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

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ClinicalTrials.gov Identifier: NCT03128528
Recruitment Status : Recruiting
First Posted : April 25, 2017
Last Update Posted : January 12, 2018
Sponsor:
Information provided by (Responsible Party):
University of Erlangen-Nürnberg Medical School

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Chronic Heart Failure Drug: Empagliflozin 10mg Drug: Placebo Oral Tablet Phase 2

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 Using this technology, our first yet unpublished data (clinicaltrials.gov: NCT02383238) indicate that SGLT-2 inhibition decreases sodium content in the skin in patients with diabetes.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  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase II, randomized (2:1), prospective, double-blind, placebo controlled, parallel-group, single center study.
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 1, 2017
Estimated Primary Completion Date : June 1, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

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 Name: 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 Name: EMPA




Primary Outcome Measures :
  1. Skin sodium content [ Time Frame: 14 weeks ]
    Skin sodium content (23Na-MRI) assessed at the lower leg


Secondary Outcome Measures :
  1. Muscle sodium content [ Time Frame: 14 weeks ]
    Sodium content of muscles

  2. Water content of skin and muscle [ Time Frame: 14 weeks ]
    Water content (1H) of skin and muscle

  3. Sodium excretion [ Time Frame: 14 weeks ]
    Sodium excretion as assessed by sodium creatinine ratio in spot urine

  4. 24-hour urine sodium excretion [ Time Frame: 14 weeks ]
    24-hour urine sodium excretion

  5. 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

  6. Flow mediated vasodilation [ Time Frame: 14 weeks ]
    Flow mediated vasodilation (FMD) as measured by semiautomated ultrasound system

  7. 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

  8. Body weight [ Time Frame: 14 weeks ]
    Measurement of body weight in kg

  9. HbA1c [ Time Frame: 14 weeks ]
    Diabetic control (e.g. fasting glucose, glycosylated hemoglobin [HbA1c])

  10. ABPM [ Time Frame: 14 weeks ]
    24-hour ambulatory blood pressure (ABP)

  11. Visual analogue scale for dyspnea [ Time Frame: 14 weeks ]
    Visual analogue scale for dyspnea to assess their relation to change in tissue sodium Content.

  12. Body constitution [ Time Frame: 14 weeks ]
    Body constitution (fluid status based on three compartment model lean body mass, adipose tissue mass and overhydration)

  13. 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



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03128528


Locations
Germany
Clinical Research Center, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg Recruiting
Erlangen, Germany, 91054
Contact: Roland E Schmieder, MD    +49-9131-85 ext 36245    roland.schmieder@uk-erlangen.de   
Contact: , MD         
Principal Investigator: Roland E Schmieder, MD         
Sponsors and Collaborators
University of Erlangen-Nürnberg Medical School
Investigators
Principal Investigator: Roland E Schmieder, Prof. Dr. Universitätsklinikum Erlangen

Publications:
Responsible Party: University of Erlangen-Nürnberg Medical School
ClinicalTrials.gov Identifier: NCT03128528     History of Changes
Other Study ID Numbers: CRC2017ELSI
First Posted: April 25, 2017    Key Record Dates
Last Update Posted: January 12, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Erlangen-Nürnberg Medical School:
SGLT-2 inhibitor, Chronic heart failure, tissue sodium,

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Empagliflozin
Hypoglycemic Agents
Physiological Effects of Drugs