Empagliflozin as Adjunctive to Insulin Therapy Over 26 Weeks in Patients With T1DM (EASE-3)

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02580591
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 977
• Locations: 189
• Arms: 4
• Actual Duration (Months): 21
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The study will investigate the efficacy, safety, tolerability and Pharmacokinetic(PK) of 3 doses of empagliflozin compared with placebo over 26 weeks in 960 patients with type 1 diabetes mellitus as adjunctive therapy to insulin

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Empagliflozin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 977 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• 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 26 Weeks in Patients With Type 1 Diabetes Mellitus (EASE-3)
• Actual Study Start Date: Dec 22, 2015
• Actual Primary Completion Date: Sep 12, 2017
• Actual Study Completion Date: Sep 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Empagliflozin low dose	Drug: Empagliflozin; Drug: Placebo; For blinding purposes
Experimental: Empagliflozin high dose	Drug: Empagliflozin; Drug: Placebo; For blinding purposes
Experimental: Empagliflozin medium dose	Drug: Empagliflozin; Drug: Placebo; For blinding purposes
Placebo Comparator: Placebo	Drug: Placebo; For blinding purposes

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC]) [Baseline to week 26]

   Change from baseline in Glycated hemoglobin (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 randomized trial medication. Least squares mean is adjusted mean change from baseline.

2. Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD)) [Baseline to week 26]

   Change from baseline in Glycated hemoglobin (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 randomized trial medication. Least squares mean is adjusted mean change from baseline.

Secondary Outcome Measures

1. Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) [Week 5 to Week 26, Week 1 to Week 26]

   Rate per patient-year of investigator-reported symptomatic hypoglycemic adverse events (AEs) with confirmed plasma glucose (PG) <54 milligram per deciliter (mg/dL) (<3.0 millimoles per litre (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) 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. This is key secondary endpoints.

2. Change From Baseline in Body Weight at Week 26 [Baseline to week 26]

   Change from baseline in body weight is presented With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.

3. Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26 [Baseline to week 26]

   Change from baseline in Total daily insulin dose (TDID) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.

4. Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 [Baseline to week 26]

   Change from baseline in Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Signed and dated written informed consent

• Male or female patient receiving insulin for the treatment of documented diagnosis of type 1 diabetes mellitus (T1DM) > 1 year

• C-peptide value of < 0.7 ng/mL

• Use of Multiple Daily Injections (MDI) of insulin or insulin pump user with total daily insulin >= 0.3 and <= 1.5 U/kg

• Glycated haemoglobin (HbA1c) >= 7.5% and <= 10.0%

• Good understanding of T1DM

• Age >= 18 years

• Body Mass Index (BMI) >= 18.5 kg/m2

• Estimated glomerular filtration rate >= 30 mL/min/1.73 m2

• Women of child-bearing potential must use highly effective methods of birth control

• Compliance with trial medication administration between 80% and 120% during placebo run-in period Further inclusion criteria apply

Exclusion criteria:

• History of type 2 diabetes mellitus, 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 except subcutaneous basal and bolus insulin within last 3 months

• Occurrence of severe hypoglycaemia within last 3 months and until randomisation

• Occurence of diabetic ketoacidosis within 3 months prior to Visit 1 and until Visit 6

• Irregular sleep/wake cycle

• Acute coronary syndrome, stroke or Transient Ischaemic Attack (TIA) within last 3 months

• Severe gastroparesis

• Brittle diabetes

• Liver disease

• Eating disorders

• Treatment with anti-obesity drugs, weight-loss surgery or aggressive diet regimen

