supplementary data - diabetes care€¦ · supplementary data ©2018 american diabetes association....

SUPPLEMENTARY DATA

©2018 American Diabetes Association. Published online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc18-1749/-/DC1

Supplementary Appendix:

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Rosenstock J et al. Empagliflozin as Adjunct Therapy to Insulin in Type 1 Diabetes:

The EASE Trials

SUPPLEMENTARY DATA


Table of Contents:

Clinical trial site list in EASE-2 and EASE-3

Ethics approvals and patient consenting

EASE-2 and EASE-3 list of inclusion and exclusion criteria

Guidance on insulin dose adjustment

Ketoacidosis risk mitigation strategies used in EASE-2 and EASE-3

Ketoacidosis event identification and case categorization based on adjudication

Clinical course of events in the fatal ketoacidosis case

Definitions of hypoglycemia

Case definitions and categorization of events undergoing severe hypoglycemia adjudication

List of safety laboratory tests

Independent committees overseeing safety and event adjudication

EASE-2 and EASE-3 primary, key secondary and safety end points

Statistical analysis details and testing hierarchy

Devices use: Blood glucose-ketone meter, e-diary and continuous glucose monitoring

Supplementary Figure S1: Schematic design of EASE-2 and EASE-3 trials

Supplementary Figure S2: CONSORT diagrams of patient disposition in EASE-2 and EASE-3

Supplementary Figure S3: Glycated hemoglobin effectiveness analysis

Supplementary Figure S4: Body weight - over time graphs and analyses

Supplementary Figure S5: Systolic blood pressure – over time graphs and analyses

Supplementary Figure S6: Diastolic blood pressure – over time graphs and analyses

Supplementary Figure S7: EASE-2 and EASE-3 CGM-based glucose time in range and inter-quartile analyses

Supplementary Figure S8: Total daily insulin dose - over time graphs and analyses

Supplementary Figure S9: Total daily basal insulin dose - over time graphs and analyses

Supplementary Figure S10: Total daily bolus insulin dose - over time graphs and analyses

Supplementary Figure S11: Fasting Plasma glucose – over time graphs and analyses

Supplementary Figure S12: Waist circumference – over time graphs and analyses

Supplementary Figure S13: Safety analysis of hypoglycemia during week 1-4 of treatment

Supplementary Figure S14: Net benefit analysis

Supplementary Figure S15: Explanations for differences in urinary glucose excretion in T1D vs T2D

Supplementary Table S1: Clinical characteristics of adjudicated certain ketoacidosis

Supplementary Table S2: Analysis of adjudicated certain or potential ketoacidosis based on sex and insulin

therapy

References for supplementary information

SUPPLEMENTARY DATA


CLINICAL TRIAL SITE LIST IN EASE-2 AND EASE-3

EASE-2:

Sultan Linjawi, Coffs Endocrine & Diabetes Centre, New South Wales, Australia; Michael d’Emden, Royal

Brisbane & Women’s Hospital, Endocrinology Research Unit, Queensland, Australia; Claire Morbey, AIM

Centre Level 1, New South Wales, Australia; Rudolf Prager, Hospital Hietzing Krankenhaus Hietzing mit NZR 3.

Medizinische Abteilung, Wien, Austria; Bernhard Ludvik, KH Rudolfstiftung, 1. Med.Abt. Wein Krankenanstalt

Rudolfstiftung inkl. Semmelweis Frauenklinik, Wein, Austria; Heinz Drexel, VIVIT Instit.am LKH Feldkirch

Abteilung fuer Innere Medizin und Kardiologie, Feldkirch, Austria; Christian Hengl, LKH Steyr Innere Medizin

II, Steyr, Austria; Pieter Gillard, UZ Leuven – Campus Gasthuisberg I.G. Endocrinologie, Leuven, Belgium;

Chris Vercammen, Bonheiden – HOSP Imelda, Imelda ZH Bonheiden endocrinology, Bonheiden, Belgium;

Fabienne Lienart, La Louvière - UNIV CHU Tivoli CHU Tivoli Diabétologie, La Louvière, Belgium; Corinne

Debroye, Brussels – UNIV UZ Brussel, UZ Brussel Diabeteskliniek, Brussel, Belgium; Marie Strivay, Liège -

HOSP CHR de la Citadelle CHR de la Citadelle Service, Liège, Belgium; Luc Van Gaal, Edegem - UNIV UZ

Antwerpen UZA Dienst Endocrinologie, Edegem, Belgium; Bernard Jandrain, Centre Hospitalier Universitaire

de Liège Diabétologie/Unite de Pharmacologie Clinique, Liège, Belgium; Laurent Crenier, ULB Hopital Erasme,

Service d’Endocrinologie, Bruxelles, Belgium; Bruno Lapauw, UNIV UZ Gent Endocrinologie en

Stofwisselingsziekten, Gent, Belgium; Ann Verhaegen, Merksem – HOSP ZNA Jan Palfijn, Merksem, Belgium;

Eric Weber, Arlon – HOSP Sud Luxembourg – Vivalia, Arlon, Belgium; Ronald Goldenberg, LMC Clinical

Research Inc. (Thornhill), Thornhill, Ontario, Canada; Robyn Houlden, Kingston General Hospital, Kingston,

Ontario, Canada; Bruce Perkins, Mount Sinai Hospital Lunenfeld-Tanenbaum Research Institute, Toronto,

Ontario, Canada; Thomas Ransom, Nova Scotia Health Authority, Centre for Clinical Research Endocrinology

Research and Metabolism, Halifax, Nova Scotia, Canada; Buki Ajala, LMC Clinical Research Inc. (Thornhill),

Thornhill, Ontario, Canada; Vincent Woo, Winnipeg Regional Health Authority, Health Sciences Centre

Winnipeg, Diabetes Research Group, Winnipeg, Manitoba, Canada; Jean-Francois Yale, The Research Institute of

the Mc Gill University Health Centre-Glen Site, Montreal, Quebec, Canada; Jean-Louis Chiasson, Centre

Hospitalier de l’universite de Montreal-Pavillon R, Montreal, Quebec, Canada; David Miller, Royal Jubilee

Hospital, Victoria, British Columbia, Canada; Josias Badenhorst, The Bailey Clinic, Red Deer, Alberta, Canada;

Martin Prazny, General University Hospital in Prague (VFN), Praha, Czech Republic; Jiri Lastuvka, Masaryk

Hospital, Usti nad Labem, Czech Republic; Vladimir Lelek, Diabetology and Internal Practice Dr. Vladimir

Lelek, Slany, Czech Republic; Steen Anderson, Nordsjællands Hospital Kardiologisk, Nefrologisk &

Endokrinologisk Afdeling, Hillerød, Denmark; Henrik Ullits Anderson, Steno Diabetes Center Copenhagen,

Gentofte, Denmark; Leif Breum, Sjællands Universitetshospital Køge Medicinsk afdeling, Endokrinologisk

Afsnit, Køge, Denmark; Tina Schou Anderson, Aalborg Sygehus Syd Aalborg Universitetshospital Klinik

Medicin, Aalborg, Denmark; Per Løgstrup Poulsen, Aarhus Universitetshospital Medicinsk endokrinologisk afd.

M, Aarhus C, Denmark; Jorma Strand, Terveystalo Oulu, Diapolis, Oulu, Finland; Lassi Nelimarkka, TYKS

Turun yliopistollinen keskussairaala Sisätautien klinikka, Turku, Finland; Sakari Nieminen, IteLasaretti, Kuopio,

Finland; Jean-Pierre Courrèges, HOP de Narbonne, Narbonne, France; Thierry Delmas, HOP Brabois,

Vandoeuvre-lès-Nancy, France; Céline Lukas-Croisier , Hôpital Robert Debré Service d'Endocrinologie, de

Diabétologie et de Nutrition, Reims, France; Yves Reznik, HOP Côte de Nacre CHU de Caen-Centre Hospitalier

Universitaire, Caen, France; Didier Gouet, HOP Saint Louis Diabétologie endocrinology, France; Pierre

Serusclat, HOP les Portes du Sud, Diabéto, Vénissieux France; Veronika Wenzl-Bauer, Allgemeinmedizinische

und Diabetologische Schwepunktpraxis, Rehlingen-Siersburg, Germany; Bärbel Hirschhäuser, Praxis Dr.

Hirschhäuser, Saarbrücken, Germany; Alexander Segner, Praxis Dr. Segner, St. Ingbert Praxis für

Allgemeinmedizin und Innere Medizin, Oberwürzbach, Germany; Karl-Michael Derwahl, ikfe - Institut für

klinische Forschung und Entwicklung Berlin GmbH, Berlin, Germany; Rolf Göbel, Gemeinschaftspraxis, Asslar

Schwerpunktpraxis Diabetes, Asslar, Germany; Gerhard Klausmann, Studienzentrum Klausmann Studienzentrum

Aschaffenburg, Aschaffenburg, Germany; Joachim Müller, Ambulanzzentrum Schweinfurt Gemeinschaftspraxis

Dr. J. Müller, Dr. S. Appelt & Kollegen, Schweinfurt, Germany; Christine Kosch, Praxis Dr. Kosch, Pirna

Diabetologische Schwerpunktpraxis, Pirna, Germany; Helga Eufemia Zeller-Stefan, InnoDiab Forschung GmbH

Institut für Stoffwechselerkrankungen, Essen, Germany; Max Nieuwdorp, Academisch Medisch Centrum

(AMC), Amsterdam, Netherlands; Suat Simsek, Noordwest Ziekenhuisgroep, Alkmaar, Netherlands; Adriaan

Kooy, Bethesda Ziekenhuis Hoogeveen, Hoogeveen, Netherlands; Janneke Wiebolt, Sint Franciscus Gasthuis,

SUPPLEMENTARY DATA


Rotterdam, Netherlands; Ruud van Leendert, Albert Schweitzer Ziekenhuis Zwijndrecht, Zwijndrecht,

Netherlands; K Hoogenberg, Martini Ziekenhuis, Groningen, Netherlands; MMC Hovens, Rijnstate Hospital,

Arnhem, Netherlands; Elisabeth Qvigstad, Oslo Universitetssykehus HF, Aker Sykehus - Avd. Endokrinologisk

Poliklinikk Postboks Nydalen, Oslo, Norway; Hilde Selsås, Helse Møre og Romsdal HF, Ålesund sjukehus

Medisinsk Poliklinikk for Diabetes, Ålesund, Norway; Archana Sharma, Akershus Universitetssykehus HF

Department of Endocrinology, Lørenskog, Norway; Trine E. Finnes, Sykehuset Innlandet HF, Avd. Hamar

Endokrinologisk seksjon, Hamar, Norway; Katarzyna Klodawska, NBR Polska, Warsaw, Poland; Bogna

Wierusz-Wysocka, Karol Marcinkowski Poznan University of Medical Sciences, Poznan, Poland; Ewa

