A Study That Looks at the Function of the Heart in Patients With Heart Failure Who Take Empagliflozin

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03332212
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 72
• Location: 1
• Arms: 2
• Actual Duration (Months): 26.9
• Patients Per Site Per Month: 2.7

Study Details

Study Description

Brief Summary

The objective of this trial is to assess the effect of empagliflozin on cardiac physiology and metabolism aiming to provide a scientific explanation of the underlying mechanism by which empagliflozin improves HF related outcomes in patients with chronic heart failure

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: EMPA-VISION: A Randomised, Double-blind, Placebo-controlled, Mechanistic Cardiac Magnetic Resonance Study to Investigate the Effects of Empagliflozin Treatment on Cardiac Physiology and Metabolism in Patients With Heart Failure
• Actual Study Start Date: Mar 1, 2018
• Actual Primary Completion Date: May 21, 2020
• Actual Study Completion Date: May 28, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A (Empagliflozin + Placebo) Heart Failure with Reduced Ejection Fraction	Drug: Empagliflozin; 12 weeks; Other Names: JARDIANCE, JARDIANZ, GIBTULIO ; Drug: Placebo; 12 Weeks; Other Names: JARDIANCE, JARDIANZ, GIBTULIO
Experimental: Cohort B (Empagliflozin + Placebo) Heart Failure with Preserved Ejection Fraction	Drug: Empagliflozin; 12 weeks; Other Names: JARDIANCE, JARDIANZ, GIBTULIO ; Drug: Placebo; 12 Weeks; Other Names: JARDIANCE, JARDIANZ, GIBTULIO

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 12 in PCr/ATP Ratio in the Resting State Measured by 31P Cardiac Magnetic Resonance Spectroscopy (MRS). [At baseline and at week 12.]

   The primary endpoint of efficacy was the change from baseline to Week 12 in phosphocreatine/adenosine triphosphate (PCr/ATP) ratio in the resting state measured by 31P cardiac magnetic resonance spectroscopy (MRS). Adjusted mean values were calculated using an analysis of variance (ANOVA) model, with treatment, history of diabetes, and history of atrial fibrillation (AF) as fixed effects.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Chronic heart failure diagnosed at least 3 months before informed consent

• NYHA class II-IV at screening

• Age ≥ 18 years at screening

• Male or female patients. Women of childbearing potential (WOCBP) 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 ICH-GCP and local legislation prior to admission to the trial

Cohort A Heart Failure with Reduced Ejection Fraction (HFrEF)

• Left ventricular ejection fraction (LVEF) ≤ 40% as measured by ECHO at screening

• The following signs of heart failure;

• Elevated NT-proBNP (>125 pg/mL) at screening in patient without atrial fibrillation (AF)

• Elevated NT-proBNP (>600 pg/mL) at screening in patient with AF

• Appropriate dose of medical therapy for HF (such as ACEi, ARB, β-blocker, oral diuretics, MRA, ARNI, ivabradine) consistent with prevailing local and international HF guidelines, stable for at least one week prior to Visit 1 and during screening period until Visit 2 (Randomisation) with the exception of diuretics which must be stable for at least one week prior to Visit 2 to control symptoms. If required, the investigator must document in the source documents the reason why the patient is not on the target dose per local guidelines.

Cohort B Heart Failure with Preserved Ejection Fraction (HFpEF)

• Left ventricular ejection fraction (LVEF) ≥ 50% as measured by ECHO at screening and no previous measurement of LVEF ≤ 40%.

• The following combined signs of heart failure;

• Structural heart disease (LA enlargement [LAVI >34 mL/m2] and/or LVH [LVMI ≥ 115 g/m2 for males and ≥ 95 g/m2 for females]) by ECHO at screening or within 3 months prior to informed consent AND

• NT-proBNP > 125pg/mL at screening in patient without AF or NT-pro-BNP > 600 pg/mL in patient with AF

• Oral diuretics, if prescribed, should be stable for at least one week prior to Visit 1 and during screening period until Visit 2 (Randomisation).

Exclusion Criteria:

• Stroke or transient ischaemic attack (TIA) within 6 months prior to informed consent.

• Any patients with myocardial scars and/or non-viable myocardium in the interventricular septum, unstable angina due to significant coronary artery disease (CAD), or major (in the opinion of the investigator) cardiovascular surgery.

• Any contraindication for MRI, CPET and/or dobutamine stress test in accordance with the institution guidance, including implanted left ventricular assist device (LVAD),implantable cardioverter defibrillator (ICD), cardiac resynchronisation therapy (CRT) or any cardiac device.

• Heart transplant recipient or listed for heart transplant

• Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy or known pericardial constriction

• Moderate to severe uncorrected valvular heart disease, obstructive or regurgitant, or any valvular heart disease expected to lead to surgery in the Investigator's opinion

• Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.) diuretics, i.v. inotropes or i.v. vasodilators, or LVAD or hospitalisation within 1 week prior to Visit 1 (Screening), or during screening period until Visit 2 (Randomisation)

• Systolic blood pressure (SBP) ≥ 180 mmHg at screening. If SBP >150 mmHg and <180mmHg at screening, the patient is ineligible if receiving 3 or more antihypertensive drugs

• Symptomatic hypotension and/or a SBP < 100 mmHg at Screening

• Atrial fibrillation which is uncontrolled in the opinion of the investigator

• Untreated ventricular arrhythmia with syncope documented within the 3 months prior to informed consent in patients without ICD

• Diagnosis of cardiomyopathy induced by chemotherapy or peripartum within the 12 months prior to informed consent

• Symptomatic bradycardia or second or third degree heart block in need of a pacemaker after adjusting beta-blocker therapy or any other negative inotropic agents, if appropriate

• Chronic pulmonary disease requiring home oxygen, oral steroid therapy or hospitalisation for exacerbation within 12 months prior to informed consent, or significant chronic pulmonary disease in the Investigator's opinion, or primary pulmonary arterial hypertension

• Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT),or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at screening

• Impaired renal function, defined as estimated Creatinine Clearance < 30 mL/min (using Cockcroft-Gault formula) or requiring dialysis, as determined at screening

• Haemoglobin < 10 g/dL at screening

• Type 1 Diabetes Mellitus (T1DM)

• History of ketoacidosis

• Major surgery (major according to the investigator's assessment) performed within 3 months prior to informed consent, or scheduled major elective surgery (e.g. hip replacement) within 3 months after Visit 1

• Gastrointestinal (GI) surgery or GI disorder that could interfere with absorption of trial medication in the investigator's opinion

• Any documented active or suspected malignancy or history of malignancy within 6 months prior to informed consent, except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of uterine cervix or low risk prostate cancer (patients with pretreatment PSA <10 ng/mL, and biopsy Gleason score of ≤ 6 and clinical stage T1c or T2a)

• Presence of any other disease than heart failure with a life expectancy of <1 year in the investigator's opinion

• Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial

• Patients with requirement for treatment with empagliflozin according to local standard of care

• Treatment with any SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor within 1 week prior to informed consent or during screening period until Visit 2 (Randomisation)

• Currently enrolled in another investigational device or drug study, or less than 30 days between randomisation and ending another investigational device or drug study, or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded.

• Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors

• Chronic alcohol or drug abuse or any condition that, in the investigator's opinion, makes them an unreliable trial subject or unlikely to complete the trial

• Women who are pregnant, breastfeeding, or who plan to become pregnant while in the trial

• Any clinical condition that would jeopardise patients safety while participating in this trial, or may prevent the subject from adhering to the trial protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	John Radcliffe Hospital	Oxford		United Kingdom	OX3 9DU

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Aug 14, 2018
• Statistical Analysis Plan - Mar 12, 2020

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03332212
• Other Study ID Numbers: 1245-0148; 2017-000376-28
• First Posted: Nov 6, 2017
• Last Update Posted: Jun 18, 2021
• Last Verified: May 1, 2021

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

Study Results

Participant Flow

Recruitment Details	A randomised, double-blind, placebo controlled, mechanistic cardiac magnetic resonance study to investigate the effects of empagliflozin treatment on cardiac physiology and metabolism in patients with heart failure.
Pre-assignment Detail	All subjects were screened for eligibility to participate in trial. Subjects attended specialist site to ensure that they (the subjects) met all implemented inclusion/exclusion criteria.

Arm/Group Title	Placebo Cohort A	Placebo Cohort B	Empagliflozin 10mg Cohort A	Empagliflozin 10mg Cohort B
Arm/Group Description	Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks. Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF).	Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks. Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF).	Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks. Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF).	Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks. Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF).
Period Title: Overall Study
STARTED	19	18	17	18
Treated	19	17	17	18
COMPLETED	18	16	17	17
NOT COMPLETED	1	2	0	1