• Treatment with systemic corticosteroids

• Change in dose of thyroid hormones within last 6 weeks and until randomisation

• Cancer or treatment for cancer in the last five years

• Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells

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

• Alcohol or drug abuse

• Intake of an investigational drug in another trial within last 30 days Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Healthscan Clinical Trials LLC	Montgomery	Alabama	United States	36106
2	John Muir Physician Network Clinical Research Center	Concord	California	United States	94520
3	Valley Research	Fresno	California	United States	93720
4	Marin Endocrine Care and Research	Greenbrae	California	United States	94904
5	Pacific Research Partners, LLC	Oakland	California	United States	94607
6	NorCal Endocrinology and Internal Medicine	San Ramon	California	United States	94583
7	William Sansum Diabetes Center	Santa Barbara	California	United States	93105
8	University of Colorado Denver	Aurora	Colorado	United States	80045
9	International Research Associates, LLC	Hialeah	Florida	United States	33012
10	Solutions Through Advanced Research, Inc.	Jacksonville	Florida	United States	32225
11	University of Miami	Miami	Florida	United States	33136
12	Suncoast Clinical Research, Inc.	New Port Richey	Florida	United States	34652
13	Atlanta Diabetes Associates	Atlanta	Georgia	United States	30318
14	Physicians Research Associates, LLC	Lawrenceville	Georgia	United States	30046
15	Sestron Clinical Research	Marietta	Georgia	United States	30060
16	Eagle's Landing Diabetes and Endocrinology	Stockbridge	Georgia	United States	30281
17	Northwest Endo Diabetes Research, LLC	Arlington Heights	Illinois	United States	60005
18	Kentucky Diabetes Endocrinology Center	Lexington	Kentucky	United States	40503
19	University of Maryland School of Medicine	Baltimore	Maryland	United States	21201
20	MODEL Clinical Research	Baltimore	Maryland	United States	21204
21	Clinical Research Consultants, LLC	Kansas City	Missouri	United States	64111
22	Desert Endocrinology Clinical Research Center	Henderson	Nevada	United States	89052
23	Palm Research Center	Las Vegas	Nevada	United States	89128
24	Endocrine-Diabetes Care and Resource Center	Rochester	New York	United States	14607
25	Endocrine Associates of Long Island, PC	Smithtown	New York	United States	11787
26	Diabetes Endocrinology Research Center of Western New York	Williamsville	New York	United States	14221
27	Diabetes and Endocrinology Consultants, PC	Morehead City	North Carolina	United States	28557
28	Holzer Clinic LLC	Gallipolis	Ohio	United States	45631
29	COR Clinical Research, LLC	Oklahoma City	Oklahoma	United States	73103
30	Strand Physician Specialists dba Carolina Health Specialists	Myrtle Beach	South Carolina	United States	29572
31	AM Diabetes and Endocrinology Center	Bartlett	Tennessee	United States	38133
32	Holston Medical Group	Bristol	Tennessee	United States	37620
33	University Diabetes and Endocrine Consultants	Chattanooga	Tennessee	United States	37411
34	Texas Diabetes & Endocrinology PA	Austin	Texas	United States	78749
35	Texas Health Physicians Group	Dallas	Texas	United States	75218
36	Dallas Diabetes and Endocrine Center	Dallas	Texas	United States	75230
