This Study Tests Empagliflozin in Patients With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF). The Study Looks at How Far Patients Can Walk in 6 Minutes and at Their Heart Failure Symptoms

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03448419
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 312
• Locations: 109
• Arms: 2
• Actual Duration (Months): 18.6
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of the study is to evaluate the effect of empagliflozin 10 mg versus placebo on exercise ability using the 6 minute walk test in patients with chronic HF with reduced ejection fraction (LVEF ≤ 40%) Secondary objectives are to assess Patient-Reported Outcome (PRO)

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Empagliflozin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 312 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomised, Double-blind Trial to Evaluate the Effect of 12 Weeks Treatment of Once Daily EMPagliflozin 10 mg Compared With Placebo on ExeRcise Ability and Heart Failure Symptoms, In Patients With Chronic HeArt FaiLure With Reduced Ejection Fraction (HFrEF) (EMPERIAL-reduced)
• Actual Study Start Date: Mar 20, 2018
• Actual Primary Completion Date: Sep 30, 2019
• Actual Study Completion Date: Oct 7, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Empagliflozin	Drug: Empagliflozin; Film-coated tablet; Other Names: JARDIANCE, JARDIANZ, GIBTULIO
Placebo Comparator: Placebo	Drug: Placebo; Film-coated tablet

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 12 in Exercise Capacity as Measured by the 6-Minutes-Walking-Test (6MWT) Distance [At baseline and at week 12]

   Change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. If repeated 6MWT measurements were available for the same day, the longest distance was used for analysis. Change from baseline was defined as the distance walked in 6 minutes at week 12 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at week 12 but did not perform the 6MWT, the participant was evaluated as having walked a distance of 0 meter. If no value was available for week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above.

Secondary Outcome Measures

1. Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS) [At baseline and at week 12]

   Change from baseline in KCCQ-TSS was defined as the endpoint value at week 12 minus the last available measurement before start of treatment with randomised study medication. The KCCQ is 23 item self-administered questionnaire and comprises 7 domains: physical limitation, symptom frequency, symptom burden, symptom stability, social limitation, self-efficacy and quality of life. Additionally 3 summary scores exist: TSS, clinical summary score, and overall summary score. The scores of the KCCQ domains and summary scores range from 0 to 100, with higher score indicating better outcome. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.

2. Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score [At baseline and at week 12]

   Change from baseline in CHQ-SAS was defined as the endpoint value at week 12 minus the last available endpoint value before start of treatment with randomised study medication. The CHQ-SAS evaluates 3 domains: dyspnoea, fatigue, and emotional function. Scores of the domains range from 1 to 7, with higher score indicating better quality of life. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.

3. Change From Baseline to Week 6 in Exercise Capacity as Measured by the 6-Minutes-Walking-Test (6MWT) Distance [At baseline and at week 6]

   Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. Change from baseline was defined as the distance walked in 6 minutes at week 6 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at week 6 but did not perform the 6MWT, the participant was evaluated as having walked a distance of 0 meter. If no value was available for week 6, an imputed value was used.

4. Change From Baseline to Week 12 in Clinical Congestion Score [At baseline and at week 12]

   Change from baseline to week 12 in Clinical Congestion score is defined as the score-value at week 12 minus the score-value at baseline. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. The Clinical Congestion Score (summary score) is based on 3 items: orthopnoea, jugular venous distention (JVD) and oedema. Each item was assessed through a 4-measure questionnaire, which was further converted to a standardised 4-point scale ranging from 0 to 3, with 0 indicating no or fewer symptoms and 3 indicating continous or more symptoms. If at least 2 of the 3 items are not missing, the summary score is calculated as: (average over items JVD, orthopnea and oedema actually answered)*3. The summary score range from 0 to 9, with lower value indicating better health, and higher value indicating worse health. Mean is adjusted mean.

5. Change From Baseline to Week 12 in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms [At baseline and at week 12]

   Change from baseline to week 12 in PGI-S of Heart Failure Symptoms. The Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the Patient to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-point scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12.

6. Change From Baseline to Week 12 in Patient Global Impression of Severity (PGI-S) of Dyspnoea [At baseline and at week 12]

   Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of dyspnoea. The PGI-S of Dyspnoea is a 1-item questionnaire designed to assess the participant´s impression of symptom severity, specifically dyspnoea. The PGI-S item asks the participant to choose one response that best describes how his/her dyspnoea is now on a 5-point scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12.

7. Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 [At week 12]

   The Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of change in heart failure symptoms, specifically: shortness of breath, fatigue, and swelling. The PGI-C asks the patient to choose one Response that best describes the overall change (if any) in his/her heart failure symptoms, specifically: shortness of breath, fatigue, and swelling since he/she started taking the study medication on a 7- category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3).

8. Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 [At week 12]

   The PGI-C in Dyspnoea is a 1-item questionnaire designed to assess the patient's Impression of change in dyspnoea. The PGI-C asks the patient to choose one response that best describes the change (if any) in his/her shortness of breath when performing usual activities since he/she started taking the study medication on a 7-category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3).

9. Relative Change From Baseline to Week 12 in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) [Within 3 weeks prior to treatment start and at Week 12]

   Relative change from baseline to week 12 in N-terminal pro-brain natriuretic peptide (NTproBNP). Relative change from baseline is expressed as ratio of week 12 to baseline. Baseline value was defined as the mean of all available measurements from the screening visit until start of treatment with randomised study medication.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Of full age of consent (according to local legislation, usually ≥ 18 years) at screening.

• Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information.

• Signed and dated written informed consent in accordance with ICHGCP and local legislation prior to admission to the trial

• 6MWT distance ≤350 m at screening and at baseline.

• Patients with chronic HF diagnosed for at least 3 months before Visit 1 and currently in NYHA class II-IV

• Chronic HF with reduced EF defined as LVEF ≤ 40 % as per echocardiography at Visit 1 as per local reading (obtained under stable condition).

• Elevated NT-proBNP > 450 pg/ml for patients without atrial fibrillation (AF) OR NTproBNP > 600 pg/ml for patients with AF as analysed at the Central laboratory at Visit 1

• Patients must be clinically stable and on appropriate and stable dose of medical therapy for HF (such as ACEi, ARB, β-blocker, oral diuretics, MRA, ARNI, ivabradine), consistent with prevailing CV guidelines, stable for at least 4 weeks prior to Visit 1(screening) with the exception of diuretics which must have been stable for at least two weeks prior to Visit 1. The investigator must document the reason in case the patient is not on such medication or if not on target dose of any heart failure medication as per local guidelines.

• Clinically stable at randomization with no signs of heart failure decompensation (as per investigator judgement).

• Appropriate use of medical devices such as cardioverter defibrillator (ICD) or a cardiac resynchronization therapy (CRT) consistent with prevailing local or international CV guidelines, and if a device is required, it must have been implanted for at least 3 months prior to visit 1 for CRT and 1 month prior to visit 1 for ICD.

Exclusion Criteria:

• Myocardial infarction (increase in cardiac enzymes in combination with symptoms of ischaemia or newly developed ischaemic ECG changes), coronary artery bypass graft surgery or other major cardiovascular surgery, stroke or TIA in past 90 days prior to Visit 1

• Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.) diuretics, i.v. inotropes or i.v. vasodilators, or left ventricular assist device within 4 weeks prior to Visit 1, and/or during screening period until Visit 2

• Previous or current randomisation in another Empagliflozin Heart Failure trial (i.e. studies 1245.110, 1245.121, 1245-0167)

• Type 1 Diabetes Mellitus (T1DM)

• Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 (CKD-EPIcr) or requiring dialysis, as determined at Visit 1

• Symptomatic hypotension or a SBP < 100 mmHg at Visit 1 or 2

• Systolic blood pressure (SBP) ≥ 180 mmHg at Visit 1 or 2, or SBP >160mmHg at both Visit 1 and 2

• Atrial fibrillation or atrial flutter with a resting heart rate >110 bpm documented by ECG at Visit 1 (Screening)

• Unstable angina pectoris in past 30 days prior to Visit 1

• Largest distance walked in 6 minutes (6MWTD) at baseline <100m.

• Any presence of condition that precludes exercise testing such as:

• claudication,

• uncontrolled (according to investigator judgement) bradyarrhythmia or tachyarrhythmia,

• significant musculoskeletal disease,

• primary pulmonary hypertension,

• severe obesity (body mass index ≥40.0 kg/m2),

• orthopedic conditions that limit the ability to walk (such as arthritis in the leg, knee or hip injuries)

• amputation with artificial limb without stable prosthesis function for the past 3 months

• Any condition that, in the opinion of the investigator, would contraindicate the assessment of 6MWT

• Patients in a structured (according to Investigator judgement) exercise training program in the 1 month prior to screening or planned to start one during the course of this trial.

• Planned implantation of ICD or CRT during the course of the trial.