Skokowska, NZOZ Specialized Ambulance “MEDICA”, Lublin, Poland; Maria Gorska, Medical University of

Bialystok Clinical Department of Endocrinology, Diabetology & Int Dis., Białystok, Poland; Malgorzata

Arciszewska, NZOZ Specjalistyczny Osrodek Internistyczno-Diabetologiczny, Białystok, Poland; Antoni

Sokalski, NZOZ Centrum Medyczne AESKULAP, Private practice, Radom, Poland; Stanisław Mazur, Centrum

Medyczne Medyk Private Practice, Rzeszow, Poland; Andziej Dyczek, Dobry Lekarz, Spec. Med. Clinics, Private

Practice, Krakow, Poland; Jordi Mesa, Hospital Vall d’Hebron, Barcelona, Spain; Carlos Brotons, CAP Sardenya

Servicio de Atención Primaria / Medicina de Familia, Barcelona, Spain; Juan José Linares, Hospital de la

Inmaculada Concepción Clinica Inmaculada Concepcion Medicina Interna. Unidad de HTA y Síndrome

Metabólico, Granada, Spain; FranciscoTinahones Madueño, Hospital Virgen de la Victoria, Malaga, Spain;

Santiago Durán García, Hospital Universitario Nuestra Señora De Valme, Sevilla, Spain; Cristobal Morales

Portillo, Hospital Universitario Virgen Macarena, Sevilla, Spain; Fernando Gómez Peralta, Hospital General de

Segovia, Segovia, Spain; Johan Jendle, Centralsjukhuset, Karlstad Centralsjukhuset Endokrin- och

diabetescentrum, Karlstad, Sweden; Katarina Berndtsson Blom, Ladulaas Kliniska Studier, Borås, Sweden; Bo

Liu, Läkarhuset, Vällingby Läkarhus, Vällingby, Sweden; Lee-Ming Chuang, National Taiwan University

Hospital Department of Oncology, Taipei, Taiwan; Yi-Jen Hung, Tri-Service General Hospital, Taipei, Taiwan;

Chien-Ning Huang, Chung Shan Medical University Hospital, Taichung, Taiwan; Kai-Jen Tien, Chi Mei, Medical

Center, Tainan, Taiwan; Ching-Chu Chen, China Medical University Hospital, Taichung, Taiwan; Mark Evans,

Cambridge University Hospitals NHS Foundation Trust – Addenbrooke’s Hospital, Cambridge, United Kingdom;

Ken Darzy, East and North NHS Trust – Queen Elizabeth II Hospital, Welwyn Garden City, United Kingdom;

Melanie Davies, Leicester General Hospital, Leicester, United Kingdom; Mohammed Huda, The Barts Health

NHS Trust, Royal London Hospital, London, United Kingdom; Ben Field, Surrey & Sussex Healthcare NHS

Trust East Surrey Hospital, Surrey, United Kingdom; Peter Mansell, Nottingham University Hospitals NHS Trust,

Queen’s Medical Centre, Nottingham, United Kingdom; Asif Ali, Milton Keynes University Hospital –

Diabetes/Endocrinology Department, Buckinghamshire, United Kingdom; Ponnusamy Saravanan, George Eliot

Hospital NHS Trust Diabetes Centre, Nuneaton, United Kingdom; John McKnight, Wellcome Trust Clinical

Research Facility, Edinburgh, United Kingdom; Paul D. Rosenblit, Diabetes/Lipid Management & Research

Center, Huntington Beach, California, United States; Sam Lerman, Jellinger and Lerman, MD, PA dba The

Center for Diabetes and Endocrine Care, Fort Lauderdale, Florida, United States; Betsy Palal, Palm Research

Center, Inc. Las Vegas, Nevada, United States; Jack D. Wahlen, Advanced Research Institute, Ogden, Utah,

United States; Yehuda Handelsman, Metabolic Institute of America, Tarzana, California, United States; Leslie

Klaff, Rainier Clinical Research Center, Inc., Renton, Washington, United States; Peter N. Weissman, Baptist

Diabetes Associates, PA., Miami, Florida, United States; Kerem Ozer, Texas Diabetes & Endocrinology, P.A.,

Round Rock, Texas, United States; Hiralal Maheshwari, Midwest CRC, Crystal Lake, Illinois, United States;

Joanna Thuy Van Do, University Clinical Investigators, Inc., Tustin, California, United States; Juan Pablo Frias,

National Research Institute, Los Angeles, California, United States; Leonard R. Zemel, Creekside Endocrine

Associates, PC., Denver, Colorado, United States; Timothy S. Bailey, AMCR Institute Inc., Escondido,

California, United States; Gregg Gerety, Albany Medical College, Division of Community Endocrinology,

Albany, New York, United States; John Chip Reed, Endocrine Research Solutions, Inc., Roswell, Georgia, United

States; Carl Vance, Rocky Mountain Diabetes and Osteoporosis Center, PA., Idaho Falls, Idaho, United States;

Jeffrey Rothman, University Physicians Group Research Division, Staten Island, New York, United States;

Lucinda Bateman, Bateman Horne Center, Salt Lake City, Utah, United States; Adeniyi Olabiyi Odugbesan,

Physicians Research Associates, LLC., Lawrenceville, Georgia, United States; David Klonoff, Mills-Peninsula

Health Services – Diabetes Research Institute, San Mateo, California, United States; Luis Soruco, Northwest

Endo Diabetes Research, LLC., Arlington Heights, Illinois, United States; William Reid Litchfield, Desert

Endocrinology Clinical Research Center, Henderson, Nevada, United States; Ronald Graf, MultiCare Institute for

Research and Innovation, Tacoma, Washington, United States; Peter Bressler, North Texas Endocrine Center,

SUPPLEMENTARY DATA


Dallas, Texas, United States; Michelle Zaniewski-Singh, Michelle Zaniewski MD, PA., Houston, Texas, United

States; Kathryn Jean Lucas, Diabetes and Endocrinology Consultants, PC., Morehead City, North Carolina,

United States; Anuj Bhargava, Iowa Diabetes and Endocrinology Research Center, West Des Moines, Iowa,

United States; Claire Baker, Diabetes & Endocrine Associates, PC., Omaha, Nebraska, United States; Howard

A. Baum, Diabetes and Obesity Clinical Trials Center, Nashville, Tennessee, United States; Robert J. Silver,

Southern New Hampshire Diabetes and Endocrinology, Nashua, New Hampshire, United States; Meenakashi

Iyer, The Lindner Center for Research and Education at The Christ Hospital, Cincinnati, Ohio, United States;

Kenneth M. Gross, The Polyclinic, Seattle, Washington, United States; David Rickenbeck Sutton Jr., East Coast

Institute for Research, LLC., Jacksonville, Florida, United States; Larry D. Stonesifer, Larry D. Stonesifer MD

Inc., PS, Washington, United States

EASE-3:

Anthony Roberts, SA Endocrine Research P/L, Keswick, South Australia, Australia; Parind Vora, Lyell McEwin

Hospital Clinical Trials Unit, Elizabeth Vale, South Australia, Australia; Murray Gerstman, Eastern Clinical

Research Unit, ECRU Maroondah, East Ringwood, Victoria, Australia; Sultan Linjawi, Coffs Endocrine &

Diabetes Centre, New South Wales, Australia; Lawrence Leiter, St. Michael’s Hospital, Toronto, Ontario,

Canada; Stewart Harris, Centre for Studies in Family Medicine Western University, London, Ontario, Canada;

Josias Badenhorst, The Bailey Clinic, Red Deer, Alberta, Canada; Guy Tellier, Omnispec Recherche Clinique

Inc., Mirabel, Quebec, Canada; John Weisnagel, Clinique des maladies Lipidiques de Quebec, Quebec, Quebec,

Canada; Ron Sigal, Richmond Road and Diagnostic Treatment Centre, Calgary, Alberta, Canada; Christopher

Kovacs, Eastern Health (MUN) Division of Endocrinology – Health Science Centre, St. John’s, Newfoundland,

Canada; George Michael Tsoukas, Applied Medical Informatics Research INC., Westmount, Quebec, Canada;

Elena Silhova, University hospital Kralovske Vinohrady, II. Clinic of Internal Medicine – Dept Diabetology,

Prague, Czech Republic; Emilia Malicherova, ResTrail s.r.o. Diabetology Ambulance, Prague, Czech Republic;

Dagmar Bartaskova, Milan Kvapil s.r.o. Diabetology Ambulance, Prague, Czech Republic; Vlasta Kutejova,

AIDIN VK s.r.o. Department Diabetology, Hranice, Czech Republic; Dana Burdova, DiaGolfova s.r.o.

Department Diabetology, Prague, Czech Republic; Jitka Hasalova Zapletalova, Diahaza s.r.o. Internal Medicine

Outpatient Clinic – Diabetology, Holesov, Czech Republic; Jana Belobradkova, University Hospital Brno,

Internal Hepatogastroenterology Clinic, Brno, Czech Republic; Kirsi Pietiläinen, HUS, Lihavuustutkimusyksikkö

Biomedicum Helsinski, Helsinki, Finland; Petteri Ahtiainen, Mehiläinen Jyväskylä, Jyväskylä, Finland; Jorma

Lahtela, FinnMedi Oy, Tampere FinnMedi Oy FM 3, Tampere, Finland; Pirkko Korsoff, Satakunnan

Diabetesasema Pori, Pori, Finland; Lassi Nelimarkka, TYKS Turun yliopistollinen keskussairaala Sisätautien

klinikka, Turku, Finland; Samy Hadjadj, HOP de Poitiers, CHU de la Milétrie Centre Investigation, Poitiers,

France; Sylvaine Clavel, HOP Le Creusot -Hôtel Dieu du Creusot Service d'Endocrinologie Site Harfleur, Le

Creusot, France; Olivier Dupuy, HOP Saint Joseph, Endo, Paris G H Paris Saint-Joseph Service de Diabétologie

Endocrinologie, Paris, France; Michel Marre, HOP Bichat, Hôpital Blichat-Claude Bernard Service de

Diabétologie Endocrinologie, Paris, France; Hélène Hanaire, HOP Rangueil, Hôpital Rangueil – CHU Toulouse

Service Diabétologie, Toulouse Cedex, France; Franck Schillo, Hôpital Jean Minjoz, Service d’Endocrinologie,

Diabétologie et Maladies métaboliques, Besancon, France; Nathalie Jeandidier, Hôpital Civil Service

Endocrinologie, Diabétologie, Strasbourg, France; Marcel Kaiser, Diabetologische Schwerpunktpraxis, Frankfurt,

Germany; Thomas Behnke, Zentrum für klinische Studien, Neuwied, Germany; Thomas Haak, Diabetes Zentrum

Bad Mergentheim Diabetes Klinik, Bad Mergentheim, Germany; Andreas Hagenow, Zentrum für klinische