37	Research Institute of Dallas	Dallas	Texas	United States	75231
38	Endeavor Clinical Trials, PA	San Antonio	Texas	United States	78229
39	Virginia Endocrinology Research	Chesapeake	Virginia	United States	23321
40	Coffs Endocrine & Diabetes Services	Coffs Harbour	New South Wales	Australia	2450
41	Lyell McEwin Hospital	Elizabeth Vale	South Australia	Australia	5112
42	SA Endocrine Research P/L	Keswick	South Australia	Australia	5035
43	Eastern Clinical Research Unit	East Ringwood	Victoria	Australia	3135
44	Richmond Road and Diagnostic Treatment Centre	Calgary	Alberta	Canada	T2T 5C7
45	The Bailey Clinic	Red Deer	Alberta	Canada	T4N 6V7
46	Eastern Health (MUN)	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
47	Centre for Studies in Family Medicine	London	Ontario	Canada	N6G 2M1
48	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
49	Omnispec Recherche Clinique Inc.	Mirabel	Quebec	Canada	J7J 2K8
50	Applied Medical Informatics Research INC.	Westmount	Quebec	Canada	H3Z 1E5
51	Clinique des maladies Lipidiques de Quebec	Quebec		Canada	G1V 4M6
52	University Hospital Brno	Brno		Czechia	625 00
53	Diahaza s.r.o.Intern.Med.Outpat.Clin.Dep.Diabetology,Holesov	Holesov		Czechia	769 01
54	AIDIN VK s.r.o.,Department Diabetology, Hranice	Hranice		Czechia	753 01
55	Univ. Hospital Kralovske Vinohrady	Prague		Czechia	100 42
56	DiaGolfova s.r.o., Department Diabetology, Prague	Prague		Czechia	102 00
57	Milan Kvapil s.r.o.,Diabetology ambulance,Prague	Prague		Czechia	149 00
58	ResTrial s.r.o.Diabetology Ambulance,Prague	Prague		Czechia	18100
59	HUS, Lihavuustutkimusyksikkö Biomedicum Helsinki	Helsinki		Finland	00290
60	Mehiläinen Jyväskylä	Jyväskylä		Finland	40100
61	Satakunnan Diabetesasema, Pori	Pori		Finland	28100
62	FinnMedi Oy, Tampere	Tampere		Finland	33520
63	TYKS	Turku		Finland	FI-20520
64	HOP Jean Minjoz	Besancon		France	25030
65	HOP Le Creusot	Le Creusot		France	71200
66	HOP Paris Saint-Joseph	Paris		France	75014
67	HOP Bichat	Paris		France	75018
68	HOP de Poitiers	Poitiers		France	86021
69	HOP Civil	Strasbourg		France	67091
70	HOP Rangueil	Toulouse Cédex 04		France	31059
71	Diabetes-Klinik Bad Mergentheim GmbH & Co. KG	Bad Mergentheim		Germany	97980
72	Diabetologische Schwerpunktpraxis, Bosenheim	Bosenheim		Germany	55545
73	Praxis Dr. Busch, Dortmund	Dortmund		Germany	44137
74	GWT-TUD GmbH	Dresden		Germany	01307
75	ZKS Südbrandenburg GmbH	Elsterwerda		Germany	04910
76	InnoDiab Forschung GmbH	Essen		Germany	45136
77	Praxis Dr. Kaiser, Frankfurt	Frankfurt		Germany	60388
78	Institut für Diabetesforschung Münster GmbH	Münster		Germany	48145
79	Diabetologische Schwerpunktpraxis	Münster		Germany	48153
80	Praxis Dr. Behnke, Neuwied	Neuwied		Germany	56564
81	Praxis Dr. Hilgenberg	Rehburg-Loccum		Germany	31547
82	"Korgialeneio-Benakeio" Hellenic Red Cross Hospital	Athens		Greece	115 26
83	General Hospital of Athens "Laiko"	Athens		Greece	11527
84	Univ. Gen. Hosp. of Ioannina	Ioannina		Greece	45500
85	General Hospital of Nikaia	Nikaia		Greece	18484
86	General Hopsital of Thessaloniki "Ippokrateio"	Thessaloniki		Greece	54642
87	General Hospital of Thessaloniki "G. Papanikolaou"	Thessaloniki		Greece	57010
88	Clinexpert Kft.	Budapest		Hungary	1033
89	Synexus Magyarorszag Kft.	Budapest		Hungary	1036
90	University Debrecen Hospital	Debrecen		Hungary	4032