• Treatment with i.v. iron therapy or erythropoietin within 3 months prior to screening

• Treatment with i.v. iron therapy or erythropoietin within 3 months prior to screening

• Further exclusion criteria applies

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mobile Heart Specialists, PC	Mobile	Alabama	United States	36608
2	The Center for Clinical Trials, Inc.	Saraland	Alabama	United States	36571
3	California Heart Specialists	Huntington Beach	California	United States	92648
4	Manshadi Heart Institute, Inc	Stockton	California	United States	95204
5	University of California Los Angeles	Torrance	California	United States	90502
6	University of Colorado Denver	Aurora	Colorado	United States	80045
7	Western Connecticut Health Network	Danbury	Connecticut	United States	06810
8	Bio1 Clinical Research	Miami Beach	Florida	United States	33140
9	Infinite Clinical Research	Miami	Florida	United States	33133
10	Advance Medical Research Center	Miami	Florida	United States	33135
11	Pharmacology Research, LLC	North Miami Beach	Florida	United States	33169
12	Palm Beach Gardens Research Center, LLC	Palm Beach Gardens	Florida	United States	33410
13	East Coast Institute for Research, LLC	Saint Augustine	Florida	United States	32086
14	Cozy Research LLC	Zephyrhills	Florida	United States	33541
15	Grady Memorial Hospital	Atlanta	Georgia	United States	30303
16	Georgia Arrhythmia Consultants and Research Institute	Warner Robins	Georgia	United States	31093
17	St Luke's Clinic - Idaho Cardiology Associates	Boise	Idaho	United States	83712
18	Northwest Heart Clinical Research, LLC	Arlington Heights	Illinois	United States	60005
19	Clinical Investigation Specialists, Inc	Gurnee	Illinois	United States	60031
20	Chicago Medical Research	Hazel Crest	Illinois	United States	60429
21	Midwest Heart and Vascular Specialists	Overland Park	Kansas	United States	66211
22	Grace Research, LLC	Bossier City	Louisiana	United States	71111
23	Grace Research, LLC	Shreveport	Louisiana	United States	71107
24	Clinical Trials of America LA, LLC	West Monroe	Louisiana	United States	71291
25	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
26	University Of Mississippi Medical Center	Jackson	Mississippi	United States	39216
27	Med Research One	Florissant	Missouri	United States	63031
28	The DOCS	Las Vegas	Nevada	United States	89113
29	Rutgers Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08901
30	New York Heart Research Foundation, Inc.	Mineola	New York	United States	11501
31	PMG Research of Rocky Mount, LLC	Rocky Mount	North Carolina	United States	27804
32	PMG Research of Wilmington, LLC	Wilmington	North Carolina	United States	28401
33	Rama Research LLC	Marion	Ohio	United States	43302
34	Columbia Heart Clinic	Columbia	South Carolina	United States	29203
35	Black Hills Cardiovascular Research	Rapid City	South Dakota	United States	57701
36	The Jackson Clinic, PA	Jackson	Tennessee	United States	38301
37	DiscoveResearch, Inc.	Beaumont	Texas	United States	77701
38	Angiocardiac Care of Texas	Houston	Texas	United States	77025
39	Mary Washington Hospital Research Department	Fredericksburg	Virginia	United States	22401
40	York Clinical Research, LLC	Norfolk	Virginia	United States	23510
41	Aspirus Research Institute	Wausau	Wisconsin	United States	54401
42	Canberra Hospital	Garran	Australian Capital Territory	Australia	2605
43	St Vincent's Hospital Sydney	Darlinghurst	New South Wales	Australia	2010
44	University of the Sunshine Coast	Birtinya	Queensland	Australia	4575
45	Cairns Base Hospital	Cairns	Queensland	Australia	4870
46	Peninsular Health CV Research Unit	Frankston	Victoria	Australia	3199
47	University of Calgary	Calgary	Alberta	Canada	T2N 4Z6
48	KMH Cardiology Centres Inc.	Mississauga	Ontario	Canada	L5K 2L3
49	Toronto Heart Centre	Toronto	Ontario	Canada	M4P 1E4