Studien Südbrandenburg GmbH, Elsterwerda, Germany; Elena Henkel, GWT-TUD GmbH, Studienzentrum

Metabolisch-Vaskuläre Medizin, Dresden, Germany; Jost Hilgenberg, Diabetologische Schwerpunktpraxis Leeser

Straße 21, Rehburg-Loccum, Germany; Winfried Keuthage, Schwerpunktpraxis für Diabetes und

Ernährungsmedizin, Münster, Germany; Stephan Maxeiner, Diabetologische hausärztliche Gemeinschaftspraxis

Bosenheim, Bosenheim, Germany; Ludger Rose, Institut für Diabetesforschung, Münster, Germany; Klaus Busch,

Diabeteszentrum DO Diabetologische Schwerpunktpraxis Dortmund, Dortmund, Germany; Helga Eufemia

Zeller-Stefan, InnoDiab Forschung GmbH, Institut für Stoffwechselerkrankungen, Essen, Germany; Iakovos

Avramidis, General Hospital of Thessaloniki “G. Papanikolaou”, Division of Diabetes, Thessaloniki, Greece;

Nikolaos Tentolouris, General Hospital of Athens “Laiko”, Athens, Greece; Stavros Bousboulas, General

Hospital of Nikaia, 3rd Internal Medicine Clinic, Nikaia, Greece; Andromachi Vrionidou-Bompota,

“Korgialeneio-Benakeio” Hellenic Red Cross Hospital, Dept. of Endocrinology, Diabetes and Metabolism,

SUPPLEMENTARY DATA


Athens, Greece; Evangelos Rizos, University Hospital of Ioannina, 2nd Pathology Clinic, Ioannina, Greece;

Christos Sambanis, General Hospital of Thessaloniki “Ippokrateio”, 2nd Propedeutic-Internal Medicine Clinic,

Thessaloniki, Greece; Csaba Salamon, Clinfan SMO Ltd., Szekszard, Hungary; Iren Foldesi, Csongrad Country

Dr Bugyi Istvan Hospital Diabetic Outpatient Clinic, Szentes, Hungary; Gyorgy Paragh, University of Debrecen –

1st Internal Clinic, Debrecen, Hungary; Katalin Csomós, CRU Hungary Ltd., Private Practice Miskolc, Miskolc,

Hungary; Tamas Oroszlan, Diabetic Outpatient Clinic, Zala Megyei Szent Rafael Hospital, Zalaegerszeg,

Hungary; Victor Vass, Synexus Magyarorszag Kft. Synexus Hungary Health Care Service Ltd., Budapest,

Hungary; Gyongyi Csecsei, Clinexpert Kft., Budapest, Hungary; Maria Byrne, Mater Misericordiae University

Hospital Metabolic Research Department, Dublin, Ireland; Ezio Ghigo, Ospedale Molinette, AO Città della Salute

e della, CDU Endocrinologia, Diabetologie e Metabolismo Dipartimento di Medicina, Torino, Piemonte, Italy;

Massimo Boemi Dottore, INRCA-IRCCS, U.O.C. Malattie Metaboliche e Diabetologia Centro Diabetico,

Ancona, Marche, Italy; Alberto Di Carlo, Osp. Campo di Marte Servizio di Diabetologia e Malattie Metaboliche

Cittadella della Salute “Campo di Marte”, Lucca, Toscana, Italy; Francesco Dotta, A.O.U. Senese Policlinico

Santa Maria alle Scotte, U.O. di Diabetologia Dipartimento di Medicina Interna, Siena, Toscana, Italy; Simona

Frontoni, Osp. S. Giovanni Calibita Fatebenefratelli, U.O.C. Endocrinologia, Diabetologia e Malattie Metaboliche

Centro Antidiabetico, Roma, Lazio, Italy; Loredana Bucciarelli Dottoressa, IRCCS Gruppo Multimedica Unita’ di

Diabetologia IRCCS “Sesto S. Giovanni-Gruppo Multimedica”, Lombardia, Italy; Dario Pitocco Dottore,

Policlinico Gemelli U.O.C. di Medicina Interna e Angiologia Dipartimento di Scienze Mediche, Roma, Lazio,

Italy; Gabriele Riccardi, Azienda Ospedaliera Universitaria “Federico II” DAI Medicina Clinica U.O.C.

Diabetologia e Malattie del Metabolismo DAI Medicina Clinica, Napoli, Campania, Italy; Umberto Valentini

Dottore, A.O. Spedali Civili di Brescia U.O. di Diabetologia, Brescia, Lombardia, Italy; Renate Helda, Sigulda

Hospital Outpatient Department, Sigulda, Latvia; Valda Stalte, VSV Centrs, Stalte Private Practice, Talsi, Latvia;

Dace Teterovska, Dace Teterovska Doctor’s Private Practice in Endocrinology, Ogre, Latvia; Sigita Pastare,

Zemgale’s Centre of Diabetes, Jelgava, Latvia; Valdis Pirags, P. Stradins Clinical University Hospital

Endocrinology Center, Riga, Latvia; Anatolijs Lucenko, A. Lucenko’s Internist & Endocrinologist Doctor’s

Practice, Liepaja, Latvia; Inta Leitane, Riga Health Centre, Private Practice, Riga, Latvia; Guillermo Gonzalez

Galvez, Instituto Jaliscience de Inv. en Diabetes y Obesidad, S.C., Jalisco – Guadalajara, Mexico; Maricela Vidrio

Velazquez, Unidad de Investigación Clínica Cardiometabólica Departamento de Nutrición, Metabolismo y

Diabetología Departamento de Nutrición, Metabolismo y Diabetología, Jalisco-Guadalajara, Mexico; Guillermo

Antonio Llamas Esperon, Hospital Cardiologica Aguascalientes, Aguscalientes, Mexico; Ricardo Choza Romero,

Clínica EndocrInol en Diabetes Obesidad y Tiroides (DOT), Aguascalientes, Mexico; María del Rosario

Arechavaleta Granell, Unidad de Patologia Clinica, Jalisco- Guadalajara, Mexico; Jan Westerink, Universitair

Medisch Centrum Utrecht UMC Utrecht Locatie AZU, Utrecht, Netherlands; P.A.M. de Vries, Ziekenhuisgroep

Twente locatie Almelo ZGT Almelo, Almelo, Netherlands; T. van Bemmel, Gelre Ziekenhuizen Apeldoorn,

Apeldoorn, Netherlands; P.C. Oldenburg-Ligtenberg, Meander Medisch Centrum, Amersfoort, Netherlands; M.

Alhakim, EB FlevoResearch BV, locatie Utrecht, Utrecht, Netherlands; Suat Simsek, Noordwest

Ziekenhuisgroep, Alkmaar, Netherlands; Russell Scott, Lipid and Diabetes Research Group, Don Beaven Medical

Research Centre, Christchurch Hospital Campus, Christchurch, New Zealand; Edward Watson, South Pacific

Clinical Trials, Auckland, New Zealand; Ragnar Joakimsen, Universitetssykehuset Nord-Norge, Tromsø,

Norway; John Graham Cooper, Stavanger Helseforskning, Stavanger, Norway; Cecilie Wium, Oslo

Universitetssykehus HF, Lipidklinikken, Rikshospitalet, Oslo, Norway; Hans Olav Høivik, M3 Helse AS, Hamar

Avd. For Medisinsk Forskning, Hamar, Norway; Elzbieta Bandurska-Stankiewicz, Regional Specialist Hospital in

Olsztyn Clinic of Endocrinology, Diabetics and Internal Medicine, Olsztyn, Poland; Jaroslaw Opiela, Omedica

Medical Centre, Poznan, Poland; Grazyna Cieslik, Medical Centre Pratia Krakow, Krakow, Poland; Grzegorz

Dzida, Independent Public Clin.Hosp.no1 Lublin Dept. Internal Diseases, Lublin, Poland; Anna Tochman-Gawda,

Witold Chodzko Institute of Rural Medicine Department of Diabetology, Lublin, Poland; Iwona Kobielusz-

Gembala, Clinical Research Center Medicome, private practice, Oswiecim, Poland; Violetta Szostek-Gawel,

NZOZ Med-Art. Specialist Clinics, Zory private practice, Zory, Poland; Aleksandra Madej-Dmochowska,

Medical Centre Pratia Gdynia Private practice, Gdynia, Poland; Jolanta Kitowska-Koterla, Medical Centre Pratia

Katowice I, Katowice, Poland; Grazyna Popenda, DiabSerwis S.C., Chorzow private practice, Chorzow, Poland;

Agnieszka Tiuryn-Petrulewicz, Medical Centre Pratia Warszawa, Medica Pro Familia S.A. private practice,

Warszaw, Poland; Maciej Malecki, University Hospital in Krakow, Department of Metabolic Diseases, Krakow,

Poland; Jorge Dores, Centro Hospitalar do Porto, EPE CHP, Porto, Portugal; Rosa Ballesteros, Centro Hospitalar

da Cova da Beira, Covilhã, Portugal; Cristina Rogado, APDP-Associação Protectora dos Diabéticos de Portugal,

SUPPLEMENTARY DATA


Lisboa, Portugal; Celestino Neves, Centro Hospitalar São Joao, EPE Serviço de Endocrinologia, Portugal;

Cristina Roque, ULSAM, EPE – Hospital de Santa Luzia Serviço Endocrinologia, Viana do Castelo, Portugal;

Marta Alves/Olinda Marques, Hospital de Braga-Escala Braga Serviço Endocrinologia, Braga, Portugal; Maria

João Oliveira, Centro Hospitalar de Vila Nova Gaia/ Espinho Serviço de Endocrinologia, Vila Nova de Gaia,

Portugal; Ciprian Constantin, Dr. Carol Davila Central Military Emergency University Hospital Diabetes,

Bucharest, Romania; Gabriela Doina Negrisanu, Medical Centre Dr Negrisanu SRL, Timisoara, Romania;

Nicoleta Mihaela Mindrescu, SC Nicodiab SRL, Bucharest, Romania; Dana Cosma, SC Pelican Impex SRL

Cabinet Nr. 11 Diabetes Dept., Nutrition & Metabolic Diseases, Oradea, Romania; Adriana Dumitrescu, SC

“Sanatatea Ta” Medical Centre SRL, Bucharest, Romania; Ruslan Sardinov, Policlinic No. 1 of Russian Academy

of Sciences Dept. Endocrinology Dept., St. Petersburg, Russian Federation; Anton Edin, City of Outpatient

department no. 107, Clinical Pharmacology, St. Petersburg, Russian Federation; Natalia Vorokhobina, City

Hospital Saint Elizaveta Dept. Endocrinology, St. Petersburg State Health Care, St. Petersburg, Russian

federation; Nina A. Petunina, City Clinical Hospital No. 67, Moscow, Russian Federation; Vitaly Baranov,

