogeveen	Hoogeveen
Netherlands	Sint Franciscus Gasthuis	Rotterdam
Netherlands	Albert Schweitzer Ziekenhuis, Zwijndrecht	Zwijndrecht
Norway	Helse Møre og Romsdal HF, Ålesund sjukehus	Ålesund
Norway	Sykehuset Innlandet HF, Avd. Hamar	Hamar
Norway	Akershus Universitetssykehus HF	Lørenskog
Norway	Oslo Universitetssykehus HF, Aker Sykehus	Oslo
Poland	Med Univ Bialystok Clin Dep Endocrinol, Diabetol & Int Dis	Bialystok
Poland	NZOZ Specjalistyczny Osrodek Internistyczno-Diabetologiczny	Bialystok
Poland	Dobry Lekarz,Spec.Med.Clinics,Private Prac,Krakow	Krakow
Poland	NZOZ Specialized Ambulance "MEDICA"	Lublin
Poland	Marcinkowski Poznan Univ of Med Sci, Clin Dept Diab, Poznan	Poznan
Poland	NZOZ Centrum Medyczne AESKULAP,Private Prac, Radom	Radom
Poland	Centrum Medyczne Medyk	Rzeszow
Poland	NBR Polska	Warsaw
Spain	C.A.P. Sardenya	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital de la Inmaculada Concepción	Granada
Spain	Hospital Virgen de la Victoria	Malaga
Spain	Hospital General de Segovia	Segovia
Spain	Hospital Nuestra Señora de Valme	Sevilla
Spain	Hospital Virgen Macarena	Sevilla
Sweden	Ladulaas Kliniska Studier	Borås
Sweden	Centralsjukhuset, Karlstad	Karlstad
Sweden	Läkarhuset, Vällingby	Vällingby
Taiwan	China Medical University Hospital	Taichung
Taiwan	Chung Shan Medical University Hospital	Taichung
Taiwan	Chi Mei Medical Center	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
United Kingdom	Milton Keynes Hospital	Buckinghamshire
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Wellcome Trust Clinical Research Facility	Edinburgh
United Kingdom	Leicester General Hospital	Leicester
United Kingdom	Royal London Hospital	London
United Kingdom	Queen's Medical Centre	Nottingham
United Kingdom	George Eliot Hospital	Nuneaton
United Kingdom	East Surrey Hospital	Surrey
United Kingdom	Queen Elizabeth II Hospital	Welwyn Garden City
United States	Albany Medical Center / Albany Medical College	Albany	New York
United States	Northwest Endo Diabetes Research, LLC	Arlington Heights	Illinois
United States	The Carl and Edyth Lindner Center for Research & Education at The Christ Hospital	Cincinnati	Ohio
United States	Midwest Endocrinology	Crystal Lake	Illinois
United States	North Texas Endocrine Center	Dallas	Texas
United States	Creekside Endocrine Associates, PC	Denver	Colorado
United States	AMCR Institute, Inc.	Escondido	California
United States	Larry D Stonesifer, MD Inc., PS	Federal Way	Washington
United States	The Center for Diabetes and Endocrine Care	Fort Lauderdale	Florida
United States	Desert Endocrinology Clinical Research Center	Henderson	Nevada
United States	Office of Dr. Michelle Zaniewski-Singh	Houston	Texas
United States	Diabetes/Lipid Management and Research Center	Huntington Beach	California
United States	Rocky Mountain Diabetes and Osteoporosis Center	Idaho Falls	Idaho
United States	East Coast Institute for Research, LLC	Jacksonville	Florida
United States	Palm Research Center	Las Vegas	Nevada
United States	Physicians Research Associates, LLC	Lawrenceville	Georgia
United States	National Research Institute	Los Angeles	California
United States	Baptist Diabetes Associates, PA	Miami	Florida
United States	Diabetes and Endocrinology Consultants, PC	Morehead City	North Carolina
United States	Southern New Hampshire Diabetes and Endocrinology	Nashua	New Hampshire
United States	Diabetes and Obesity Clinical Trials Center	Nashville	Tennessee
United States	Diabetes anddocrine Associates, PC	Omaha	Nebraska
United States	Rainier Clinical Research Center, Inc	Renton	Washington
United States	Endocrine Research Solutions, Inc.	Roswell	Georgia
United States	Texas Diabetes and Endocrinology	Round Rock	Texas
United States	Bateman Horne Center	Salt Lake City	Utah
United States	Mills-Peninsula Health Services	San Mateo	California
United States	The Polyclinic	Seattle	Washington
United States	Advanced Research Institute	South Ogden	Utah
United States	University Physicians Group Research Division	Staten Island	New York
United States	MultiCare Institute for Research and Innovation	Tacoma	Washington
United States	Metabolic Institute of America	Tarzana	California
United States	University Clinical Investigators, Inc.	Tustin	California
United States	Iowa Diabetes and Endocrinology Research Center	West Des Moines	Iowa

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  Denmark,  Finland,  France,  Germany,  Netherlands,  Norway,  Poland,  Spain,  Sweden,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Glycated Haemoglobin (HbA1c) at 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
Primary	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) )	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	Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG)	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
Secondary	Change From Baseline in Body Weight at 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
Secondary	Change From Baseline in Percentage of Time Spent in Target Glucose Range From Weeks 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
Secondary	Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 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
Secondary	Change From Baseline in Total Daily Insulin Dose (TDID) at 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
Secondary	Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at 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

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