Baseline Characteristics

Arm/Group Title	Placebo Cohort A	Placebo Cohort B	Empagliflozin 10mg Cohort A	Empagliflozin 10mg Cohort B	Total
Arm/Group Description	Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks. Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF).	Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks. Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF).	Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks. Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF).	Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks. Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF).	Total of all reporting groups
Overall Participants	19	18	17	18	72
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.7 (12.7)	72.1 (7.0)	67.5 (14.1)	69.1 (10.9)	68.3 (11.5)
Sex: Female, Male (Count of Participants)
Female	6 31.6%	9 50%	7 41.2%	8 44.4%	30 41.7%
Male	13 68.4%	9 50%	10 58.8%	10 55.6%	42 58.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	19 100%	18 100%	17 100%	18 100%	72 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	1 5.6%	1 1.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	1 5.6%	1 1.4%
White	19 100%	18 100%	17 100%	16 88.9%	70 97.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Ratio of phosphocreatine to adenosine triphosphate concentration (Ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Ratio]	1.924 (0.354)	1.719 (0.431)	1.889 (0.407)	1.896 (0.462)	1.859 (0.413)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12 in PCr/ATP Ratio in the Resting State Measured by 31P Cardiac Magnetic Resonance Spectroscopy (MRS).
Description	The primary endpoint of efficacy was the change from baseline to Week 12 in phosphocreatine/adenosine triphosphate (PCr/ATP) ratio in the resting state measured by 31P cardiac magnetic resonance spectroscopy (MRS). Adjusted mean values were calculated using an analysis of variance (ANOVA) model, with treatment, history of diabetes, and history of atrial fibrillation (AF) as fixed effects.
Time Frame	At baseline and at week 12.

Outcome Measure Data

Analysis Population Description

Per protocol set (PPS): The primary endpoint analysis was performed using the per protocol (PP) set of patients with valid PCr/ATP ratio measurements available at baseline and Week 12, and no important protocol violation relevant to the primary endpoint.

Arm/Group Title	Placebo Cohort A	Placebo Cohort B	Empagliflozin 10mg Cohort A	Empagliflozin 10mg Cohort B
Arm/Group Description	Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks. Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF).	Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks. Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF).	Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks. Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF).	Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks. Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF).
Measure Participants	18	11	17	13
Least Squares Mean (Standard Error) [PCr / ATP Ratio]	0.068 (0.114)	0.259 (0.156)	-0.179 (0.117)	0.100 (0.143)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Cohort A, Empagliflozin 10mg Cohort A
	Comments	ANOVA on the PCr/ATP ratio absolute change using treatment (empagliflozin vs. placebo), history of diabetes (yes vs, no) and history of atrial fibrillation (yes vs no) as between subjects factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1418
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.247
	Confidence Interval	(2-Sided) 95%; -0.582 to 0.087
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.164
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Cohort B, Empagliflozin 10mg Cohort B
	Comments	ANOVA on the PCr/ATP ratio absolute change using treatment (empagliflozin vs. placebo), history of diabetes (yes vs, no) and history of atrial fibrillation (yes vs no) as between subjects factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4650
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.159
	Confidence Interval	(2-Sided) 95%; -0.604 to 0.286
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.213
	Estimation Comments

Adverse Events

Time Frame	All adverse events occurring between the start of treatment and end of the residual effect period, 7 days after the last dose of medication. Up to 95 days.
Adverse Event Reporting Description	Treated set (TS): All randomised and treated patients were included in the safety analysis and safety summaries were presented by actual treatment received.
Arm/Group Title	Placebo		Empagliflozin 10mg
Arm/Group Description	Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks. Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF) and Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF).		Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks. Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF) and Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF).
All Cause Mortality
	Placebo		Empagliflozin 10mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/35 (0%)
Serious Adverse Events
	Placebo		Empagliflozin 10mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/36 (19.4%)		1/35 (2.9%)
Cardiac disorders
Cardiac arrest	1/36 (2.8%)		0/35 (0%)
Cardiac failure	1/36 (2.8%)		0/35 (0%)
Cardiac failure congestive	2/36 (5.6%)		0/35 (0%)
Eye disorders
Glaucoma	1/36 (2.8%)		0/35 (0%)
Infections and infestations
Lower respiratory tract infection	1/36 (2.8%)		0/35 (0%)
Metabolism and nutrition disorders
Euglycaemic diabetic ketoacidosis	1/36 (2.8%)		0/35 (0%)
Hypomagnesaemia	0/36 (0%)		1/35 (2.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour benign	1/36 (2.8%)		0/35 (0%)
Nervous system disorders
Syncope	1/36 (2.8%)		0/35 (0%)
Renal and urinary disorders
Acute kidney injury	2/36 (5.6%)		1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	Placebo		Empagliflozin 10mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/36 (8.3%)		8/35 (22.9%)
Infections and infestations
Lower respiratory tract infection	2/36 (5.6%)		1/35 (2.9%)
Urinary tract infection	1/36 (2.8%)		3/35 (8.6%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/36 (0%)		2/35 (5.7%)
Skin and subcutaneous tissue disorders
Pruritus	0/36 (0%)		2/35 (5.7%)

Limitations/Caveats

Due to the suspension of face-to-face contact imposed in March 2020 to restrict transmission of COVID-19, the number of patients included in the analysis of efficacy for the Heart failure with preserved ejection fraction was substantially reduced, which meant that this cohort was also under powered (reduced from 80% to 70%) for the planned analysis of the primary endpoint.

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.