91	CRU Hungary Ltd, Private Practice, Miskolc	Miskolc		Hungary	3529
92	Clinfan SMO Ltd.	Szekszard		Hungary	7100
93	Csongrad Country Dr Bugyi Istvan Hosp.	Szentes		Hungary	6600
94	Zala Country Hospital, Diabetic Outpatient Clinic	Zalaegerszeg		Hungary	8900
95	Mater Misericordiae University Hospital	Dublin		Ireland	7
96	Inrca-Irccs	Ancona		Italy	60124
97	A.O. Spedali Civili di Brescia	Brescia		Italy	25123
98	Osp. Campo di Marte	Lucca		Italy	55100
99	Azienda Ospedaliera Universitaria "Federico II"	Napoli		Italy	80131
100	Policlinico Gemelli	Roma		Italy	00168
101	Osp. S. Giovanni Calibita Fatebenefratelli	Roma		Italy	00186
102	IRCCS Gruppo Multimedica	Sesto San Giovanni (MI)		Italy	20099
103	A.O.U. Senese Policlinico Santa Maria alle Scotte	Siena		Italy	53100
104	Ospedale Molinette, AO Città della Salute e della	Torino		Italy	10126
105	Zemgales Center of diabetes, Jelgava	Jelgava		Latvia	3001
106	A. Lucenko's Internist & Endocrinologist Doctor's Practice	Liepaja		Latvia	3401
107	Dace Teterovska Doctor's Practice in Endocrinology,Ogre	Ogre		Latvia	5001
108	P. Stradins Clinical University Hospital, Riga	Riga		Latvia	1002
109	Riga Health Center, Private Practice	Riga		Latvia	1002
110	Sigulda Hospital, Outpatient department	Sigulda		Latvia	2150
111	VSV Centrs, Stalte Private Practice, Talsi	Talsi		Latvia	3201
112	Clínica EndocrInol en Diabetes Obesidad y Tiroides (DOT)	Aguascalientes		Mexico	20129
113	Hospital Cardiologica Aguascalientes	Aguascalientes		Mexico	20230
114	Unidad de Investigacion Clinica Cardiometabolica de Occident	Guadalajara		Mexico	44150
115	Instituto Jaliscience de Inv. en Diabetes y Obesidad, S.C.	Guadalajara		Mexico	44600
116	Unidad de Patologia Clinica	Guadalajara		Mexico	CP 44650
117	Noordwest Ziekenhuisgroep	Alkmaar		Netherlands	1815 JD
118	Ziekenhuisgroep Twente locatie Almelo	Almelo		Netherlands	7609 PP
119	Meander Medisch Centrum	Amersfoort		Netherlands	3813 TZ
120	Gelre Ziekenhuizen Apeldoorn	Apeldoorn		Netherlands	7334 DZ
121	EB Utrecht Research	Utrecht		Netherlands	3511 NH
122	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584 CX
123	South Pacific Clinical Trials	Auckland, New Zealand		New Zealand	0610
124	Lipid and Diabetes Research Group	Christchurch		New Zealand	8011
125	M3 Helse AS	Hamar		Norway	N-2317
126	Oslo Universitetssykehus HF, Lipidklinikken	Oslo		Norway	N-0027
127	Stavanger Helseforskning	Stavanger		Norway	N-4068
128	Universitetssykehuset Nord-Norge, Tromsø	Tromsø		Norway	N-9038
129	DiabSerwis S.C., Chorzow	Chorzow		Poland	41-500
130	Medical Centre Pratia Gdynia	Gdynia		Poland	81-338
131	Medical Centre Pratia Katowice I	Katowice		Poland	40-954
132	Medical Centre Pratia Krakow	Krakow		Poland	30-002
133	University Hospital in Krakow	Krakow		Poland	31-501
134	Independent Public Clin.Hosp.no1Lublin,Dep.Internal Diseases	Lublin		Poland	20-081
135	Witold Chodzko Institute Rural Medic,Dep.Diabetology,Lublin	Lublin		Poland	20-090
136	Reg.Spec.Hosp.Olsztyn,Clin,Endocrinology,Diabetics.&Int.Med.	Olsztyn		Poland	10-561
137	Clinical Research Center Medicome, Oswiecim	Oswiecim		Poland	32-600
138	Omedica Medical Centre, Poznan	Poznan		Poland	60-111
139	Medical Centre Pratia Warszawa	Warsaw		Poland	01-868
140	NZOZ Med-Art.Specialist Clinics, Zory	Zory		Poland	44-240
141	Hospital de Braga-Escala Braga	Braga		Portugal	4710-243