Medical Academy named after I. Mechnikov Dept. Endocrinology, St. Petersburg, Russian Federation; Elena

Arefyeva, CJSC “Polyclinic complex”, Dept. Endocrinology, St. Petersburg, Russian Federation; Lawrence

Distiller, Dr. L. A. Distiller Centre for Diabetes & Endocrinology, Johannesburg, South Africa; Hilton Kaplan,

Dr. Hilton Kaplan, Cape Town, South Africa; Luthando Adams, LCS Clinical Research Unit, LCS Cosmo Day

Clinic, Johannesburg, South Africa; Paul Abrahams, VX Pharma (Pty) Ltd., Pretoria Syzygy Clinical Research

Services, Pretoria, South Africa; Samantha du Toit/ Lize Maritz, TREAD Research, Cape Town, South Africa;

Shaifali Joshi, Diabetes Care Centre, Pretoria, South Africa; Olga González, Hospital General universitario

Gregorio Marañon, Madrid, Spain; Francisco Javier del Cañizo, Hospital Universitario Infanta Leonor, Madrid,

Spain; Martin López de la Torre, CM+ Investigación, CM Avances Médicos, Granada, Spain; Francisco Javier

Ampudia, Hospital Clínico de Valencia, Valencia, Spain; Alfonso Soto González, Hospital A Coruña, Coruña,

Spain; Santiago Durán García, Endo-Diabesidad-Clínica Durán & Asociados, Sevilla, Spain; Juan José Linares,

Hospital de la Immaculada Concepción, Granada, Spain; Isabel Serrano Olmedo, Hospital Universitario Virgen

Macarena, Sevilla, Spain; Magnus Löndahl, Skånes universitetssjukhus Endokrinmottagningen, Lund, Sweden;

Dan Curiac, CTC Sahlgrenska Universitetssjukhuset, Göteborg, Sweden; Martin Ferletta, Karlskoga lasarett,

Karlskoga, Sweden; Peter Kalén, Sjukhuset, Ängelholm Diabetes/Endokrinsektionen, Ängelhom, Sweden; Bo

Liu, S3 Clinical Research Centers, Vällingby, Sweden; Pratik Choudhary, King’s College London Weston

Education Centre, London, United Kingdom; Nick Oliver, St. Mary’s Hospital Clinical Research Network,

London, United Kingdom; Thozhukat Sathyapalan, Hull Royal Infirmary Diabetes, Endocrinology and

Metabolism Research Centre, Hull, United Kingdom; Vijayaraman Arutchelvam, The James Cook University

Hospital Academic Centre, Middlesbrough, United Kingdom; Luigi Gnudi, Guy’s Hospital Dept. of Diabetes and

Endocrinology, London, United Kingdom; Stuart Little, Royal Victoria Infirmary, The Newcastle upon Tyne

Hospitals, United Kingdom; Gerry Rayman, Ipswich Hospital Diabetes Centre, Ipswich, United Kingdom; Susana

Gonzalez, Bradford Royal Infirmary, Department of Diabetes and Endocrinology, Bradford, United Kingdom;

Helen Partridge, Royal Bournemouth and Christchurch Hospital NHS Foundation Trust, Bournemouth, United

Kingdom; Melanie Davies, Leicester Diabetes Centre, Leicester, United Kingdom; Peter Mansell, Queen’s

Medical Centre, Deptartement of Diabetes and Endocrinology, Nottingham, United Kingdom; Ponnusamy

Saravanan, George Eliot Hospital Diabetes Centre, Nuneaton, United Kingdom; Bruce Trippe, Healthscan

Clinical Trials LLC, Montgomery, Alabama, United States; Kristin Castorino, William Sansum Diabetes Center,

Santa Barbara, California, United States; Thanh Minh Nguyen, Solutions Through Advanced Research Inc.,

Jacksonville, Florida, United States; Kashif Latif, AM Diabetes and Endocrinology Center, Bartlett, Tennessee,

United States; Andrew P. Brockmyre, Holston Medical Group, Bristol, Tennessee, United States; David Huffman,

University Diabetes and Endocrine Consultants, Chattanooga, Tennessee, United States; Lindsay Harrison, Texas

Diabetes & Endocrinology, P.A., Austin, Texas, United States; Rodney Stout, Holzer Clinic LLC, Gallipolis,

Ohio, United States; Glenn Blaise Gatipon, Sestron Clinical Research, Marietta, Georgia, United States; Michael

Shanik, Endocrine Associates of Long Island, PC, Smithtown, New York, United States; Julio Rosenstock, Dallas

Diabetes and Endocrine Center, Dallas, Texas, United States; Bresta Miranda, University of Miami Diabetes

Research Institute, Miami, Florida, United States; Wendell Miers, Kentucky Diabetes Endocrinology Center,

Lexington, Kentucky, United States; Dan Lender, Texas Health Physicians Group, Dallas, Texas, United States;

Linda Gaudiani, Marin Endocrine Care and Research Inc., Greenbrae, California, United States; Yshay

Shlesinger, NorCal Endocrinology and Internal Medicine, San Ramon, California, United States; Antonio Pinero-

Pilona, Suncoast Clinical Research Inc., New Port Richey, Florida, United States; Donald Eagerton, Strand

SUPPLEMENTARY DATA


Physician Specialists dba Carolina Health Specialists, Myrtle Beach, South Carolina, United States; Stephen

Aronoff, Research Institute of Dallas, Dallas, Texas, United States; Paul Norwood Jr., Valley Research, Fresno,

California, United States; Philip Levin, MODEL Clinical Research, Baltimore, Maryland, United States; Anna

Chang, John Muir Physician Network Clinical Research Center, Concord, California, United States; Bruce Bode,

Atlanta Diabetes Associates, Atlanta, Georgia, United States; Firas Akhrass, Endeavor Clinical Trials, LLC, San

Antonio, Texas, United States; Samer Nakhle, Palm Research Center Inc., Las Vegas, Nevada, United States;

Luis Carlos Quintero, International Research Associates, LLC., Hialeah, Florida, United States; Paresh Dandona,

Diabetes Endocrinology Research Center of Western New York, Williamsville, New York, United States; Kristi

Silver, University of Maryland Medical Center, Baltimore, Maryland, United States; Ahmed M. Awad, Clinical

Research Consultants, LLC., Kansas City, Missouri, United States; Zachary Freedman, Endocrine-Diabetes Care

and Resource Center, Rochester, New York, United States; Neda Rasouli, University of Colorado Hospital,

Aurora, Colorado, United States; James LaRocque, Virginia Endocrinology Research, Chesapeake, Virginia,

United States; Clinton Corder, COR Clinical Research, LLC., Oklahoma City, Oklahoma, United States; Ronald

Watts, Eagles Landing Diabetes & Endocrinology, Stockbridge, Georgia, United States; Anand Mehta, Pacific

Research Partners, LLC., Oakland, California, United States; Luis Soruco, Northwest Endo Diabetes Research,

LLC., Arlington Heights, Illinois, United States; William Reid Litchfield, Desert Endocrinology Clinical

Research Center, Henderson, Nevada, United States; Kathryn Jean Lucas, Diabetes and Endocrinology

Consultants, PC., Morehead City, North Carolina, United States; Adeniyi Olabiyi Odugbesan, Physicians

Research Associates, LLC., Lawrenceville, Georgia, United States

SUPPLEMENTARY DATA


ETHICS APPROVALS AND PATIENT CONSENTING

The EASE-2 and EASE-3 clinical trials were carried out in compliance with the protocol, the ethical principles

laid down in the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for GCP,

relevant BI SOPs and relevant regulations. Standard medical care (prophylactic, diagnostic and therapeutic

procedures) remained in the responsibility of the treating physician of the patient.

Trials were initiated only after all required legal documents had been reviewed and approved by the respective

ethics board and competent authority body according to national and international regulations. The same applied

for the implementation of changes introduced by amendments.

Prior to patient participation in the trial, written informed consent was obtained from each patient (or the patient’s

legally accepted representative) according to ICH / GCP and based on the regulatory and legal requirements of the

participating country.

Prior to the initiation of any trial-related procedure, all patients were informed about the trial verbally and in

writing by the investigator. The patient was allowed sufficient time to consider participation in the trial and to ask

questions concerning the details of the trial. Each patient signed and dated an informed consent form according to

the local regulatory and legal requirements. The signed informed consent form and additional documents for

patient information were retained by the investigator as part of the trial records. Each patient received a copy of

the signed informed consent form and additional documents for patient information.

SUPPLEMENTARY DATA


EASE-2 AND EASE-3 LIST OF INCLUSION AND EXCLUSION CRITERIA

Inclusion criteria:

1. Signed and dated written informed consent by the date of Visit 1 in accordance with Good Clinical

Practice (GCP) and local legislation

2. Male or female patient receiving insulin for the treatment of documented diagnosis of T1D for at least 1

year at the time of Visit 1

3. Fasting C-peptide value of < 0.7 ng/mL (0.23 nmol/L) at Visit 2 measured by the central laboratory

4. Use of, and be willing, based on the Investigator’s judgement, to continue throughout the duration of the

trial, either:

a. MDI of insulin consisting of at least one basal insulin injection and at least three daily bolus

injections OR

b. CSII of any insulin type, with at least 5 months experience of using CSII prior to Visit 1

For both MDI and CSII, the total daily insulin dose must be ≥ 0.3 U/kg and ≤ 1.5 U/kg at Visit 1

5. HbA1c ≥ 7.5% and ≤ 10.0% at Visit 5 measured by the central laboratory, and provided that the patient’s

HbA1c does not increase by > 0.5% between Visit 1 and Visit 5

6. Based on the Investigator’s judgement patient must have a good understanding of his/her disease and how

to manage it, and be willing and capable of performing the following study assessments (assessed at

Visits 1-5 and just before randomisation):

patient-led management and adjustment of insulin therapy

reliable approach to insulin dose adjustment for meals, such as carbohydrate counting

reliable and regular home-based blood glucose monitoring

recognise the symptoms of DKA, and reliably monitor for ketones

implementation of an established “sick day” management regimen

7. Age ≥ 18 years at Visit 1

8. Body Mass Index (BMI) of ≥ 18.5 kg/m2 at Visit 1

9. eGFR ≥ 30 mL/min/1.73 m² as calculated by the CKD-EPI formula, based on creatinine measured by the

central laboratory at Visit 1

10. Women of child-bearing potential* must be ready and able to use highly effective methods of birth

control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently

and correctly. Such methods should be used throughout the study and the patient must agree to periodic

pregnancy testing during participation in the trial. A list of contraceptive methods meeting these criteria

provided in the patient information

*Women of child-bearing potential are defined as follows: Any female who has experienced menarche

and is not post-menopausal (defined as at least 12 months with no menses without an alternative medical

cause) or who is not permanently sterilised (e.g. hysterectomy, bilateral oophorectomy or bilateral

salpingectomy)