50	Sameh Fikry Medicine Professional Corporation	Waterloo	Ontario	Canada	N2J 1C4
51	CIMS Studienzentrum Bamberg GmbH	Bamberg		Germany	96049
52	Klinische Forschung Berlin GbR	Berlin		Germany	10787
53	Charité - Universitätsmedizin Berlin	Berlin		Germany	13353
54	Bremer Institut für Herz- und Kreislaufforschung (BIHKF) am Klinikum Links der Weser	Bremen		Germany	28277
55	Cardiologicum Dresden und Pirna	Dresden		Germany	01277
56	Universitätsklinikum Düsseldorf	Düsseldorf		Germany	40225
57	Klinikum Esslingen GmbH	Esslingen		Germany	73730
58	IKF Pneumologie GmbH & Co. KG	Frankfurt		Germany	60596
59	Universitäts-Herzzentrum Freiburg, Bad Krozingen GmbH	Freiburg		Germany	79106
60	Universitätsklinikum Köln (AöR)	Köln		Germany	50937
61	Universitätsklinikum Leipzig	Leipzig		Germany	04103
62	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55131
63	Universitätsklinikum Ulm	Ulm		Germany	89081
64	Universitätsklinikum Würzburg	Würzburg		Germany	97080
65	General Hospital of Athens Konstantopoulio-Agia Olga	Athens		Greece	14233
66	General Hospital of Athens "G. Gennimatas"	Athens		Greece	15669
67	General University Hospital "Attikon"	Haidari, Athens		Greece	12410
68	University General Hospital of Heraklion	Herakleion, Crete		Greece	71110
69	Univ. Gen. Hosp. of Ioannina	Ioannina		Greece	45500
70	University Hospital of Thessaloniki AHEPA	Thessaloniki		Greece	54636
71	Centro Cardiologico Monzino-IRCCS	Milano		Italy	20138
72	Asst Santi Paolo E Carlo	Milano		Italy	20142
73	ASST Grande Ospedale Metropolitano Niguarda	Milano		Italy	20162
74	Università Federico II	Napoli		Italy	80131
75	Università degli studi di Palermo	Palermo		Italy	90133
76	IRCCS San Raffaele	Roma		Italy	00163
77	Sykehuset Østfold Kalnes	Grålum		Norway	N-1714
78	Vestre Viken, Ringerike Sykehus HF	Hønefoss		Norway	N-3511
79	Oslo Universitetssykehus HF, Rikshospitalet	Oslo		Norway	N-0372
80	Helse Stavanger, Stavanger Universitetssykehus	Stavanger		Norway	N-4011
81	St. Olavs Hospital, Universitetssykehuset i Trondheim	Trondheim		Norway	N-7030
82	INTERCORE Medical Center	Bydgoszcz		Poland	85-605
83	Leszek Bryniarski Specialized Medical Cabinet	Krakow		Poland	30-082
84	Card.Cli.Mil.Med.Ac.Uni.Cli.Hosp. Cent.Vetera.Hosp.Lodz	Lodz		Poland	91-425
85	Cent.Clin.Hosp.Med.Univ.Lodz,Electrocard	Lodz		Poland	92-213
86	Provincial Specialist M. Kopernik Hospital	Lodz		Poland	93-513
87	Independent Public Healthcare, Dept. of Cardiology, Pulawy	Pulawy		Poland	24100
88	The Provincial Polyclinical Hospital in Torun	Torun		Poland	87-100
89	Central Hospital of Medical Academy, Warsaw	Warsaw		Poland	02-097
90	4. Military Clinical Hospital with Polyclinic SP ZOZ	Wroclaw		Poland	50 981
91	CHLO, EPE - Hospital de Santa Cruz	Carnaxide		Portugal	2795
92	CHUC - Centro Hospitalar e Universitário de Coimbra, EPE	Coimbra		Portugal	3041-801
93	Centro Hosp. de Leiria-Pombal	Leiria		Portugal	2410-197
94	CHLC, EPE - Hospital de Santa Marta	Lisboa		Portugal	1169-024
95	CHLO, EPE - Hospital S. Francisco Xavier	Lisboa		Portugal	1449-005
96	CHULN, EPE - Hospital de Santa Maria	Lisboa		Portugal	1649-035
97	CHTS, EPE - Hospital Padre Américo	Penafiel		Portugal	4560-007
98	Centro Hospitalar Universitário São João,EPE	Porto		Portugal	4200-319
99	Hospital General Universitario de Alicante	Alicante		Spain	03010
100	Hospital Germans Trias i Pujol	Badalona		Spain	08916
101	Hospital San Rafael	Granada		Spain	18001
102	Hospital de la Inmaculada Concepción	Granada		Spain	18004
103	Hospital Universitario Virgen de las Nieves	Granada		Spain	18014
104	Hospital de Bellvitge	L'Hospitalet de Llobregat		Spain	08907
105	Hospital La Princesa	Madrid		Spain	28006
106	Hospital Clínico de Valencia	Valencia		Spain	46010
107	Sahlgrenska US, Göteborg	Göteborg		Sweden	413 45
108	Sahlgrenska Universitetssjukhuset, Östra	Göteborg		Sweden	416 85
109	Akardo Med Site	Stockholm		Sweden	11446

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Oct 21, 2019
• Study Protocol - Jul 20, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03448419
• Other Study ID Numbers: 1245-0168; 2017-004073-14
• First Posted: Feb 28, 2018
• Last Update Posted: Nov 27, 2020
• Last Verified: Nov 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Heart Failure; Empagliflozin

Study Results

Participant Flow

Recruitment Details	Randomised, double-blind, placebo-controlled, parallel-group trial in patients with chronic Heart Failure with reduced Ejection Fraction (HFrEF) to evaluate the effect of Empagliflozin versus Placebo on exercise and heart failure symptoms.
Pre-assignment Detail	Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Period Title: Overall Study
STARTED	156	156
Treated	156	155
COMPLETED	143	140
NOT COMPLETED	13	16

Baseline Characteristics

Arm/Group Title	Placebo	10 mg Empagliflozin	Total
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	Total of all reporting groups
Overall Participants	156	156	312
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	69.3 (10.6)	68.7 (9.9)	69.0 (10.2)
Sex: Female, Male (Count of Participants)
Female	45 28.8%	35 22.4%	80 25.6%
Male	111 71.2%	121 77.6%	232 74.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 14.7%	20 12.8%	43 13.8%
Not Hispanic or Latino	132 84.6%	136 87.2%	268 85.9%
Unknown or Not Reported	1 0.6%	0 0%	1 0.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	1 0.6%	2 0.6%
Asian	2 1.3%	1 0.6%	3 1%
Native Hawaiian or Other Pacific Islander	1 0.6%	0 0%	1 0.3%
Black or African American	18 11.5%	24 15.4%	42 13.5%
White	133 85.3%	130 83.3%	263 84.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.6%	0 0%	1 0.3%
Exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance at baseline (Meter) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Meter]	309.0	306.0	307.5

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12 in Exercise Capacity as Measured by the 6-Minutes-Walking-Test (6MWT) Distance
Description	Change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. If repeated 6MWT measurements were available for the same day, the longest distance was used for analysis. Change from baseline was defined as the distance walked in 6 minutes at week 12 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at week 12 but did not perform the 6MWT, the participant was evaluated as having walked a distance of 0 meter. If no value was available for week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above.
Time Frame	At baseline and at week 12

Outcome Measure Data

Analysis Population Description

Randomised Set: All participants that were randomised, regardless of whether treated or not.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	156	156
Median (Inter-Quartile Range) [Meter (m)]	18.0	13.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments	H0: There is no difference between the effect of placebo and the effect of empagliflozin.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4236
	Comments
	Method	Wilcoxon rank test, normal approximation
	Comments
Method of Estimation	Estimation Parameter	Median difference (HL-estimate)
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -16.0 to 6.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin vs. Placebo. For estimation of effect, the non-parametric Hodge-Lehman (HL) estimate for the median difference was calculated.

2. Secondary Outcome

Title	Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)
Description	Change from baseline in KCCQ-TSS was defined as the endpoint value at week 12 minus the last available measurement before start of treatment with randomised study medication. The KCCQ is 23 item self-administered questionnaire and comprises 7 domains: physical limitation, symptom frequency, symptom burden, symptom stability, social limitation, self-efficacy and quality of life. Additionally 3 summary scores exist: TSS, clinical summary score, and overall summary score. The scores of the KCCQ domains and summary scores range from 0 to 100, with higher score indicating better outcome. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.
Time Frame	At baseline and at week 12

Outcome Measure Data

Analysis Population Description

Randomised Set: All participants that were randomised, regardless of whether treated or not.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	156	156
Median (Inter-Quartile Range) [Score on a scale]	3.65	7.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments	H0: There is no difference between the effect of placebo and the effect of empagliflozin.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0893
	Comments
	Method	Wilcoxon rank test, normal approximation
	Comments
Method of Estimation	Estimation Parameter	Median difference (HL-estimate)
	Estimated Value	3.13
	Confidence Interval	(2-Sided) 95%; 0.00 to 7.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin vs. Placebo. For estimation of effect, the non-parametric Hodge-Lehman (HL) estimate for the median difference was calculated.

3. Secondary Outcome

Title	Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score
Description	Change from baseline in CHQ-SAS was defined as the endpoint value at week 12 minus the last available endpoint value before start of treatment with randomised study medication. The CHQ-SAS evaluates 3 domains: dyspnoea, fatigue, and emotional function. Scores of the domains range from 1 to 7, with higher score indicating better quality of life. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.
Time Frame	At baseline and at week 12

Outcome Measure Data

Analysis Population Description

Participants in the randomised set (RS) who have no missing values at baseline.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	156	154
Median (95% Confidence Interval) [Score on scale]	0.40	0.40

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments	H0: There is no difference between the effect of placebo and the effect of empagliflozin.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4702
	Comments
	Method	Wilcoxon rank test, normal approximation
	Comments
Method of Estimation	Estimation Parameter	Median Difference (HL-estimate)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.20 to 0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin vs. Placebo. For estimation of effect, the non-parametric Hodge-Lehman (HL) estimate for the median difference was calculated.

4. Secondary Outcome

Title	Change From Baseline to Week 6 in Exercise Capacity as Measured by the 6-Minutes-Walking-Test (6MWT) Distance
Description	Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. Change from baseline was defined as the distance walked in 6 minutes at week 6 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at week 6 but did not perform the 6MWT, the participant was evaluated as having walked a distance of 0 meter. If no value was available for week 6, an imputed value was used.
Time Frame	At baseline and at week 6

Outcome Measure Data

Analysis Population Description

Randomised Set: All participants that were randomised, regardless of whether treated or not.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	156	156
Median (Inter-Quartile Range) [Meter (m)]	7.0	9.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments	H0: There is no difference between the effect of placebo and the effect of empagliflozin.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9830
	Comments
	Method	Wilcoxon rank test, normal approximation
	Comments
Method of Estimation	Estimation Parameter	Median difference (HL-estimate)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -9.0 to 9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Empagliflozin vs. Placebo. For estimation of effect, the non-parametric Hodge-Lehman (HL) estimate for the median difference was calculated.

5. Secondary Outcome

Title	Change From Baseline to Week 12 in Clinical Congestion Score
Description	Change from baseline to week 12 in Clinical Congestion score is defined as the score-value at week 12 minus the score-value at baseline. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. The Clinical Congestion Score (summary score) is based on 3 items: orthopnoea, jugular venous distention (JVD) and oedema. Each item was assessed through a 4-measure questionnaire, which was further converted to a standardised 4-point scale ranging from 0 to 3, with 0 indicating no or fewer symptoms and 3 indicating continous or more symptoms. If at least 2 of the 3 items are not missing, the summary score is calculated as: (average over items JVD, orthopnea and oedema actually answered)*3. The summary score range from 0 to 9, with lower value indicating better health, and higher value indicating worse health. Mean is adjusted mean.
Time Frame	At baseline and at week 12

Outcome Measure Data

Analysis Population Description

Only participants in the randomised set (RS) who have baseline and at least one post-baseline value.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	153	155
Mean (Standard Error) [Score on a scale]	-0.30 (0.08)	-0.61 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0053
	Comments
	Method	Mixed Model repeated Measures (MMRM)
	Comments	Covariates: visit-by-treatment interaction, baseline-by-visit interaction. Unstructured covariance structure was used to model within-patient errors.
Method of Estimation	Estimation Parameter	Difference of adjusted means
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to Week 12 in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms
Description	Change from baseline to week 12 in PGI-S of Heart Failure Symptoms. The Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the Patient to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-point scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12.
Time Frame	At baseline and at week 12

Outcome Measure Data

Analysis Population Description

Only participants in the randomised set (RS) who have values at baseline and at week 12.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	149	147
4 categories improvement	0 0%	0 0%
3 categories improvement	1 0.6%	1 0.6%
2 categories improvement	13 8.3%	14 9%
1 category improvement	41 26.3%	41 26.3%
No change	73 46.8%	74 47.4%
1 category deterioration	16 10.3%	16 10.3%
2 categories deterioration	4 2.6%	1 0.6%
3 categories deterioration	1 0.6%	0 0%
4 categories deterioration	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6189
	Comments
	Method	Cochran-Mantel-Haenszel test
	Comments	Test on difference in mean treatment scores, based on modified ridit scores.

7. Secondary Outcome

Title	Change From Baseline to Week 12 in Patient Global Impression of Severity (PGI-S) of Dyspnoea
Description	Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of dyspnoea. The PGI-S of Dyspnoea is a 1-item questionnaire designed to assess the participant´s impression of symptom severity, specifically dyspnoea. The PGI-S item asks the participant to choose one response that best describes how his/her dyspnoea is now on a 5-point scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12.
Time Frame	At baseline and at week 12

Outcome Measure Data

Analysis Population Description

Only participants in the randomised set (RS) who have values at baseline and at week 12.

Arm/Group Title	10 mg Empagliflozin	Placebo
Arm/Group Description	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	150	147
4 categories improvment	0 0%	0 0%
3 categories improvment	2 1.3%	3 1.9%
2 categories improvement	11 7.1%	8 5.1%
1 category improvement	46 29.5%	38 24.4%
No change	70 44.9%	83 53.2%
1 category deterioration	17 10.9%	13 8.3%
2 categories deterioration	4 2.6%	2 1.3%
3 categories deterioration	0 0%	0 0%
4 categories deterioration	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6672
	Comments
	Method	Cochran-Mantel-Haenszel test
	Comments	Test on difference in mean treatment scores, based on modified ridit scores.

8. Secondary Outcome

Title	Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12
Description	The Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of change in heart failure symptoms, specifically: shortness of breath, fatigue, and swelling. The PGI-C asks the patient to choose one Response that best describes the overall change (if any) in his/her heart failure symptoms, specifically: shortness of breath, fatigue, and swelling since he/she started taking the study medication on a 7- category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3).
Time Frame	At week 12

Outcome Measure Data

Analysis Population Description

Only participants in the randomised set (RS) who have week 12 value.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	150	147
Very much worse	0 0%	0 0%
Much worse	3 1.9%	0 0%
A little worse	7 4.5%	5 3.2%
No change	57 36.5%	51 32.7%
A little better	40 25.6%	52 33.3%
Much better	34 21.8%	33 21.2%
Very much better	9 5.8%	6 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5147
	Comments
	Method	Cochran-Mantel-Haenszel test
	Comments	Test on difference in mean treatment scores, based on modified ridit scores.

9. Secondary Outcome

Title	Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12
Description	The PGI-C in Dyspnoea is a 1-item questionnaire designed to assess the patient's Impression of change in dyspnoea. The PGI-C asks the patient to choose one response that best describes the change (if any) in his/her shortness of breath when performing usual activities since he/she started taking the study medication on a 7-category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3).
Time Frame	At week 12

Outcome Measure Data

Analysis Population Description

Only participants in the randomised set (RS) who have week 12 value.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	149	147
Very much worse	0 0%	0 0%
Much worse	2 1.3%	0 0%
A little worse	6 3.8%	3 1.9%
No change	52 33.3%	49 31.4%
A little better	45 28.8%	59 37.8%
Much better	34 21.8%	30 19.2%
Very much better	10 6.4%	6 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8630
	Comments
	Method	Cochran-Mantel-Haenszel test
	Comments	Test on difference in mean treatment scores, based on modified ridit scores.

10. Secondary Outcome

Title	Relative Change From Baseline to Week 12 in N-terminal Pro-brain Natriuretic Peptide (NTproBNP)
Description	Relative change from baseline to week 12 in N-terminal pro-brain natriuretic peptide (NTproBNP). Relative change from baseline is expressed as ratio of week 12 to baseline. Baseline value was defined as the mean of all available measurements from the screening visit until start of treatment with randomised study medication.
Time Frame	Within 3 weeks prior to treatment start and at Week 12

Outcome Measure Data

Analysis Population Description

Only participants in the randomised set (RS) who have baseline and at least one baseline value.

Arm/Group Title	Placebo	10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).	1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
Measure Participants	153	155
Mean (95% Confidence Interval) [Ratio]	0.98	0.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg Empagliflozin
	Comments	The endpoint 'relative change from baseline in NT-proBNP at Week 12' (after log-transformation) was evaluated using an MMRM analysis over time with baseline log-transformed NT-proBNP-by-visit interaction and visit-by-treatment interaction as covariates.Unstructured covariance structure was used to model within-patient errors.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1410
	Comments
	Method	Mixed Model repeated Measures (MMRM)
	Comments	Covariates: NT-proBNP-by-visit interaction and visit-by-treatment interaction. Unstructured covariance structure to model within-patient errors.
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted geometric mean ratio [Empagliflozin/Placebo] of relative change to baseline.

Adverse Events

Time Frame	From first intake of study medication, until 7 days after last intake of study medication, up to 91 days.
Adverse Event Reporting Description	Treated Set: All participants wo were treated with at least 1 dose of the study medication.
Arm/Group Title	Placebo		10 mg Empagliflozin
Arm/Group Description	1 film-coated tablet of Placebo matching empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).		1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with reduced left ventricular ejection fraction (LVEF≤40%).
All Cause Mortality
	Placebo		10 mg Empagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/156 (1.9%)		3/155 (1.9%)
Serious Adverse Events
	Placebo		10 mg Empagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/156 (17.3%)		21/155 (13.5%)
Blood and lymphatic system disorders
Anaemia	0/156 (0%)		1/155 (0.6%)
Cardiac disorders
Acute myocardial infarction	0/156 (0%)		1/155 (0.6%)
Angina pectoris	0/156 (0%)		1/155 (0.6%)
Angina unstable	1/156 (0.6%)		0/155 (0%)
Atrial fibrillation	1/156 (0.6%)		0/155 (0%)
Cardiac failure	12/156 (7.7%)		6/155 (3.9%)
Cardiac failure acute	0/156 (0%)		1/155 (0.6%)
Cardiac failure congestive	1/156 (0.6%)		0/155 (0%)
Congestive cardiomyopathy	0/156 (0%)		1/155 (0.6%)
Myocardial infarction	1/156 (0.6%)		0/155 (0%)
Ventricular tachycardia	1/156 (0.6%)		0/155 (0%)
Ear and labyrinth disorders
Vertigo	0/156 (0%)		1/155 (0.6%)
Gastrointestinal disorders
Duodenal ulcer haemorrhage	0/156 (0%)		1/155 (0.6%)
Gastrointestinal haemorrhage	0/156 (0%)		1/155 (0.6%)
Mallory-Weiss syndrome	0/156 (0%)		1/155 (0.6%)
Vomiting	0/156 (0%)		1/155 (0.6%)
General disorders
Oedema peripheral	1/156 (0.6%)		0/155 (0%)
Hepatobiliary disorders
Cholelithiasis	1/156 (0.6%)		0/155 (0%)
Liver injury	1/156 (0.6%)		0/155 (0%)
Infections and infestations
Bronchitis	0/156 (0%)		1/155 (0.6%)
Gastroenteritis	1/156 (0.6%)		0/155 (0%)
Osteomyelitis	0/156 (0%)		1/155 (0.6%)
Parotitis	0/156 (0%)		1/155 (0.6%)
Pneumonia	1/156 (0.6%)		2/155 (1.3%)
Respiratory tract infection	1/156 (0.6%)		0/155 (0%)
Septic shock	0/156 (0%)		1/155 (0.6%)
Urinary tract infection	1/156 (0.6%)		0/155 (0%)
Vulval abscess	1/156 (0.6%)		0/155 (0%)
Injury, poisoning and procedural complications
Fall	1/156 (0.6%)		1/155 (0.6%)
Femur fracture	0/156 (0%)		1/155 (0.6%)
Metabolism and nutrition disorders
Hypoglycaemia	0/156 (0%)		1/155 (0.6%)
Musculoskeletal and connective tissue disorders
Spinal pain	1/156 (0.6%)		0/155 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic	1/156 (0.6%)		0/155 (0%)
Squamous cell carcinoma of skin	1/156 (0.6%)		0/155 (0%)
Nervous system disorders
Cerebrovascular accident	0/156 (0%)		2/155 (1.3%)
Dizziness	1/156 (0.6%)		1/155 (0.6%)
Epilepsy	0/156 (0%)		1/155 (0.6%)
Somnolence	1/156 (0.6%)		0/155 (0%)
Syncope	1/156 (0.6%)		0/155 (0%)
Transient ischaemic attack	0/156 (0%)		1/155 (0.6%)
Product Issues
Device malfunction	0/156 (0%)		1/155 (0.6%)
Renal and urinary disorders
Acute kidney injury	1/156 (0.6%)		1/155 (0.6%)
Bladder cyst	0/156 (0%)		1/155 (0.6%)
Chronic kidney disease	0/156 (0%)		1/155 (0.6%)
Renal failure	1/156 (0.6%)		0/155 (0%)
Renal injury	1/156 (0.6%)		0/155 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/156 (0%)		1/155 (0.6%)
Asthma	1/156 (0.6%)		0/155 (0%)
Atelectasis	1/156 (0.6%)		0/155 (0%)
Dyspnoea	1/156 (0.6%)		0/155 (0%)
Pleural effusion	1/156 (0.6%)		0/155 (0%)
Pulmonary oedema	1/156 (0.6%)		0/155 (0%)
Skin and subcutaneous tissue disorders
Subcutaneous emphysema	1/156 (0.6%)		0/155 (0%)
Vascular disorders
Hypertensive urgency	1/156 (0.6%)		0/155 (0%)
Hypotension	0/156 (0%)		2/155 (1.3%)
Other (Not Including Serious) Adverse Events
	Placebo		10 mg Empagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/156 (0%)		0/155 (0%)

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.