142	Centro Hospitalar da Cova da Beira Hospital Pêro da Covilhã	Covilhã		Portugal	6200-251
143	APDP - Associação Protectora dos Diabéticos de Portugal	Lisboa		Portugal	1250-189
144	H. Santo António - Centro Hospitalar do Porto	Porto		Portugal	4099-001
145	Centro Hospitalar São João,EPE	Porto		Portugal	4200-319
146	ULSAM, EPE - Hospital de Santa Luzia	Viana do Castelo		Portugal	4901-858
147	Centro Hospitalar de Vila Nova de Gaia	Vila Nova de Gaia		Portugal	4400-129
148	Nicodiab SRL, Bucharest	Bucharest		Romania	010507
149	Milit. Cent. Emerg. Univ. Hosp. Dr. Davila, Met. Dis. Dept.	Bucharest		Romania	010825
150	SC Medical Centre "Sanatatea Ta" SRL, Bucharest	Bucharest		Romania	020603
151	SC Pelican Impex SRL, Cabinet Nr. 201, Diabetes Dept.	Oradea, Bihor County		Romania	410469
152	Centrul Medical Dr Negrisanu SRL	Timisoara		Romania	300456
153	City Clinical Hospital no. 67, Moscow	Moscow		Russian Federation	123423
154	CJSC"Polyclinic complex",Dep.Endocrinology,St.Petersburg	St. Petersburg		Russian Federation	190013
155	City Outpatient dep.no.107;clinc.pharmacology,st.petersburg	St. Petersburg		Russian Federation	195030
156	Medical Academy named after I. Mechnikov, St. Petersburg	St. Petersburg		Russian Federation	195067
157	City Hospital Saint Elizaveta, Dept. Endocrinology	St. Petersburg		Russian Federation	195257
158	Policlinic No. 1 of Russian Academy of Sciences, St. Petersburg	St. Petersburg		Russian Federation	199034
159	LCS Clinical Research Unit	Bryanston		South Africa	2021
160	TREAD Research	Cape Town		South Africa	7530
161	Dr Hilton Kaplan	Cape Town		South Africa	7708
162	Dr. L. A.Distiller	Johannesburg		South Africa	2198
163	VX Pharma (Pty) Ltd Pretoria	Pretoria		South Africa	0087
164	Diabetes Care Centre	Pretoria		South Africa	0181
165	Hospital A Coruña	A Coruña		Spain	15006
166	CM Avances Médicos	Granada		Spain	18003
167	Hospital de la Inmaculada Concepción	Granada		Spain	18004
168	Hospital General Universitario Gregorio Marañón	Madrid		Spain	28007
169	Hospital Universitario Infanta Leonor	Madrid		Spain	28031
170	Endo-Diabesidad-Clínica Durán & Asociados	Sevilla		Spain	41018
171	Hospital Virgen Macarena	Sevilla		Spain	41071
172	Hospital Clínico de Valencia	Valencia		Spain	46010
173	CTC Sahlgrenska Universitetssjukhuset	Göteborg		Sweden	413 45
174	Karlskoga lasarett	Karlskoga		Sweden	691 81
175	Skånes universitetssjukhus, Lund	Lund		Sweden	221 85
176	S3 Clinical Research Centers	Vällingby		Sweden	162 68
177	Ängelholms Sjukhus	Ängelholm		Sweden	262 81
178	Royal Bournemouth and Christchurch Hospital	Bournemouth		United Kingdom	BH7 7DW
179	Bradford Royal Infirmary	Bradford		United Kingdom	BD9 6RJ
180	Hull Royal Infirmary	Hull		United Kingdom	HU3 2RW
181	Ipswich Hospital	Ipswich		United Kingdom	IP4 5PD
182	Leicester General Hospital	Leicester		United Kingdom	LE5 4PW
183	Guy's Hospital	London		United Kingdom	SE1 9RT
184	King's College Hospital	London		United Kingdom	SE5 9RJ
185	St Mary's Hospital	London		United Kingdom	W2 1NY
186	James Cook University Hospital	Middlesbrough		United Kingdom	TS4 3BW
187	Royal Victoria Infirmary	Newcastle Upon Tyne		United Kingdom	NE1 4LP
188	Queen's Medical Centre	Nottingham		United Kingdom	NG7 2UH
189	George Eliot Hospital	Nuneaton		United Kingdom	CV10 7DJ

