NCT03448406

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

Completed Phase 3 Results posted Last updated 8 December 2020

What this trial tests

Phase 3 trial testing Empagliflozin in Heart Failure in 315 participants. Completed in 9 October 2019.

Timeline

20 March 2018

Primary endpoint
4 October 2019

9 October 2019

Quick facts

Lead sponsor	Boehringer Ingelheim
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	315
Start date	20 March 2018
Primary completion	4 October 2019
Estimated completion	9 October 2019
Sites	108 locations across Italy, Greece, Sweden, Germany, Poland, Norway, Canada, Australia

Drugs / interventions tested

• Empagliflozin (empagliflozin) — full drug profile →
• Placebo

Conditions studied

• Heart Failure — all drugs for Heart Failure →

Sponsor

Boehringer Ingelheim — full company profile →

Who can join

18 and older, any sex, with Heart Failure. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline to Week 12 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes in Standardised Conditions (6MWTD) Primary · 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 (6MWTD). If repeated 6-minutes walk test (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 eva

Group	Value	95% CI
Placebo	5.0	-20.0 – 33.0
10 mg Empagliflozin	10.0	-10.0 – 32.0

Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS) Secondary · 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 ques

Group	Value	95% CI
Placebo	2.08	-6.25 – 20.83
10 mg Empagliflozin	4.17	-3.13 – 16.67

Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score Secondary · 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

Group	Value	95% CI
Placebo	0.20	-0.40 – 1.00
10 mg Empagliflozin	0.10	-0.40 – 1.00

Change From Baseline to Week 6 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes Secondary · 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 6-Minuted Walking Test, 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.

Group	Value	95% CI
Placebo	1.0	-17.0 – 21.0
10 mg Empagliflozin	7.0	-14.0 – 23.0

Change From Baseline in Clinical Congestion Score at Week 12 Secondary · 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 sympto

Group	Value	95% CI
Placebo	-0.28	± 0.08
10 mg Empagliflozin	-0.36	± 0.08

Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 Secondary · 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-category scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score

Group	Value	95% CI
Placebo	1
10 mg Empagliflozin	0
Placebo	2
10 mg Empagliflozin	1
Placebo	11
10 mg Empagliflozin	8
Placebo	46
10 mg Empagliflozin	42

Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 Secondary · 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-category 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.

Group	Value	95% CI
Placebo	1
10 mg Empagliflozin	0
Placebo	4
10 mg Empagliflozin	1
Placebo	8
10 mg Empagliflozin	13
Placebo	45
10 mg Empagliflozin	48

Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 Secondary · 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).

Group	Value	95% CI
Placebo	1
10 mg Empagliflozin	0
Placebo	0
10 mg Empagliflozin	3
Placebo	11
10 mg Empagliflozin	7
Placebo	62
10 mg Empagliflozin	55

Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 Secondary · 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).

Group	Value	95% CI
Placebo	0
10 mg Empagliflozin	0
Placebo	2
10 mg Empagliflozin	3
Placebo	6
10 mg Empagliflozin	7
Placebo	72
10 mg Empagliflozin	57

Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 12 Secondary · 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. Mean is adjusted mean.

Group	Value	95% CI
Placebo	1.04	0.96 – 1.13
10 mg Empagliflozin	0.99	0.92 – 1.08

Adverse events — posted to ClinicalTrials.gov

Time frame: From first intake of study medication, until 7 days after last intake of study medication, up to 92 days.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 29/158 (18%)

Deaths: 0/158

10 mg Empagliflozin

Serious: 20/157 (13%)

Deaths: 1/157

Serious adverse events (54 terms)

Reaction	System	Placebo	10 mg Empagliflozin
Cardiac failure	Cardiac disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Angina unstable	Cardiac disorders	—	—
Atrial flutter	Cardiac disorders	—	—
Cardiac arrest	Cardiac disorders	—	—
Pericarditis	Cardiac disorders	—	—
Hypothyroidism	Endocrine disorders	—	—
Abdominal hernia	Gastrointestinal disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Dysphagia	Gastrointestinal disorders	—	—
Chest pain	General disorders	—	—
Generalised oedema	General disorders	—	—
Cholecystitis	Hepatobiliary disorders	—	—
Cholecystitis acute	Hepatobiliary disorders	—	—
Drug-induced liver injury	Hepatobiliary disorders	—	—
Hepatic haemorrhage	Hepatobiliary disorders	—	—
Hepatic mass	Hepatobiliary disorders	—	—
Arthritis bacterial	Infections and infestations	—	—
Asymptomatic bacteriuria	Infections and infestations	—	—
Cellulitis	Infections and infestations	—	—
Diverticulitis	Infections and infestations	—	—
Helicobacter duodenitis	Infections and infestations	—	—
Helicobacter gastritis	Infections and infestations	—	—

Most-reported serious reactions: Cardiac failure, Atrial fibrillation, Anaemia, Angina unstable, Atrial flutter, Cardiac arrest, Pericarditis, Hypothyroidism.

Data from ClinicalTrials.gov NCT03448406 adverse events section.

Sponsor's own description

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 (6MWT) in patients with chronic heart failure (CHF) with preserved ejection fraction (LVEF \> 40%).

Secondary objectives are to assess Patient-Reported Outcome (PRO)

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future.
   Wintrich J, Kindermann I, Ukena C, Selejan S, et al · · 2020 · cited 76× · PMID 32236720 · DOI 10.1007/s00392-020-01633-w
2. Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects.
   Palmiero G, Cesaro A, Vetrano E, Pafundi PC, et al · · 2021 · cited 72× · PMID 34070765 · DOI 10.3390/ijms22115863
3. Rationale and design of the EMPERIAL-Preserved and EMPERIAL-Reduced trials of empagliflozin in patients with chronic heart failure.
   Abraham WT, Ponikowski P, Brueckmann M, Zeller C, et al · · 2019 · cited 36× · PMID 31218819 · DOI 10.1002/ejhf.1486
4. Protective Effects of Sodium-Glucose Transporter 2 Inhibitors on Atrial Fibrillation and Atrial Flutter: A Systematic Review and Meta- Analysis of Randomized Placebo-Controlled Trials.
   Li D, Liu Y, Hidru TH, Yang X, et al · · 2021 · cited 34× · PMID 33815278 · DOI 10.3389/fendo.2021.619586
5. Repurposing Antidiabetic Drugs for Cardiovascular Disease.
   Schubert M, Hansen S, Leefmann J, Guan K. · · 2020 · cited 33× · PMID 33041865 · DOI 10.3389/fphys.2020.568632
6. Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis.
   Yu YW, Zhao XM, Wang YH, Zhou Q, et al · · 2021 · cited 32× · PMID 33494751 · DOI 10.1186/s12933-020-01209-y
7. New perspectives and future directions in the treatment of heart failure.
   Pellicori P, Khan MJI, Graham FJ, Cleland JGF. · · 2020 · cited 32× · PMID 31327116 · DOI 10.1007/s10741-019-09829-7
8. The effectiveness of SGLT2 inhibitor in the incidence of atrial fibrillation/atrial flutter in patients with type 2 diabetes mellitus/heart failure: a systematic review and meta-analysis.
   Wang M, Zhang Y, Wang Z, Liu D, et al · · 2022 · cited 29× · PMID 35693625 · DOI 10.21037/jtd-22-550