11. Compliance with trial medication administration must be between 80% and 120% during the open-label

placebo run-in period, to be judged before randomisation

12. Only in EASE-3: To participate in the optional CGM substudy: Patient is willing to participate in that

substudy and eligible based on Investigator’s judgement to perform CGM. CGM substudy is conducted at

the trial site

13. Only in EASE-3: To participate in the optional CGM substudy: Patient is willing, based on the

Investigator’s judgement, not to take any paracetamol (acetaminophen) containing drugs throughout the

CGM monitoring periods, since this may falsely raise CGM glucose readings

Exclusion criteria:

1. History of T2DM, maturity onset diabetes of the young (MODY), pancreatic surgery or chronic

pancreatitis

2. Pancreas, pancreatic islet cells or renal transplant recipient

3. T1D treatment with any other antihyperglycaemic drug (e.g. metformin, alphaglucosidase inhibitors,

glucagon-like-peptide 1 [GLP-1] analogues, SGLT-2 inhibitors, pramlintide, inhaled insulin, pre-mixed

SUPPLEMENTARY DATA


insulins etc.) except subcutaneous basal and bolus insulin within 3 months prior to Visit 1 or any history

of clinically relevant hypersensitivity according to Investigator’s judgement

4. 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

5. Occurrence of DKA within 3 months prior to Visit 1 and until randomisation at Visit 6

6. Irregular sleep/wake cycle (e.g. patients who habitually sleep during the day and work during the night)

based on Investigator’s judgement

7. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or transient

ischaemic attack (TIA) within 3 months prior to Visit 1

8. Diagnosis of severe gastroparesis (based on Investigator’s judgement)

9. Diagnosis of brittle diabetes based on Investigator judgement

10. Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), aspartate

transaminase (AST), or alkaline phosphatase above 3 x upper limit of normal

(ULN) at Visit 1 or Visit 5 as measured by the central laboratory

11. Eating disorders such as bulimia or anorexia nervosa

12. Treatment with anti-obesity drugs, weight-loss surgery or aggressive diet regimen leading to unstable

body weight (based on Investigator’s judgement) 3 months prior to Visit 1and until randomisation

13. Treatment with systemic corticosteroids or planned initiation of such therapy at Visit 1and until

randomisation. Inhaled or topical use of corticosteroids (e.g. for asthma/chronic obstructive pulmonary

disease) is acceptable

14. Change in dose of thyroid hormones within 6 weeks prior to Visit 1 or planned change or initiation of

such a therapy at Visit 1 and until randomisation

15. Only in EASE-2: Patient is unwilling, based on the Investigator’s judgement, to avoid use of paracetamol

(acetaminophen) containing drugs throughout the CGM monitoring periods, since this may falsely raise

CGM glucose readings

16. Medical history of cancer or treatment for cancer in the last five years prior to Visit 1. Resected basal cell

carcinoma considered cured is exempted

17. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis,

haemolytic anaemia) at Visit 1

18. Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial

19. Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial participation

based on Investigator’s judgement

20. Intake of an investigational drug in another trial within 30 days prior to Visit 1

21. Patient not able to understand and comply with study requirements, including the use of an e-diary, based

on Investigator’s judgement

22. Any other clinical condition that, based on Investigator’s judgement, would jeopardise patient safety

during trial participation or would affect the study outcome (e.g. immunocompromised patients who

might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections

etc.)

SUPPLEMENTARY DATA


GUIDANCE ON INSULIN DOSE ADJUSTMENT

All patients were required to keep their existing insulin therapy as stable as possible from the first screening visit

until the beginning of the therapy optimization (intensification) period. A 6-week insulin therapy optimization

(intensification) phase was an integral part of the study designs aimed to ensure that, in the investigator’s opinion,

a patient was achieving the best standard of care in accordance with local guidelines. In patients using CSII, and

where considered appropriate, adjustments in type 1 diabetes therapy could be supported by basal rate testing.

Type 1 diabetes therapy optimization was to be complete by the end of the 6-week optimization period so that a

patient’s insulin regimen was as stable as possible as they entered the placebo run-in period and for 2 weeks prior

to randomization.

During periods of stability, in the case of hypoglycemia (e.g. with measured glucose concentration ≤70 mg/dL

(≤3.9 mmol/L)), patients were preferably to ingest additional carbohydrates according to standard practice in the

management of type 1 diabetes. However, a patient’s existing insulin regimen was to be adjusted at any time for

safety reasons if deemed necessary by the investigator, e.g. in the case of persisting hyperglycemia or

hypoglycemia despite adequate carbohydrate intake.

At randomization for patients with an HbA1c of 7.5 to <8.0% following treatment optimization, investigators

were advised to reduce the patient’s total insulin dose by 10% to avoid potential hypoglycemia. For patients with

an HbA1c of ≥8.0% post-optimization, investigators were advised to adjust the patient’s total insulin dose based

on need as assessed by frequent self-blood glucose monitoring and close patient follow-up upon initiation of

randomized trial medication. In all cases, the actual reduction was to be dependent upon individual glucose

values. Thereafter and until the end of the trial, further adjustments to insulin therapy (both basal and bolus

insulin) could be made as necessary to avoid hypoglycemia and also hyperglycemia to ensure that, in the

investigator’s opinion, the patient was achieving the best standard of care in accordance with local guidelines.

Apart from the recommendation for the initial insulin reduction at the start of the randomized treatment, as

mentioned above, there was no protocol-defined algorithm for insulin adjustment in this trial as investigator’s

were expected to follow real-life practice based on their judgement following local guideline and standards of

practice to achieve the best standard of care. Throughout the trial, adjustment needed to balance a patient’s

individual risk for hypoglycemia on the one hand, and the risk for hyperglycemia and DKA on the other hand,

with special caution at the beginning of the treatment period and in the follow-up period, when empagliflozin

treatment was started and stopped, respectively. Any insulin dose change or adjustment had to be based on

laboratory tests or self-monitoring of blood glucose. Whenever possible, patients were to keep to the same

trademark and application device for their existing insulin during the trial; for medical/safety reasons, however

(e.g. malfunction of a pump in a patient with CSII), switches in mode of insulin delivery were permitted. There

were to be no major changes of the injection sites/areas.

Investigators had to ensure that patients selected for the trial were capable of leading the management and

adjustment of their insulin therapy when at home, including a ‘sick day’ management plan and, at the same time,

could be relied upon to contact the investigator for advice at the appropriate point in time, as this was an

outpatient trial. Investigator oversight was an important element of the insulin adjustment process.

SUPPLEMENTARY DATA


KETOACIDOSIS RISK MITIGATION STRATEGIES USED IN EASE-2 AND EASE-3

Information contained in clinical trial protocol:

Special attention was paid to the prevention of DKA. Investigators were reminded that, due to the mechanism of

action, patients receiving empagliflozin were at risk to underestimate their need for insulin in case of blood sugar

levels within their individual target range. Insulin deficiency might lead to ketoacidosis which could be life-

threatening if not recognized, and appropriately treated. All patients were made aware of this risk and were

instructed not to reduce their insulin intake below Investigator recommendations.

Investigators were reminded that not all criteria in the table below needed to apply for the diagnosis of DKA, and

clinical judgement should also be taken into consideration. General diagnostic criteria for DKA

In addition to performing glucose monitoring, patients were also equipped with an electronic device to determine

their ketone concentration (i.e. a blood glucose monitoring device/meter that is also capable of measuring blood

ketones: beta-hydroxybutyrate (BHB)).

Patients were reminded to test their ketones in case of any symptoms of DKA, e.g. nausea, vomiting, abdominal

pain etc., irrespective of the glucose value. Patients were reminded about the signs and symptoms of DKA, on the

interpretation of ketone values measured via the meter, and on appropriate action to take in the event of increased

ketone levels (see below). In the same way as during routine clinical care, patients were reminded to test for

ketones in case of repeatedly elevated blood glucose levels (e.g. > 200 -240 mg/dL [> 11.1 - 13.3 mmol/L]) which

cannot be explained. Regular (e.g. 2-3 times a week) measurements before breakfast were recommended

throughout the trial from Visit 2. More frequent (e.g. once daily) measurements before breakfast were

recommended during the run-in period and during the first 4 weeks of the treatment period and beyond if agreed

upon with the patient afterwards and if deemed necessary by the Investigator.

In the event of increased ketones, patients were to follow the rules given by their Investigator (e.g. increased fluid

intake and/or insulin bolus; food intake and insulin bolus in case of near-normal blood glucose) or contact their

trial site. In case of deteriorating ketosis, blood glucose and ketone levels were to be checked every 1-2 hours

until they were back in a range considered to be normal for the patient. Patients were instructed to immediately

refer themselves to hospital and/or the Investigator, or to contact an emergency physician, in case of a blood

ketone concentration > 1.5 mmol/L (as indicated in the meter manual). In case of a suspected DKA the

SUPPLEMENTARY DATA


Investigator were to ensure that appropriate tests were performed at the earliest opportunity according to local

guidelines, such as a blood gas test (pH, bicarbonate). The results were to be collected on the relevant page of the

electronic case report form.

Investigators were also asked to differentiate clinically deteriorating ketosis/DKA from any mild to moderate

increase of ketones which may be seen due to the mechanism of action of empagliflozin, especially in the fasted

state (e.g. in the morning). Investigators were also asked to carefully select patients for the study in terms of their

ability to comply with ketone measurement requirements. Patients not adhering to the instructions given by the

Investigator were to be retrained at the earliest possible opportunity.

Information contained in the core patient information sheet:

Ketoacidosis is a serious problem that happens to people with diabetes when chemicals called “ketones” build up

in their blood. In extreme cases, it can be fatal. It occurs because people with Type 1 diabetes, like you, make

little or no insulin, and this is the hormone that allows the body to use sugar as a source of energy.

Normally, the body breaks down sugar as a source of energy. However, in people with Type 1 diabetes who do

not make any insulin, the body is unable to use sugar. Instead the body burns fat as a source of energy; but

burning fat can cause too many ketones to be made, and when they build up in the blood, they can be toxic.

There are a few reasons why people might get ketoacidosis (e.g. they are not receiving treatment for their diabetes

since they don’t know they have it, they don’t take their insulin as directed, their insulin pump does not work

correctly etc.). You can reduce your chances of getting ketoacidosis by taking your insulin exactly as directed, and

measuring your blood sugar often to make sure it is not too high or too low. It is also important that you avoid

losing too much water (dehydration) and do not start any diet with very low carbohydrate intake (e.g. the Atkins

diet) since such diets might increase the production of ketones in your body. In case you have already started a

low-carbohydrate diet, you should stop that diet. Reducing alcohol intake also reduces your risks of developing

ketoacidosis.

Your risk for ketoacidosis might be increased if you:

have fever

had ketoacidosis in the past

have, or have had, problems with your pancreas, including pancreatitis or surgery on your pancreas

If any of these points apply to you, you should inform your Study Doctor about them.

Under empagliflozin treatment ketoacidosis could occur even at normal or near-normal glucose levels. Therefore,

you should test your blood ketone level in case of any signs of ketoacidosis, even if your blood glucose levels are

not elevated. These include:

nausea (feeling sick)

vomiting (being sick)

abdominal (tummy) pain

loss of appetite

shortness of breath

rapid heartbeat (tachycardia)

rapid breathing, where you breathe in more oxygen than your body actually needs (hyperventilation)

low blood pressure (hypotension), which can make you feel dizzy and lightheaded

a noticeable smell of ketones on your breath, which is often described as smelling like pear drops or nail

varnish remover (not everyone is able to smell ketones)

mental confusion

unconsciousness (coma)

SUPPLEMENTARY DATA


general malaise

any other unspecific symptoms

You should also measure your ketone levels in the event of unusually high urine production or pronounced thirst;

however, both are also side effects of the study medication empagliflozin. In addition, ketones should be

measured in case of repeatedly elevated blood glucose levels in the range of more than 200 – 240 mg/dL which

cannot be clearly explained by another reason (e.g. a high carbohydrate intake).

In the event of elevated ketones, you should either follow the rules given to you by your Study Doctor (e.g.

increased fluid intake and/or administration of an insulin bolus; in case of near-normal glucose, consider food

intake with insulin injection), or contact the research site.

If ketoacidosis is suspected, hospital treatment is needed, so you should immediately refer yourself to hospital

and/or your Study Doctor, or contact an emergency physician if you think you might have it.

Information contained in the core patient alert card:

IMPORTANT INFORMATION

Trial No.: Patient No.:_____________

Trial Name: EASE-X: A placebo-controlled clinical study with

empagliflozin (SGLT2 inhibitor) in the indication type 1 diabetes mellitus.

Patient Name: __________________________________

Trial Doctor: _______________ :___ _____________

The patient is in a placebo-controlled clinical trial

where empagliflozin (SGLT-2 inhibitor) is being

studied in patients with Type 1 Diabetes

(see REVERSE for important information)

To the treating physician / health care provider:

Diabetic ketoacidosis (DKA) is not uncommon in patients

with Type 1 Diabetes. Please recognise that SGLT-2

inhibitors may modify its presentation: Blood glucose may

appear normal or slightly elevated (<250 mg/dL/ <13.9

mmol/L). Regardless of blood glucose levels, in the event

of illness, nausea, or vomiting please measure ketones.

Especially if elevated, consider performing a blood gas

test (incl. pH, bicarbonate) and initiation of appropriate

therapy when required (e.g. correction of fluid and

electrolyte abnormalities, etc).

Trial Information Card, Version 1 (21-Oct-2016)

SUPPLEMENTARY DATA


KETOACIDOSIS EVENT IDENTIFICATION AND CASE CATEGORIZATION BASED ON

ADJUDICATION

Summary of ketoacidosis trigger identification, adjudication parameters and case definitions:

*2 BHB readings ≥ 3.8 mmol within 24 hours in the absence of symptoms to fulfill the criterion of potential

ketoacidosis

The following are details related to triggers which were used to identify potential ketoacidosis events that were

sent for adjudication:

Any AE where the electronic case report form tick box ‘ketoacidosis’ had been ticked

Selected trigger search terms indicative of ketoacidosis and/or DKA

Selected trigger search terms indicative of acetonemia, when accompanied by reported symptoms

suggestive of ketoacidosis, accompanied by a report of hospitalization, and/or reported as an SAE

Any BHB value >1.5 and <3.8 mmol/L, when accompanied by reported symptoms suggestive of

ketoacidosis, accompanied by a report of hospitalization, and/or reported as an SAE

Any BHB value ≥3.8 mmol/L, based on laboratory data (any source) and investigator-confirmed readings

from the e-diary

Single or multiple triggers consisting of BHB values >1.5 and <3.8 mmol/L without accompanying typical

ketoacidosis symptoms, hospitalization, or SAE reporting were classified as ketosis and did not undergo

adjudication. In addition to the events identified using the triggers above, a periodic review was performed of all

AEs to identify additional events for adjudication.

The events identified by the triggers or by periodic review were adjudicated by the CEC according to the case

definitions defined below, taken from the CEC Charter for Ketoacidosis and Severe Hypoglycaemia Events.

These definitions were created based on a composite of various diagnostic criteria in accordance with the ADA,

the European Association for the Study of Diabetes (EASD), the Association of British Clinical Diabetologists

(ABCD), the Canadian Diabetes Association (CDA), the International Society for Pediatric and Adolescent

Diabetes (ISPAD), and in accordance with published work (1).

SUPPLEMENTARY DATA


Case definitions for ketoacidosis adjudication:

KA = ketoacidosis; N/A = data not available

1. For potential KA, a blood BHB value ≥3.8 mmol/L was to be confirmed by an additional measurement ≥3.8

mmol/L within 24 h. A single BHB value ≥3.8 mmol/L without symptoms/suggestive history was to be

regarded as unlikely KA but ketosis.

2.

++/+++ is equivalent to moderate/large, which translates to 1.5 to 2.9 mmol/L blood BHB; ++++ is

equivalent to very large, which translates to ≥3 mmol/L blood BHB.

3. Suggestive history means pump failure, insulin dose omission, illness, improper sick day plan, etc.

4. Typical KA symptoms means neurological (confusion, drowsiness, loss of consciousness, etc.) and non-

neurological symptoms (dehydration, nausea/vomiting, abdominal pain, kussmaul breathing, etc.).

The occurrence of 2 BHB values ≥3.8 mmol/L within 60 min constituted clinically the same reading, it was

required that 2 BHB values ≥3.8 mmol/L within 24 h be separated by more than 60 min (in the absence of any

other parameters) to fulfil the criterion needed for the classification of such an event as potential ketoacidosis.

The CEC assessed ketoacidosis severity using pH per ADA criteria as the primary differentiator (mild: pH 7.25 to

7.30; moderate: pH 7.00 to 7.24; severe: pH <7.00). If pH was not available then bicarbonate level was used

(mild: 15 to 18 mEq/L; moderate: 10 to <15 mEq/L; severe: <10 mEq/L). If bicarbonate values were also not

available, then the degree of neurological symptoms was to be used (mild: alert; moderate: alert/drowsy; severe:

stupor/coma). Note that the final case assessment was at the discretion of the CEC members and allowed

deviations from the above definitions of severity, if needed.

SUPPLEMENTARY DATA


CLINICAL COURSE OF EVENTS IN THE FATAL KETOACIDOSIS CASE

A 28-year-old female patient with T1D since 4 years of age

Randomized to empagliflozin 25 mg; patient on insulin pump

Start of event: 106th day after randomization; over 3 days, patient developed flu-like symptoms, sinusitis

and high ketones (maximum BHB reading of 4.6 mmol/l)

On the 109th day after randomization, patient had BHB readings of 6.3 mmol/l, blood glucose 190 mg/dl;

visited the emergency room due to emesis and sinusitis; the patient did not inform the ER physician about

high BHB or participation in the study; patient was sent home with symptomatic treatment; in the same

evening, paramedics were called due to continued vomiting and abdominal pain, at that time blood

glucose was 337 mg/dl; the patient refused to be hospitalized despite clinical advice

On last day of study medication intake (the 110th day after randomization), the patient was admitted to the

hospital in a severe general condition; patient presented with severe acidosis and hyperglycemia; therapy

in the ER included intensive hydration, and insulin infusions (with normalization of blood glucose within

4 hours). The same evening, patient developed bradycardia and later had a cardiac arrest

Patient died after the second resuscitation attempt due to circulatory-respiratory failure secondary to DKA

with cerebral edema

SUPPLEMENTARY DATA


DEFINITIONS OF HYPOGLYCEMIA

Every episode of blood/plasma glucose ≤ 70 mg/dL (≤ 3.9 mmol/L) was to be documented with the respective

time and date of occurrence. Glucose values used within the criteria for hypoglycaemic events were based on

values measuring using a self-monitoring of blood glucose (SMBG) device and from central laboratory

measurements. Glucose values originating in the SGBM device were subsequently supposed to have been entered

into the patient e-diary by the patient. This included every episode of blood/plasma glucose ≤ 70 mg/dL (≤ 3.9

mmol/L), hypoglycaemia with glucose values < 54 mg/dL (< 3.0 mmol/L) and all symptomatic and all severe

hypoglycaemic events.

For analyses, hypoglycaemia was classified according to the following criteria:

Asymptomatic hypoglycaemia: event not accompanied by typical symptoms of hypoglycaemia but with a

measured glucose concentration ≤ 70 mg/dL (≤ 3.9 mmol/L)

Documented symptomatic hypoglycaemia with glucose concentration ≥ 54 mg/dL and ≤ 70 mg/dL (≥ 3.0

mmol/L and ≤ 3.9 mmol/L): event accompanied by typical symptoms of hypoglycaemia

Documented symptomatic hypoglycaemia with glucose concentration < 54 mg/dL (< 3.0 mmol/L): event

accompanied by typical symptoms of hypoglycaemia but no need for external assistance

Severe hypoglycaemia: event requiring the assistance of another person to actively administer

carbohydrates, glucagon or take other corrective actions. Plasma glucose concentrations may not be

available during an event, but neurological recovery following the return of plasma glucose to normal is

considered sufficient evidence that the event was induced by a low plasma glucose concentration

SUPPLEMENTARY DATA


CASE DEFINITIONS AND CATEGORIZATION OF EVENTS UNDERGOING SEVERE

HYPOGLYCEMIA ADJUDICATION

Severe hypoglycemia (also known as severe hypoglycemic episode) was defined as an event requiring the

assistance of another person to actively administer carbohydrate (e.g. intravenously), glucagon or other corrective

actions (please note that assistance of another person means that the patient was genuinely physically unable to

take action). In instances when plasma glucose concentrations during the event were not available, neurological

recovery following the return of plasma glucose to normal was considered sufficient evidence that the event was

induced by a low plasma glucose concentration. This would have applied in theory to fatal hypoglycemic events.

All cases where it was indicated that “assistance was required” (either by the patient in the electronic diary or by

the investigator in AE reporting) were sent to independent Clinical Event Committee for adjudication.

SUPPLEMENTARY DATA


LIST OF SAFETY LABORATORY TESTS

SUPPLEMENTARY DATA


INDEPENDENT COMMITTEES OVERSEEING SAFETY AND EVENT ADJUDICATION

Data Monitoring Committee:

A Data Monitoring Committee (DMC), independent from the sponsor, was established to assess the progress of

the trial, including unblinded safety data and the critical efficacy end points, at intervals and to recommend to the

sponsor whether to continue, modify, or stop one or more of the trials covered by the DMC charter. Measures

were in place to ensure blinding of the sponsor and all other trial participants. The tasks and responsibilities of the

DMC were specified in the DMC Charter. The DMC maintained written records of all its meetings.