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Oct 21, 2016
• Statistical Analysis Plan - Oct 11, 2017

More Information

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02580591
• Other Study ID Numbers: 1245.72; 2014-005256-26
• First Posted: Oct 20, 2015
• Last Update Posted: Nov 2, 2018
• Last Verified: Oct 1, 2018

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Empagliflozin

Study Results

Participant Flow

Recruitment Details	A randomized, placebo-controlled, double-blind, parallel-group study compared 3 doses of empagliflozin (2.5 milligram (mg), 10 mg, and 25 mg) with placebo in patients with type 1 diabetes mellitus (T1DM) as adjunctive to optimized insulin therapy.
Pre-assignment Detail	6-Week T1DM therapy (insulin) optimisation period followed by a 2-Week placebo run-in period before randomization. Patients who successfully completed both of the periods were randomized into the 26-Week double-blind treatment period. All treatments were administered in addition to optimized insulin therapy.

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 2.5 Milligram (mg)	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Period Title: Overall Study
STARTED	242	242	248	245
Treated	241	241	248	245
COMPLETED	224	232	235	233
NOT COMPLETED	18	10	13	12

Baseline Characteristics

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 2.5 Milligram (mg)	Empagliflozin 10 mg	Empagliflozin 25 mg	Total
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Total of all reporting groups
Overall Participants	242	242	248	245	977
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	42.3 (13.2)	43.4 (14.3)	42.3 (13.2)	44.4 (13.6)	43.1 (13.6)
Sex: Female, Male (Count of Participants)
Female	126 52.1%	120 49.6%	132 53.2%	121 49.4%	499 51.1%
Male	116 47.9%	122 50.4%	116 46.8%	124 50.6%	478 48.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	215 88.8%	220 90.9%	233 94%	224 91.4%	892 91.3%
Not Hispanic or Latino	27 11.2%	22 9.1%	15 6%	21 8.6%	85 8.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	7 2.9%	0 0%	1 0.4%	5 2%	13 1.3%
Asian	2 0.8%	2 0.8%	2 0.8%	5 2%	11 1.1%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	0 0%	0 0%	1 0.1%
Black or African American	5 2.1%	3 1.2%	10 4%	4 1.6%	22 2.3%
White	227 93.8%	234 96.7%	234 94.4%	231 94.3%	926 94.8%
More than one race	0 0%	3 1.2%	1 0.4%	0 0%	4 0.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC])
Description	Change from baseline in Glycated hemoglobin (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 randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time Frame	Baseline to week 26

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) (observed cases [OC]): Patients in the Treated Set (TS) who had a baseline and at least 1 on-treatment HbA1c measurement.

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 2.5 Milligram (mg)	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Measure Participants	238	237	244	242
Least Squares Mean (Standard Error) [Percentage (%)]	0.20 (0.05)	-0.09 (0.05)	-0.25 (0.05)	-0.33 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 2.5 Milligram (mg)
	Comments	Model includes baseline HbA1c, baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 99%; -0.46 to -0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments	Mean Difference= Empagliflozin 2.5 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.45
	Confidence Interval	(2-Sided) 97.5%; -0.60 to -0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 97.5%; -0.68 to -0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

2. Primary Outcome

Title	Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD))
Description	Change from baseline in Glycated hemoglobin (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 randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time Frame	Baseline to week 26

Outcome Measure Data

Analysis Population Description

Modified intention-to-treat set (mITT) (observed case - all data [OC-AD]): Patients in the TS who had a baseline and at least 1 post-baseline HbA1c measurement.

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 2.5 Milligram (mg)	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Measure Participants	239	239	246	245
Least Squares Mean (Standard Error) [Percentage (%)]	0.21 (0.05)	-0.06 (0.05)	-0.23 (0.05)	-0.30 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 2.5 Milligram (mg)
	Comments	Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments	Mean Difference= Empagliflozin 2.5 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 97.5%; -0.59 to -0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments	Mean Difference= Empagliflozin 2.5 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 97.5%; -0.66 to -0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

3. Secondary Outcome

Title	Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG)
Description	Rate per patient-year of investigator-reported symptomatic hypoglycemic adverse events (AEs) with confirmed plasma glucose (PG) <54 milligram per deciliter (mg/dL) (<3.0 millimoles per litre (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) 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. This is key secondary endpoints.
Time Frame	Week 5 to Week 26, Week 1 to Week 26

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 2.5 Milligram (mg)	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Measure Participants	235	237	241	237
Week 5 to 26	6.13	5.77	7.37	6.25
Week 1 to 26	6.62	6.17	8.33	6.96

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 2.5 Milligram (mg)
	Comments	For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	0.940
	Confidence Interval	(2-Sided) 95%; 0.673 to 1.314
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin 2.5 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2752
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	1.202
	Confidence Interval	(2-Sided) 97.75%; 0.818 to 1.766
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin 10 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9077
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	1.020
	Confidence Interval	(2-Sided) 97.75%; 0.693 to 1.501
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin 25 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 2.5 Milligram (mg)
	Comments	For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	0.932
	Confidence Interval	(2-Sided) 95%; 0.682 to 1.274
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1438
	Comments	This is a nominal p-value.
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	1.258
	Confidence Interval	(2-Sided) 95%; 0.925 to 1.713
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin 10 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7543
	Comments	This is a nominal p-value.
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	1.051
	Confidence Interval	(2-Sided) 95%; 0.771 to 1.433
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin 25 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate.

