Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)

September 25, 2020 updated by: University of Erlangen-Nürnberg Medical School

Randomized, Double-blind, Placebo Controlled, Parallel-group, Prospective Clinical Study to Analyse the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure

The hypothesis is that the SGLT-2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure, and if the hypothesis is proven, that this mechanism contributes to the beneficial effects found in EMPA-REG Outcome trial potentially via exerting beneficial effects on the vascular structure and function of the micro- and macrocirculation.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

SGLT-2 inhibitors such as empagliflozin inhibit the SGLT-2 transport in the proximal tubular cells of the kidney, thereby causing glucosuria to approximately 100 g per day (and sometimes even more). The SGLT-2 inhibition does not only cause glucosuria but also natriuresis, since with each molecule of glucose one molecule of sodium is inhibited to be reabsorbed. Indeed, during the first week SGLT-2 inhibition causes clinically detectable natriuresis but its effect in the long run is not yet illustrated. Of course, a new sodium balance will be achieved after a certain time (otherwise the human body would be completely salt depleted), but total sodium content could be different. With new innovative magnetic resonance imaging (MRI) technology we are able to assess tissue sodium content in the skin and muscle, and observed that sodium content is significantly increased with aging, severe hypertension or hyperaldosteronism. Furthermore, skin sodium content assessed by MRI was closely related to left ventricular mass (r=0.559, p<0.0001, N=89) independently of age, gender, body mass index, and 24 h ambulatory blood pressure (β=0.343, p=0.001, N=89) 11. Using this technology, our first yet unpublished data (clinicaltrials.gov: NCT02383238) indicate that SGLT-2 inhibition decreases sodium content in the skin in patients with diabetes. Finally, we observed previously that in patients with acute chronic heart failure skin sodium content decreased from 43.5 mmol/l to 32.2 mmol/l after diuretic therapy.

Thus, the present study aims at analyzing changes in total and tissue sodium content after SGLT-2 inhibition with empagliflozin. In parallel, sodium intake and excretion and central systolic and pulse pressure as well as other vascular parameters will be assessed. In face of the upcoming studies with empagliflozin conducted in patients with reduced and preserved ejection fraction (two large-scale, prospective, doubleblind, placebo controlled studies planned by Boehringer Ingelheim as the sponsor), we thought that we focus on patients with chronic heart failure irrespective diabetic status. The hypothesis is that the SGLT-2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure, and if the hypothesis is proven, that this mechanism contributes to the beneficial effects found in EMPA-REG Outcome trial potentially via exerting beneficial effects on the vascular structure and function of the micro- and macrocirculation.

Study Type

Interventional

Enrollment (Actual)

84

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Erlangen, Germany, 91054
        • Clinical Research Center, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age of 18 - 85 years
  • Male and Female patients (females of child bearing potential must be using adequate contraceptive precautions)
  • CHF (symptoms and/or sign of CHF, ejection fraction < 40% (HfrEF) 14 or symptoms and/or signs of CHF, ejection fraction 40-49 % and NT-pro BNP > 125 pg/ml, and at least one structural abnormality of left atrium or ventricle (HFmEF) 14 in stable conditions.
  • Females of childbearing potential or within two years of the menopause must have a negative urine pregnancy test at screening visit.
  • Informed consent has to be given in written form.

Exclusion Criteria:

  • Any other form of diabetes mellitus than type 2 diabetes mellitus
  • Use of insulin or any SGLT-2 inhibitor within the past 10 weeks prior to the screening visit (visit 1).
  • Patients with more than two blood glucose lowering medications
  • Uncontrolled diabetes (fasting plasma glucose ≥ 240 mg/dl, HbA1c ≥ 10%)
  • Any history of stroke, transient ischemic attack, instable angina pectoris, or myocardial infarction within the last 6 months prior to study inclusion
  • Estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m² (following the inclusion criteria of EMPA-REG OUTCOME study 1-3)
  • Chronic heart failure NYHA stage IV
  • Use of loop diuretics above furosemide > 80 mg/day, or torasemide >40 mg/day, or piretanide > 6 mg/day
  • Implanted pacemakers or defibrillators
  • Any other relevant clinical contraindication of MRI examination
  • Uncontrolled arterial hypertension (i.e. ≥ 180/110 mmHg)
  • Severe disorders of the gastrointestinal tract or other diseases which interfere with the pharmacodynamics and pharmacokinetics of study drugs
  • Significant laboratory abnormalities such as Serum Glutamate-Oxaloacetate-Transaminase (SGOT) or Serum Glutamate-Pyruvate-Transaminase (SGPT) levels more than 3 x above the upper limit of normal range

