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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03128528
Recruitment Status : Active, not recruiting
First Posted : April 25, 2017
Last Update Posted : February 18, 2020
Sponsor:
Information provided by (Responsible Party):
University of Erlangen-Nürnberg Medical School

Tracking Information
First Submitted Date  ICMJE April 3, 2017
First Posted Date  ICMJE April 25, 2017
Last Update Posted Date February 18, 2020
Actual Study Start Date  ICMJE July 1, 2017
Actual Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 20, 2017)
Skin sodium content [ Time Frame: 14 weeks ]
Skin sodium content (23Na-MRI) assessed at the lower leg
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 20, 2017)
  • Muscle sodium content [ Time Frame: 14 weeks ]
    Sodium content of muscles
  • Water content of skin and muscle [ Time Frame: 14 weeks ]
    Water content (1H) of skin and muscle
  • Sodium excretion [ Time Frame: 14 weeks ]
    Sodium excretion as assessed by sodium creatinine ratio in spot urine
  • 24-hour urine sodium excretion [ Time Frame: 14 weeks ]
    24-hour urine sodium excretion
  • 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
  • Flow mediated vasodilation [ Time Frame: 14 weeks ]
    Flow mediated vasodilation (FMD) as measured by semiautomated ultrasound system
  • 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
  • Body weight [ Time Frame: 14 weeks ]
    Measurement of body weight in kg
  • HbA1c [ Time Frame: 14 weeks ]
    Diabetic control (e.g. fasting glucose, glycosylated hemoglobin [HbA1c])
  • ABPM [ Time Frame: 14 weeks ]
    24-hour ambulatory blood pressure (ABP)
  • Visual analogue scale for dyspnea [ Time Frame: 14 weeks ]
    Visual analogue scale for dyspnea to assess their relation to change in tissue sodium Content.
  • Body constitution [ Time Frame: 14 weeks ]
    Body constitution (fluid status based on three compartment model lean body mass, adipose tissue mass and overhydration)
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Chronic Heart Failure
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Placebo Comparator: Placebo Oral Tablet
    Patients will be randomized to empagliflozin 10 mg orally once daily or one placebo tablet orally once daily.
    Intervention: Drug: Placebo Oral Tablet
  • Active Comparator: Empagliflozin
    Patients will be randomized to empagliflozin 10 mg orally once daily or one placebo tablet orally once daily.
    Intervention: Drug: Empagliflozin 10mg
Publications * Striepe K, Jumar A, Ott C, Karg MV, Schneider MP, Kannenkeril D, Schmieder RE. Effects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus. Circulation. 2017 Sep 19;136(12):1167-1169. doi: 10.1161/CIRCULATIONAHA.117.029529.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: April 20, 2017)
84
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 30, 2020
Actual Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03128528
Other Study ID Numbers  ICMJE CRC2017ELSI
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Erlangen-Nürnberg Medical School
Study Sponsor  ICMJE University of Erlangen-Nürnberg Medical School
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Roland E Schmieder, Prof. Dr. Universitätsklinikum Erlangen
PRS Account University of Erlangen-Nürnberg Medical School
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP