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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02414958
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 730
• Locations: 131
• Arms: 3
• Actual Duration (Months): 27.8
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 730 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 52 Weeks in Patients With Type 1 Diabetes Mellitus (EASE-2)
• Actual Study Start Date: Jun 30, 2015
• Actual Primary Completion Date: Apr 20, 2017
• Actual Study Completion Date: Oct 23, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 [Baseline to week 26]

   Change from baseline in glycated haemoglobin (HbA1c) for full analysis set (FAS) (observed cases [OC]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects.

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

   Change from baseline in glycated haemoglobin (HbA1c) for modified intention-to-treat population set (mITT) (observed case - all data [OC-AD]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects.

Secondary Outcome Measures

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

   This is a key secondary endpoint. Rate per patient-year of investigator-reported symptomatic hypoglycaemia adverse events (AEs) with confirmed plasma glucose (PG) <54 milligram per deciliter (mg/dL) (<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycaemia AEs (i.e. all investigator-reported AEs that had confirmed PG <54 mg/dL [<3.0 mmol/L] with symptoms reported and all severe hypoglycaemia events that were confirmed by adjudication) is presented for (i) From week 5 to 26 and (ii) From week 1 to 26. Least squares mean is actually an adjusted event rate.

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 randomised trial medication. Least squares mean is adjusted mean change from baseline.

3. Change From Baseline in Percentage of Time Spent in Target Glucose Range From Weeks 23 to 26 [Week 23 to 26]

   Change from baseline in the percentage of time spent in target glucose range of >70 to ≤180 mg/dL (>3.9 to ≤10.0 mmol/L) as determined by continuous glucose monitoring (CGM) is presented in week 23 to 26. Least squares mean is actually an adjusted event rate.

4. Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 23 to 26 [Week 23 to 26]

   Change from baseline in interstitial glucose variability based on the IQR as determined by CGM is presented for week 23 to 26. Least squares mean is actually an adjusted event rate.

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

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

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

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

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Male or female patient receiving insulin for the treatment of documented diagnosis of Type 1 Diabetes Mellitus (T1DM) for at least 1 year at the time of Visit 1

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

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

• Multiple Daily Injections (MDI) of insulin consisting of at least one basal insulin injection and at least three daily bolus injections OR

• Continuous Subcutaneous Insulin Infusion (CSII) of any insulin type, with at least 5 months experience of using CSII prior to Visit 1

• HbA1c >/= 7.5% and </= 10.0% at Visit 5 measured by the central laboratory

• Age >/= 18 years at Visit 1

Additional inclusion criteria may apply

Exclusion criteria:

• History of Type 2 Diabetes Mellitus (T2DM), maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis

• Pancreas, pancreatic islet cells or renal transplant recipient

• T1DM treatment with any other antihyperglycaemic drug (e.g. metformin, alpha-glucosidase inhibitors, Glucagon-like-peptide 1 (GLP-1) analogues, Sodium-Glucose Co-Transporter (SGLT-2) inhibitors, pramlintide, inhaled insulin, pre-mixed insulins etc.) except subcutaneous basal and bolus insulin within 3 months prior to Visit 1

• Occurrence of severe hypoglycaemia involving coma/unconsciousness and/or seizure that required hospitalisation or hypoglycaemia-related treatment by an emergency physician or paramedic within 3 months prior to Visit 1 and until randomisation

• Occurence of Diabetic Ketoacidosis (DKA) within 3 months prior to Visit 1 and until randomisation

Additional exclusion criteria may apply

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Jan 4, 2017
• Statistical Analysis Plan - Nov 8, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02414958
• Other Study ID Numbers: 1245.69; 2014-001922-14
• First Posted: Apr 13, 2015
• Last Update Posted: Jan 3, 2019
• Last Verified: Dec 1, 2018

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

Study Results

Participant Flow

Recruitment Details	Randomised, double-blind, placebo-controlled, parallel group, 52-week trial comparing 2 oral once daily doses (10 mg and 25 mg) of empagliflozin with placebo in patients with type 1 diabetes mellitus (T1DM), each as adjunctive to optimised insulin therapy.
Pre-assignment Detail	6-week T1DM therapy (insulin) optimisation period followed by a 2-week placebo run-in period before randomisation. Patients who successfully completed both of the periods were randomised into the 52-week double-blind treatment period. All treatments were administered in addition to optimised insulin therapy.

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Period Title: Overall Study
STARTED	243	243	244
COMPLETED	211	223	230
NOT COMPLETED	32	20	14

Baseline Characteristics

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 10 mg	Empagliflozin 25 mg	Total
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Total of all reporting groups
Overall Participants	243	243	244	730
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.2 (13.6)	45.7 (12.5)	45.3 (14.0)	45.0 (13.4)
Sex: Female, Male (Count of Participants)
Female	133 54.7%	125 51.4%	131 53.7%	389 53.3%
Male	110 45.3%	118 48.6%	113 46.3%	341 46.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 2.9%	4 1.6%	6 2.5%	17 2.3%
Not Hispanic or Latino	236 97.1%	239 98.4%	238 97.5%	713 97.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	7 2.9%	6 2.5%	10 4.1%	23 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.4%	0 0%	1 0.1%
Black or African American	7 2.9%	6 2.5%	4 1.6%	17 2.3%
White	227 93.4%	230 94.7%	230 94.3%	687 94.1%
More than one race	2 0.8%	0 0%	0 0%	2 0.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26
Description	Change from baseline in glycated haemoglobin (HbA1c) for full analysis set (FAS) (observed cases [OC]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects.
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; the FAS was the basis for the primary efficacy analysis

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Measure Participants	243	243	244
Least Squares Mean (Standard Error) [Percentage (%)]	0.09 (0.04)	-0.44 (0.04)	-0.44 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	Model Mixed effect Model Repeated Measures (MMRM) included the fixed categorical effects of treatment, pre-existing insulin therapy, visit , and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline estimated glomerular filtration rate (eGFR), and baseline HbA1c-by- visit interaction. Patient was 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 Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.54
	Confidence Interval	(2-Sided) 97.5%; -0.66 to -0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	Model MMRM included the fixed categorical effects of treatment, pre-existing insulin therapy, visit, and treatment-by- visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, and baseline HbA1c-by- visit interaction. Patient was 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	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 97.5%; -0.66 to -0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean

2. Primary Outcome

Title	Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD) )
Description	Change from baseline in glycated haemoglobin (HbA1c) for modified intention-to-treat population set (mITT) (observed case - all data [OC-AD]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects.
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 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Measure Participants	243	243	244
Least Squares Mean (Standard Error) [Percentage (%)]	0.09 (0.04)	-0.43 (0.04)	-0.42 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	Model MMRM 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	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 97.5%; -0.65 to -0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.06
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	Model MMRM 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	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 97.5%; -0.64 to -0.39
	Parameter Dispersion	Type: Value:
	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 Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG)
Description	This is a key secondary endpoint. Rate per patient-year of investigator-reported symptomatic hypoglycaemia adverse events (AEs) with confirmed plasma glucose (PG) <54 milligram per deciliter (mg/dL) (<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycaemia AEs (i.e. all investigator-reported AEs that had confirmed PG <54 mg/dL [<3.0 mmol/L] with symptoms reported and all severe hypoglycaemia events that were confirmed by adjudication) is presented for (i) From week 5 to 26 and (ii) From week 1 to 26. Least squares mean is actually an adjusted event rate.
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 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Measure Participants	243	243	244
Week 5 to 26	8.92	6.64	6.48
Week 1 to 26	9.13	7.07	7.15

Statistical Analysis 1

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 hypoglycaemia, baseline HbA1c, and baseline 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	0.0623
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	0.744
	Confidence Interval	(2-Sided) 97.75%; 0.518 to 1.069
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin 10 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate.

Statistical Analysis 2

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 hypoglycaemia, baseline HbA1c, and baseline 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	0.0480
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	0.726
	Confidence Interval	(2-Sided) 97.75%; 0.502 to 1.501
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin 25 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate.

Statistical Analysis 3

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 hypoglycaemia, baseline HbA1c, and baseline 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	0.0972
	Comments	This is a nominal p-value.
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	0.774
	Confidence Interval	(2-Sided) 95%; 0.572 to 1.048
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin 10 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate.

Statistical Analysis 4

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 hypoglycaemia, baseline HbA1c, and baseline 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	0.1180
	Comments	Negative binomial model
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Adjusted Rate Ratio (%)
	Estimated Value	0.782
	Confidence Interval	(2-Sided) 97.75%; 0.575 to 1.064
	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 randomised 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 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Measure Participants	243	243	244
Least Squares Mean (Standard Error) [Kilogram (kg)]	-0.10 (0.21)	-2.79 (0.20)	-3.37 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	Model MMRM includes baseline weight, baseline 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	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.69
	Confidence Interval	(2-Sided) 99.75%; -3.57 to -1.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.29
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	Model MMRM includes baseline weight, baseline 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	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.27
	Confidence Interval	(2-Sided) 99.75%; -4.15 to -2.39
	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 Percentage of Time Spent in Target Glucose Range From Weeks 23 to 26
Description	Change from baseline in the percentage of time spent in target glucose range of >70 to ≤180 mg/dL (>3.9 to ≤10.0 mmol/L) as determined by continuous glucose monitoring (CGM) is presented in week 23 to 26. Least squares mean is actually an adjusted event rate.
Time Frame	Week 23 to 26

Outcome Measure Data

Analysis Population Description

FAS observed cases excluding data after use of paracetamol (OC-P)

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Measure Participants	243	243	244
Least Squares Mean (Standard Error) [Percentage of time]	-1.13 (0.72)	10.73 (0.71)	11.74 (0.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	The analysis of covariance (ANCOVA) model includes baseline time in the target range, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.86
	Confidence Interval	(2-Sided) 99.75%; 8.78 to 14.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	12.87
	Confidence Interval	(2-Sided) 99.75%; 9.81 to 15.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.01
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean

6. Secondary Outcome

Title	Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 23 to 26
Description	Change from baseline in interstitial glucose variability based on the IQR as determined by CGM is presented for week 23 to 26. Least squares mean is actually an adjusted event rate.
Time Frame	Week 23 to 26

Outcome Measure Data

Analysis Population Description

FAS observed cases excluding data after use of paracetamol (OC-P)

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Measure Participants	243	243	244
Least Squares Mean (Standard Error) [milligrams (mg)/ deciliter (dL)]	1.62 (1.21)	-15.30 (1.18)	-17.41 (1.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	The analysis of covariance (ANCOVA) model includes model includes baseline IQR of glucose, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.92
	Confidence Interval	(2-Sided) 99.75%; -22.04 to -11.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.68
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	The analysis of covariance (ANCOVA) model includes model includes baseline IQR of glucose, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.04
	Confidence Interval	(2-Sided) 99.75%; -24.13 to -13.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.68
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

FAS (OC)

Arm/Group Title	Placebo Matching Empagliflozin	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Measure Participants	243	243	244
Least Squares Mean (Standard Error) [Unit/kilogram (U/kg)]	-0.010 (0.007)	-0.102 (0.007)	-0.100 (0.007)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	Model MMRM includes baseline total daily insulin dose, baseline estimated 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	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.092
	Confidence Interval	(2-Sided) 99.75%; -0.121 to -0.063
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.009
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	Model MMRM includes baseline total daily insulin dose, baseline estimated 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	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.090
	Confidence Interval	(2-Sided) 99.75%; -0.119 to -0.062
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.009
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

8. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26
Description	Change from baseline in SBP and DBP is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline.
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 10 mg	Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks	Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.	Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
Measure Participants	243	243	244
SBP	-0.8 (0.7)	-2.9 (0.7)	-4.5 (0.7)
DBP	-0.3 (0.5)	-1.6 (0.5)	-2.6 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	For SBP, the model MMRM includes baseline SBP seated, baseline estimated 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	0.0397
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 99.75%; -5.2 to 1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.0
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	For SBP, the model includes baseline SBP seated, baseline estimated 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	0.0003
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 99.75%; -6.8 to -0.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.0
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 10 mg
	Comments	For DBP, the model MMRM includes baseline DBP seated, baseline 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	0.0457
	Comments	Nominal p-value
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 99.75%; -2.7 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7
	Estimation Comments	Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Empagliflozin, Empagliflozin 25 mg
	Comments	For DBP, the model MMRM includes baseline DBP seated, baseline estimated 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	0.0006
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 99.75%; -4.3 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7
	Estimation Comments	Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

Adverse Events

Time Frame	From the first dose of trial medication until 7 days after last in-take of trial medication, up to 422 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 10 mg		Empagliflozin 25 mg
Arm/Group Description	Patients administered placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimised insulin therapy for 52 weeks.		Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimised insulin therapy for 52 weeks.		Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimised insulin therapy for 52 weeks.
All Cause Mortality
	Placebo Matching Empagliflozin		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/243 (0%)		0/243 (0%)		0/244 (0%)
Serious Adverse Events
	Placebo Matching Empagliflozin		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/243 (11.5%)		43/243 (17.7%)		26/244 (10.7%)
Cardiac disorders
Acute myocardial infarction	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Cardiac failure congestive	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Coronary artery stenosis	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Ear and labyrinth disorders
Deafness	0/243 (0%)		0/243 (0%)		2/244 (0.8%)
Eye disorders
Glaucoma	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Macular fibrosis	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Normal tension glaucoma	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Gastrointestinal disorders
Colitis	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Gastrooesophageal reflux disease	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Upper gastrointestinal haemorrhage	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
General disorders
Chest pain	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Immune system disorders
Anaphylactic reaction	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Anaphylactic shock	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Infections and infestations
Appendicitis	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Cellulitis	1/243 (0.4%)		1/243 (0.4%)		0/244 (0%)
Localised infection	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Pleurisy viral	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Pneumonia	0/243 (0%)		0/243 (0%)		2/244 (0.8%)
Pneumonia klebsiella	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Rhinovirus infection	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Subcutaneous abscess	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Tinea versicolour	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Viral infection	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Injury, poisoning and procedural complications
Carbon monoxide poisoning	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Concussion	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Facial bones fracture	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Fall	0/243 (0%)		2/243 (0.8%)		0/244 (0%)
Head injury	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Hip fracture	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Joint dislocation	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Procedural pain	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Shunt malfunction	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Tendon rupture	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Ulna fracture	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Investigations
Bacterial test positive	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Blood ketone body increased	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Clostridium test positive	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Hepatic enzyme increased	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Metabolism and nutrition disorders
Dehydration	0/243 (0%)		1/243 (0.4%)		1/244 (0.4%)
Diabetes mellitus inadequate control	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Diabetic ketoacidosis	4/243 (1.6%)		12/243 (4.9%)		8/244 (3.3%)
Diabetic metabolic decompensation	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Hyperglycaemia	2/243 (0.8%)		1/243 (0.4%)		1/244 (0.4%)
Hypoglycaemia	6/243 (2.5%)		9/243 (3.7%)		3/244 (1.2%)
Ketoacidosis	2/243 (0.8%)		4/243 (1.6%)		2/244 (0.8%)
Ketosis	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Intervertebral disc disorder	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Osteoarthritis	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Periarthritis	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Spinal osteoarthritis	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign breast neoplasm	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Renal cancer	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Nervous system disorders
Cerebrovascular accident	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Dystonia	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Embolic stroke	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Headache	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Hemiparesis	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Hypoglycaemic coma	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Lacunar stroke	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Metabolic encephalopathy	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Partial seizures	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Radicular syndrome	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Sensory disturbance	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Syncope	1/243 (0.4%)		1/243 (0.4%)		0/244 (0%)
Toxic encephalopathy	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Psychiatric disorders
Bipolar disorder	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Psychiatric decompensation	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Renal and urinary disorders
Acute kidney injury	1/243 (0.4%)		0/243 (0%)		1/244 (0.4%)
Nephropathy	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Reproductive system and breast disorders
Acquired phimosis	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Menstrual disorder	1/243 (0.4%)		0/243 (0%)		0/244 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Skin and subcutaneous tissue disorders
Dermal cyst	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Skin ulcer	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Vascular disorders
Deep vein thrombosis	0/243 (0%)		1/243 (0.4%)		0/244 (0%)
Intermittent claudication	0/243 (0%)		0/243 (0%)		1/244 (0.4%)
Other (Not Including Serious) Adverse Events
	Placebo Matching Empagliflozin		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/243 (81.1%)		197/243 (81.1%)		195/244 (79.9%)
Gastrointestinal disorders
Diarrhoea	9/243 (3.7%)		13/243 (5.3%)		8/244 (3.3%)
Nausea	14/243 (5.8%)		12/243 (4.9%)		14/244 (5.7%)
Vomiting	12/243 (4.9%)		19/243 (7.8%)		12/244 (4.9%)
Infections and infestations
Influenza	11/243 (4.5%)		20/243 (8.2%)		12/244 (4.9%)
Nasopharyngitis	41/243 (16.9%)		52/243 (21.4%)		43/244 (17.6%)
Sinusitis	13/243 (5.3%)		14/243 (5.8%)		9/244 (3.7%)
Upper respiratory tract infection	25/243 (10.3%)		15/243 (6.2%)		27/244 (11.1%)
Urinary tract infection	29/243 (11.9%)		37/243 (15.2%)		20/244 (8.2%)
Vulvovaginal mycotic infection	2/243 (0.8%)		9/243 (3.7%)		14/244 (5.7%)
Investigations
Blood ketone body increased	10/243 (4.1%)		18/243 (7.4%)		20/244 (8.2%)
Metabolism and nutrition disorders
Hypoglycaemia	152/243 (62.6%)		154/243 (63.4%)		147/244 (60.2%)

Limitations/Caveats

[Not Specified]

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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.