4. Secondary Outcome

Title	Change From Baseline in Body Weight at Week 26
Description	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 randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time Frame	Baseline to week 26

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 2.5 Milligram (mg)	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Measure Participants	238	237	243	240
Least Squares Mean (Standard Error) [Kilogram (kg)]	0.21 (0.20)	-1.55 (0.20)	-2.83 (0.20)	-3.22 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 2.5 Milligram (mg)
	Comments	Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.76
	Confidence Interval	(2-Sided) 95%; -2.32 to -1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 2.5 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.04
	Confidence Interval	(2-Sided) 99.75%; -3.91 to -2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.43
	Confidence Interval	(2-Sided) 99.75%; -4.30 to -2.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

5. Secondary Outcome

Title	Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26
Description	Change from baseline in Total daily insulin dose (TDID) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time Frame	Baseline to week 26

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 2.5 Milligram (mg)	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Measure Participants	217	223	217	220
Least Squares Mean (Standard Error) [Unit/kilogram (U/kg)]	-0.011 (0.007)	-0.060 (0.007)	-0.080 (0.007)	-0.102 (0.007)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 2.5 Milligram (mg)
	Comments	Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.049
	Confidence Interval	(2-Sided) 95%; -0.069 to -0.030
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 2.5 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.070
	Confidence Interval	(2-Sided) 99.75%; -0.101 to -0.039
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.091
	Confidence Interval	(2-Sided) 99.75%; -0.122 to -0.060
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.010
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

6. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26
Description	Change from baseline in Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time Frame	Baseline to week 26

Outcome Measure Data

Analysis Population Description

FAS observed cases excluding data after change in use of anti-hypertensives (OC-H)