Clinical Event Committee – adjudication of severe hypoglycaemia and ketoacidosis:

An independent external committee was established to adjudicate centrally and in a blinded fashion events

suspected of severe hypoglycaemia and ketoacidosis. The Clinical Event Committee (CEC) evaluated whether

prespecified criteria for severe hypoglycaemia and ketoacidosis case definitions were met, according to the

charter. For any events that qualified for adjudication, trial sites were asked to provide clinical documentation

such as laboratory values, discharge summaries, etc. to support the external event adjudication.

For severe hypoglycaemia, the CEC was to decide if the events sent for adjudication met the definition in the

charter for severe hypoglycaemia (yes, no, or unclassifiable) and if yes, on the onset date and time.

For ketoacidosis, the CEC was to decide for the events sent for adjudication on the case definition classification

according to the charter (certain, potential, unlikely, ‘unlikely but ketosis’, or unclassifiable), severity (mild,

moderate, severe, or not assessable), and outcome (recovered, sequelae, or fatal). The tasks and responsibilities of

the CEC were specified in the CEC Charter for Ketoacidosis and Severe Hypoglycaemia Events.

Hepatic external adjudication:

Certain hepatic events were adjudicated by external independent experts and categorised for severity (no hepatic

injury, mild to moderate hepatic injury, other significant hepatic injury, hepatic failure, or fatal cases) and causal

relationship with the trial medication (unlikely, possible, probable, or indeterminate) in a blinded fashion. The

events which were reviewed were defined in the charter. Events may have been defined by abnormal laboratory

values and/or relevant adverse events (AEs). For events qualifying for adjudication, relevant source documents

generated from any medical evaluations of these events were requested, including laboratory values, histological

analysis, results of ultrasound, CT, MRI, scintigraphy, hospital discharge letters, and medical reports from other

physicians. All evaluations were performed in a blinded fashion. The Hepatic External Adjudication Committee

(EAC) Charter.

Clinical Event Committee – adjudication of cardiovascular events:

An independent external committee (CEC) was established to centrally adjudicate potential cardiovascular events

in a blinded fashion based on the FDA guideline (2). The CEC consisted of 2 subcommittees: CEC Cardiology

(CECC) for the adjudication of fatal and non-fatal events suspected of myocardial ischaemia and heart failure and

CEC Neurology (CECN) for the adjudication of events suspected of stroke (fatal and non-fatal strokes as well as

transient ischaemic attacks [TIA]). The criteria for a trigger event to be sent for adjudication and the definitions of

the cardiovascular end points are defined in the CEC charter. The CEC evaluated whether prespecified criteria for

adjudication end points were met. For any events that qualified for adjudication, trial sites were asked to provide

clinical documentation such as electrocardiograms (ECGs), laboratory values, angiography, echocardiography

reports, CT and/or MRI scans, discharge summaries, and autopsy reports to support the external event

adjudication. The tasks and responsibilities of the CEC were specified in the CEC Charter.

SUPPLEMENTARY DATA


EASE-2 AND EASE-3 PRIMARY, KEY SECONDARY AND SAFETY END POINTS

EFFICACY – The Primary end point was:

The primary end point was the change from baseline in HbA1c at Week 26.

EFFICACY – The key secondary end points were:

Rate per patient-year of symptomatic hypoglycemic AEs with confirmed plasma glucose (PG) <54 mg/dL

(<3.0 mmol/L) and/or severe hypoglycemic AEs (i.e. all investigator-reported AEs that had confirmed PG

<54 mg/dl [<3.0 mmol/L] with symptoms reported and all severe hypoglycemic events that were

confirmed by adjudication):

o From Week 5 to 26

o From Week 1 to 26

Change from baseline in:

o Body weight at Week 26

o Only in EASE-2: 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) in Weeks 23 to 26

o Only in EASE-2: Interstitial glucose variability based on the interquartile range (IQR) as

determined by CGM in Weeks 23 to 26

o Total daily insulin dose (TDID) at Week 26

o Systolic blood pressure (SBP) at Week 26

o Diastolic blood pressure (DBP) at Week 26

Note: Further exploratory efficacy end points (e.g. fasting plasma glucose, waist circumference) were also

assessed in both; the above end points were in addition evaluated at end of the treatment period (week 52) for the

EASE-2 trial.

SAFETY:

Safety was assessed descriptively based on Adverse Events (AEs), AEs of special interest (AESIs), and other

specific AEs.

AESIs:

Decreased renal function

Hepatic injury

Diabetic ketoacidosis

Severe hypoglycemia

Lower-limb amputation

Other specific AEs:

Hypoglycemic events

Urinary tract infection

Acute pyelonephritis

Sepsis

Asymptomatic bacteriuria

Genital infection

Bone fracture

Volume depletion

Malignancy

In addition, adjudicated cardiovascular events, clinical laboratory data, and vital signs were assessed.

Independent external clinical event committees (CECs) performed central, blinded adjudication of ketoacidosis,

severe hypoglycemia, cardiovascular/neurological events, and specific hepatic events.

SUPPLEMENTARY DATA


STATISTICAL ANALYSIS DETAILS AND TESTING HIERARCHY

EASE-2:

For the primary end point, restricted maximum likelihood estimation based on mixed-effect model for repeated

measures (MMRM) analysis was used to obtain adjusted means for the treatment effects. This model included the

fixed categorical effects of treatment, pre-existing insulin therapy, week, and treatment-by-week interaction, as

well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, and baseline HbA1c-by-week

interaction. Patient was included as random effect. The primary treatment comparisons were the Bonferroni-

adjusted contrasts between each dose of empagliflozin (10 mg or 25 mg) and placebo, with each dose tested at the

level of α=0.025 (2-sided).

The primary efficacy analysis included on-treatment data only, based on the full analysis set (FAS) and observed

cases (OC). Subsequently, an effectiveness analysis (on- and off-treatment data) was performed in a hierarchical

manner, based on the modified intention-to-treat set (mITT) and including data after treatment discontinuation

(OC-AD). If the null hypotheses were rejected for both the efficacy and effectiveness analyses, then the key

secondary end points were to be tested in a confirmatory way using a gatekeeping approach, with unequal

splitting of the α, and sequential testing as depicted below:

The 2 key secondary hypoglycemic AE-related end points were analyzed using a negative binomial model. The

model included treatment and pre-existing insulin therapy as discrete fixed effects, baseline rate, baseline HbA1c,

and baseline eGFR as continuous fixed effects, as well as logarithm of time at risk as an offset. The primary

treatment comparisons were the rate ratios comparing the rates per patient-year of each dose of empagliflozin with

placebo.

SUPPLEMENTARY DATA


The key secondary end points of change from baseline in body weight, TDID, SBP, and DBP were analyzed using

an MMRM model similar to the analysis of the primary end point, with the additional covariate of the respective

baseline parameter and using the interaction between the respective baseline parameter and week.

The key secondary end points of change from baseline in the percentage of time spent in target glucose range and

IQR were analyzed using analysis of covariance (ANCOVA), with terms for treatment, pre-existing insulin

therapy, continuous baseline HbA1c, continuous baseline eGFR, and continuous baseline of the respective CGM

end point.

No interim analysis was planned or conducted.

EASE-3:

For the primary end point, restricted maximum likelihood estimation based on mixed-effect model for repeated

measures (MMRM) analysis was used to obtain adjusted means for the treatment effects. This model included the

fixed categorical effects of treatment, pre-existing insulin therapy, week, and treatment-by-week interaction, as

well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, and baseline HbA1c-by-week

interaction. Patient was included as random effect. The primary treatment comparisons were the Bonferroni-

adjusted contrasts between each dose of empagliflozin (10 mg or 25 mg) and placebo, with each dose tested at the

level of α=0.025 (2-sided).

The primary efficacy analysis included on-treatment data only, based on the full analysis set (FAS) and observed

cases (OC). Subsequently, an effectiveness analysis (on- and off-treatment data) was performed in a hierarchical

manner, based on the modified intention-to-treat set (mITT) and including data after treatment discontinuation

(OC-AD). If the null hypotheses were rejected for both the efficacy and effectiveness analyses, then the primary

efficacy end point for empagliflozin 2.5 mg versus placebo and the key secondary end points were to be tested in

a confirmatory way using a gatekeeping approach, with

SUPPLEMENTARY DATA


unequal splitting of the α, and sequential testing as depicted below

The 2 key secondary hypoglycemic AE-related end points were analyzed using a negative binomial model. The

model included treatment and pre-existing insulin therapy as discrete fixed effects, baseline rate of hypoglycemia,

baseline HbA1c, and baseline eGFR as continuous fixed effects, as well as logarithm of time at risk as an offset.

The primary treatment comparisons were the rate ratios comparing the rates per patient-year of each dose of

empagliflozin with placebo.

The key secondary end points of change from baseline in body weight, TDID, SBP, and DBP were analyzed using

an MMRM model similar to the analysis of the primary end point, with the additional covariate of the respective

baseline parameter

No interim analysis was planned or conducted.

SUPPLEMENTARY DATA


DEVICES USE: BLOOD GLUCOSE-KETONE METER, E-DIARY AND CONTINUOUS GLUCOSE

MONITORING

Self-blood glucose and ketone monitoring:

From the beginning of the T1D therapy optimization period until the end of the follow-up period, all patients were

to be provided with a blood glucose monitoring device/meter that was also capable of measuring blood ketones

(beta-hydroxybutyrate [BHB]) for use at home during the trial for self-measurement of blood glucose and BHB

levels. Instructions on the proper use of this point of care device were to be provided by the site staff. The patient

was asked to enter data from the glucose-BHB meter in their electronic diary on a daily basis.

Electronic diary (e-diary):

From the beginning of the T1D therapy optimization period until the end of the follow-up period, all patients were

to be provided with an e-diary for daily use during these periods of the trial. Prior to its first use, instructions on

the proper use of the e-diary were provided by the site staff. Refresher training was to be provided at subsequent

time points as deemed appropriate by the investigator or designated site personnel.

Daily entries into the e-diary included at least: glucose values from self-monitoring of blood glucose, any

hypoglycemic events that had occurred, and insulin requirement.

Any ketone measurements performed (beta-hydroxybutyrate value) were also to be entered into the e-diary if and

when any data became available.

Throughout the trial, the investigator and/or designated site personnel were to review the patient’s glucose and e-

diary results to determine if treatment adjustments needed to be implemented. The e-diary data was transferred to

a vendor server for data collection and transfer to the sponsor with a cut-off date of database lock for the purposes

of data analyses.

Continuous glucose monitoring (CGM):

The CGM system was a commercially available system with single-use disposable electrochemical sensing

elements. It allowed glucose levels to be recorded for up to 7 days at a time, after which a sensor change was

required to continue CGM. Glucose values recorded by the CGM system were blinded to the patient and the

investigator/designated site personnel to ensure unbiased data. However, sites were able to access information

regarding the use of the system.