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
PLACEBO_COMPARATOR: Placebo Oral Tablet
Patients will be randomized to empagliflozin 10 mg orally once daily or one placebo tablet orally once daily.
Drug: Placebo Oral Tablet

Each patient, after the run-in/wash-out phase, will be randomly assigned in a doubleblind fashion to one of the two treatment sequences according to a randomisation list.

and provided by the sponsor.

Other Names:
  • PLACEBO
ACTIVE_COMPARATOR: Empagliflozin
Patients will be randomized to empagliflozin 10 mg orally once daily or one placebo tablet orally once daily.
Drug: Empagliflozin 10mg

Each patient, after the run-in/wash-out phase, will be randomly assigned in a doubleblind fashion to one of the two treatment sequences according to a randomisation list.

and provided by the sponsor.

Other Names:
  • EMPA

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Skin sodium content
Time Frame: 14 weeks
Skin sodium content (23Na-MRI) assessed at the lower leg
14 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Muscle sodium content
Time Frame: 14 weeks
Sodium content of muscles
14 weeks
Water content of skin and muscle
Time Frame: 14 weeks
Water content (1H) of skin and muscle
14 weeks
Sodium excretion
Time Frame: 14 weeks
Sodium excretion as assessed by sodium creatinine ratio in spot urine
14 weeks
24-hour urine sodium excretion
Time Frame: 14 weeks
24-hour urine sodium excretion
14 weeks
Vascular stiffness Parameter (central systolic pressure)
Time Frame: 14 weeks
Vascular stiffness Parameter under resting conditions and ambulatory conditions and their association to change in tissue sodium content
14 weeks
Flow mediated vasodilation
Time Frame: 14 weeks
Flow mediated vasodilation (FMD) as measured by semiautomated ultrasound system
14 weeks
N-terminal prohormone of brain natriuretic peptide
Time Frame: 14 weeks
N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP) to assess their relation to change in tissue sodium content
14 weeks
Body weight
Time Frame: 14 weeks
Measurement of body weight in kg
14 weeks
HbA1c
Time Frame: 14 weeks
Diabetic control (e.g. fasting glucose, glycosylated hemoglobin [HbA1c])
14 weeks
ABPM
Time Frame: 14 weeks
24-hour ambulatory blood pressure (ABP)
14 weeks
Visual analogue scale for dyspnea
Time Frame: 14 weeks
Visual analogue scale for dyspnea to assess their relation to change in tissue sodium Content.
14 weeks
Body constitution
Time Frame: 14 weeks
Body constitution (fluid status based on three compartment model lean body mass, adipose tissue mass and overhydration)
14 weeks
Vascular stiffness Parameter (Pulse pressure)
Time Frame: 14 weeks
Vascular stiffness Parameter under resting conditions and ambulatory conditions and their association to change in tissue sodium content
14 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Erlangen-Nürnberg Medical School

Investigators

  • Principal Investigator: Roland E Schmieder, Prof. Dr., Universitätsklinikum Erlangen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 1, 2017

Primary Completion (ACTUAL)

January 31, 2020

Study Completion (ACTUAL)

April 30, 2020

Study Registration Dates

First Submitted

April 3, 2017

First Submitted That Met QC Criteria

April 20, 2017

First Posted (ACTUAL)

April 25, 2017

Study Record Updates

Last Update Posted (ACTUAL)

September 28, 2020

Last Update Submitted That Met QC Criteria

September 25, 2020

Last Verified

September 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CRC2017ELSI

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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