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 2.5 Milligram (mg)	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.	Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
Measure Participants	237	236	240	238
SBP	0.4 (0.7)	-1.7 (0.7)	-3.5 (0.7)	-3.4 (0.7)
DBP	0.0 (0.4)	-0.4 (0.4)	-1.8 (0.4)	-1.5 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 2.5 Milligram (mg)
	Comments	For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -3.9 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 2.5 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, , treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.9
	Confidence Interval	(2-Sided) 99.75%; -6.8 to -1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 99.75%; -6.6 to -0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 2.5 Milligram (mg)
	Comments	For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -1.5 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 2.5 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, ß, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0047
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 99.75%; -3.6 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 2.5 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, ß, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0202
	Comments
	Method	Mixed effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 99.75%; -3.3 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From the first dose of trial medication until 7 days after last in-take of trial medication, up to 232 days.
Adverse Event Reporting Description	Treated set (TS): All patients who were treated with at least one dose of randomised trial medication, the TS was the basis for safety analyses. The Total Number of Participants at Risk is based on Treated set.
Arm/Group Title	Placebo Matching Empagliflozin		Empagliflozin 2.5 Milligram (mg)		Empagliflozin 10 mg		Empagliflozin 25 mg
Arm/Group Description	Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.		Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.		Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.		Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
All Cause Mortality
	Placebo Matching Empagliflozin		Empagliflozin 2.5 Milligram (mg)		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Serious Adverse Events
	Placebo Matching Empagliflozin		Empagliflozin 2.5 Milligram (mg)		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/241 (6.6%)		13/241 (5.4%)		21/248 (8.5%)		16/245 (6.5%)
Cardiac disorders
Acute myocardial infarction	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Angina unstable	0/241 (0%)		2/241 (0.8%)		0/248 (0%)		0/245 (0%)
Cardiac arrest	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Ear and labyrinth disorders
Vertigo	1/241 (0.4%)		0/241 (0%)		0/248 (0%)		0/245 (0%)
Vestibular disorder	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Eye disorders
Eye haemorrhage	1/241 (0.4%)		0/241 (0%)		0/248 (0%)		0/245 (0%)
Retinopathy haemorrhagic	1/241 (0.4%)		0/241 (0%)		0/248 (0%)		0/245 (0%)
Gastrointestinal disorders
Abdominal pain	0/241 (0%)		0/241 (0%)		2/248 (0.8%)		0/245 (0%)
Colitis	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Diarrhoea	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Gastritis	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Nausea	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Pancreatolithiasis	1/241 (0.4%)		0/241 (0%)		0/248 (0%)		0/245 (0%)
Vomiting	0/241 (0%)		0/241 (0%)		2/248 (0.8%)		1/245 (0.4%)
General disorders
Chest pain	1/241 (0.4%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Infections and infestations
Appendicitis	1/241 (0.4%)		0/241 (0%)		0/248 (0%)		0/245 (0%)
Gangrene	0/241 (0%)		1/241 (0.4%)		0/248 (0%)		0/245 (0%)
Gastroenteritis	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
H1N1 influenza	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Meningitis viral	1/241 (0.4%)		0/241 (0%)		0/248 (0%)		0/245 (0%)
Pneumonia	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Sinusitis	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Injury, poisoning and procedural complications
Hand fracture	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Humerus fracture	0/241 (0%)		1/241 (0.4%)		0/248 (0%)		0/245 (0%)
Joint dislocation	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Investigations
Anion gap increased	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Blood bicarbonate increased	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Blood gases abnormal	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Blood glucose decreased	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Blood glucose increased	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Blood ketone body increased	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Blood potassium increased	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Hepatic enzyme increased	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Urine ketone body present	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Metabolism and nutrition disorders
Acetonaemia	0/241 (0%)		1/241 (0.4%)		1/248 (0.4%)		0/245 (0%)
Dehydration	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Diabetic ketoacidosis	2/241 (0.8%)		2/241 (0.8%)		6/248 (2.4%)		5/245 (2%)
Diabetic ketosis	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Euglycaemic diabetic ketoacidosis	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Hyperglycaemia	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Hypoglycaemia	4/241 (1.7%)		3/241 (1.2%)		3/248 (1.2%)		0/245 (0%)
Ketoacidosis	1/241 (0.4%)		1/241 (0.4%)		3/248 (1.2%)		2/245 (0.8%)
Ketosis	0/241 (0%)		1/241 (0.4%)		0/248 (0%)		3/245 (1.2%)
Metabolic disorder	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anogenital warts	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Basal cell carcinoma	2/241 (0.8%)		1/241 (0.4%)		0/248 (0%)		0/245 (0%)
Vaginal cancer stage 0	0/241 (0%)		1/241 (0.4%)		0/248 (0%)		0/245 (0%)
Nervous system disorders
Demyelination	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Disturbance in attention	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Psychiatric disorders
Anxiety	1/241 (0.4%)		0/241 (0%)		0/248 (0%)		0/245 (0%)
Major depression	1/241 (0.4%)		0/241 (0%)		0/248 (0%)		0/245 (0%)
Renal and urinary disorders
Acute kidney injury	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Reproductive system and breast disorders
Endometriosis	0/241 (0%)		0/241 (0%)		1/248 (0.4%)		0/245 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory arrest	0/241 (0%)		0/241 (0%)		0/248 (0%)		1/245 (0.4%)
Other (Not Including Serious) Adverse Events
	Placebo Matching Empagliflozin		Empagliflozin 2.5 Milligram (mg)		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	153/241 (63.5%)		146/241 (60.6%)		172/248 (69.4%)		162/245 (66.1%)
Infections and infestations
Nasopharyngitis	24/241 (10%)		23/241 (9.5%)		22/248 (8.9%)		26/245 (10.6%)
Urinary tract infection	12/241 (5%)		12/241 (5%)		9/248 (3.6%)		16/245 (6.5%)
Investigations
Blood ketone body increased	3/241 (1.2%)		4/241 (1.7%)		15/248 (6%)		10/245 (4.1%)
Metabolism and nutrition disorders
Hypoglycaemia	144/241 (59.8%)		137/241 (56.8%)		162/248 (65.3%)		151/245 (61.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.