Prior to the first CGM period, patients were trained in the correct use of the CGM system, including its setup,

sensor insertion, exchange, and removal, as well as calibration using the SBGM device. Refresher training was to

be provided at subsequent time points (as deemed appropriate by the investigator or designated site personnel).

Two main periods of CGM were took place (14 days during the placebo run-in pre-treatment period and at several

time intervals spanning 14-28 days during treatment). These durations accounted for the natural variation due to

sleep/wake, eating, and activity patterns. Every 7 days after starting each CGM period, the sensor had to be

exchanged; where a clinic visit was not scheduled for this day, the patient was to change the sensor at home.

Sensors were to be inserted at least 3 inches (7.62 cm) away from insulin infusion sets or injection sites.

The CGM data were transferred to the vendor server for data collection and transfer.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S1. SCHEMATIC DESIGN OF EASE-2 AND EASE-3 TRIALS

Figure Legend: Design of the EASE-2 and EASE-3 trials *CGM was performed as a sub-study of the EASE-3 trial in approximately 30% of patients. CGM, continuous

glucose monitoring. R represents randomization.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S2. CONSORT DIAGRAMS OF PATIENT DISPOSITION IN

EASE-2 AND EASE-3

Figure legend: Patient disposition after 26 weeks (treated set)

Panel A: EASE-2 trial

Panel B: EASE-3 trial

SUPPLEMENTARY DATA


Supplementary FIGURE S3. GLYCATED HEMOGLOBIN EFFECTIVENESS ANALYSIS

Figure Legend: Glycated hemoglobin (HbA1c) Effectiveness analysis

Data from randomized patients treated with ≥1 dose of study drug who had a baseline and ≥1 postrandomization

HbA1c measurement (modified intent to treat population).

Panel A: HbA1c from baseline to week 52 (EASE-2) or week 26 (EASE-3). Values at baseline are

descriptive data. Values at weeks 4–52 are based on mixed model repeated measures analysis.

Panel B: Placebo-corrected change from baseline in HbA1c at week 26 (EASE-2 and EASE-3) and week

52 (EASE-2). Data are based on mixed model repeated measures analysis. ***p<0.0001 for difference vs

placebo.

SUPPLEMENTARY DATA


Supplementary FIGURE S4. BODY WEIGHT - OVER TIME GRAPHS AND ANALYSES

Figure Legend: Weight analyses

Data are from patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c

measurement.

Panel A: Weight from screening to week 52 (EASE-2) or week 26 (EASE-3). Values at screening and

week 0 are descriptive data. Values at weeks 1–52 are based on mixed model repeated measures analysis.

Panel B: Change from baseline in weight at week 26 (EASE-2 and EASE-3) and week 52 (EASE-2).

Data are based on mixed model repeated measures analysis.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S5. SYSTOLIC BLOOD PRESSURE – OVER TIME GRAPHS

AND ANALYSES

Figure legend: Systolic blood pressure

Data represent patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c

measurement.

Panel A: Systolic blood pressure from baseline to week 52 (EASE-2) or week 26 (EASE-3). Values at

weeks 1–52 are based on mixed model repeated measures analysis.

Panel B: Change from baseline in systolic blood pressure at week 26 (EASE-2 and EASE-3) and week 52

(EASE-2). Data are based on mixed model repeated measures analysis.

SBP, systolic blood pressure.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S6. DIASTOLIC BLOOD PRESSURE – OVER TIME GRAPHS

AND ANALYSES

Figure legend: Diastolic blood pressure


measurement.

Panel A: Diastolic blood pressure from baseline to week 26 (EASE-3) or week 52 (EASE-2). Values at


Panel B: Change from baseline in diastolic blood pressure at week 26 (EASE-3 and EASE-2) and week

52 (EASE-2). Data are based on mixed model repeated measures analysis.

DBP, diastolic blood pressure.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S7. EASE-2 AND EASE-3 CGM-BASED GLUCOSE TIME IN

RANGE AND INTER-QUARTILE ANALYSES

Figure Legend:

Time in target glucose range (>70 to ≤180 mg/dL): Change from baseline in time in target glucose

range at week 26 (EASE-2 and EASE-3) and week 52 (EASE-2). Data are from analysis of covariance

(EASE-2 (26 weeks)) or mixed model repeated measures analysis (EASE-2 (52 weeks) and EASE-3 (26

weeks)) in patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c

measurement.

Continuous glucose monitoring interquartile range: Change from baseline in interquartile range at

week 26 (EASE-2 and EASE-3) and week 52 (EASE-2). Data are from analysis of covariance (EASE-2

(26 weeks)) or mixed model repeated measures analysis (EASE-2 (52 weeks) and EASE-3 (26 weeks)) in

patients treated with ≥1 dose of study drug who had a baseline and ≥1 on-treatment HbA1c measurement.

CGM, continuous glucose monitoring; IQR, interquartile range.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S8. TOTAL DAILY INSULIN DOSE - OVER TIME GRAPHS

AND ANALYSES

Figure legend: Total daily insulin dose


measurement.

Panel A: Total daily insulin dose from screening to week 52 (EASE-2) or week 26 (EASE-3). Values at

screening and week 0 are descriptive data. Values at weeks 4–52 are based on mixed model repeated

measures analysis.

Panel B: Change from baseline in total daily insulin dose at week 26 (EASE-2 and EASE-3) and week 52


SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S9. TOTAL DAILY BASAL INSULIN DOSE - OVER TIME

GRAPHS AND ANALYSES

Figure legend: Total daily basal insulin dose.


measurement.

Panel A: Total daily basal insulin dose from screening to week 52 (EASE-2) or week 26 (EASE-3).

Values at screening and week 0 are descriptive data. Values at weeks 4–52 are based on mixed model

repeated measures analysis.

Panel B: Change from baseline in total daily basal insulin dose at week 26 (EASE-2 and EASE-3) and

week 52 (EASE-2). Data are based on mixed model repeated measures analysis.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S10. TOTAL DAILY BOLUS INSULIN DOSE - OVER TIME

GRAPHS AND ANALYSES

Figure legend: Total daily bolus insulin dose


measurement.

Panel A: Total daily bolus insulin dose from screening to week 52 (EASE-2) or week 26 (EASE-3).

Values at screening and week 0 are descriptive data. Values at weeks 4–52 are based on mixed model

repeated measures analysis.

Panel B: Change from baseline in total daily bolus insulin dose at week 26 (EASE-2 and EASE-3) and

week 52 (EASE-2). Data are based on mixed model repeated measures analysis.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S11. FASTING PLASMA GLUCOSE – OVER TIME GRAPHS

AND ANALYSES

Figure legend: Fasting plasma glucose


measurement.

Panel A: Fasting plasma glucose from baseline to week 26 (EASE-3) or week 52 (EASE-2). Values at


Panel B: Change from baseline in fasting plasma glucose at week 26 (EASE-3 and EASE-2) and week 52


FPG, fasting plasma glucose.

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S12. WAIST CIRCUMFERENCE – OVER TIME GRAPHS AND

ANALYSES

Figure Legend: Waist circumference


measurement.

Panel A: Waist circumference from baseline to week 52 (EASE-2) or week 26 (EASE-3). Values at


Panel B: Change from baseline in waist circumference at week 26 (EASE-2 and EASE-3) and week 52


SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S13. SAFETY ANALYSIS OF HYPOGLYCEMIA DURING

WEEK 1-4 OF TREATMENT

Figure Legend: Hypoglycemia in week 1–4

Investigator-reported symptomatic hypoglycemic adverse events with blood glucose <54 mg/dL and/or

severe hypoglycemic events in week 1-4. Analyses were performed using a negative binomial model in

randomized patients treated with ≥1 dose of study drug

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S14. NET BENEFIT ANALYSIS

Figure Legend: Net patient benefit analysis

Patient net benefit (post-hoc analysis): HbA1c reduction of >0.3%, >0.4% or >0.5% without weight gain,

DKA: Diabetic ketoacidosis or severe hypoglycemia. EASE-3 data up to week 26 are presented for

empagliflozin 2.5 mg and pooled EASE-2 and EASE-3 data up to week 52 are presented for

empagliflozin 10 mg and empagliflozin 25 mg. Data from patients treated with ≥1 dose of study drug who

had a baseline and ≥1 on-treatment HbA1c measurement

SUPPLEMENTARY DATA


SUPPLEMENTARY FIGURE S15. EXPLANATIONS FOR DIFFERENCES IN URINARY

GLUCOSE EXCRETION IN T1D VS T2D

Figure legend:

In T1D vs T2D, an increased state of glucose variability experienced by patients may result at times in

increased glucose load and delivery to the kidneys. In the context of a higher rate of renal filtration

observed in T1D and in conjunction with potential insulin-mediated increases in SGLT2 activity and/or

expression, higher urinary glucose excretion is observed vs T2D (3-6). As such, lower strengths of an

SGLT2 inhibitor in T1D may result in equivalent urinary glucose excretion which would be attained with use of

higher doses of the same molecule in T2D.

SUPPLEMENTARY DATA


SUPPLEMENTARY TABLE S1. CLINICAL CHARACTERISTICS OF ADJUDICATED

CERTAIN KETOACIDOSIS

SUPPLEMENTARY DATA


SUPPLEMENTARY TABLE S2: ANALYSIS OF ADJUDICATED CERTAIN OR POTENTIAL

KETOACIDOSIS BASED ON SEX AND INSULIN THERAPY

SUPPLEMENTARY DATA


REFERENCES FOR SUPPLEMENTARY INFORMATION

1. Sheikh-Ali M, Karon BS, Basu A, Kudva YC, Muller LA, Xu J, Schwenk WF, Miles JM: Can

serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care

2008;31:643-647

2. Guidance for industry - diabetes mellitus: Developing drugs and therapeutic biologics for

treatment and prevention 2008

3. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ,

Johansen OE, Broedl UC, von Eynatten M: Renal hemodynamic effect of sodium-glucose

cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587-597

4. Ghezzi C, Wright EM: Regulation of the human Na+-dependent glucose cotransporter

hSGLT2. Am J Physiol Cell Physiol 2012;303:C348-354

5. Farber SJ, Berger EY, Earle DP: Effect of diabetes and insulin of the maximum capacity of the

renal tubules to reabsorb glucose. J Clin Invest 1951;30:125-129

6. Mondick J, Riggs M, Kaspers S, Soleymanlou N, Marquard J, Nock V: Population

Pharmacokinetic- Pharmacodynamic Analysis to Characterize the Effect of Empagliflozin on

Renal Glucose Threshold in Patients With Type 1 Diabetes Mellitus. J Clin Pharmacol

2018;58:640-649

supplementary data - diabetes care€¦ · supplementary data ©2018 american diabetes association....

Documents