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Effects of the SGLT2 Inhibitor Empagliflozin in Patients With Euvolemic and Hypervolemic Hyponatremia (EMPOWER)

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ClinicalTrials.gov Identifier: NCT04447911
Recruitment Status : Recruiting
First Posted : June 25, 2020
Last Update Posted : September 9, 2022
Sponsor:
Collaborators:
Luzerner Kantonsspital
Centre Hospitalier Universitaire Vaudois
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland

Study Description
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Brief Summary:

Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. It is usually classified as hypovolemic, euvolemic or hypervolemic. The most common aetiology of euvolemic hyponatremia is the syndrome of inappropriate antidiuresis (SIAD). Hypervolemic hyponatremia is common in patients with congestive heart failure (CHF) (10-27%) and liver cirrhosis (up to approximately 50%). In SIAD, the regulation of arginine vasopressin (AVP) secretion is impaired which leads to free water retention. In CHF and liver cirrhosis, the effective arterial blood volume is decreased leading to non-osmotic baroreceptor mediated AVP release and consecutive free water retention.

Current treatments of euvolemic and hypervolemic hyponatremia, including the most used treatment fluid restriction, are of limited efficacy. Sodium-Glucose-Co-Transporter 2 (SGLT2) inhibitors reduce glucose reabsorption in the proximal tubule, resulting in glucosuria and consecutive osmotic diuresis. A placebo-controlled randomized trial of our group has shown that a short-term, i.e. a 4-days administration of the SGLT2 inhibitor empagliflozin (Jardiance)® in addition to fluid restriction was effective in increasing the serum sodium concentration in 87 patients with SIAD-induced hyponatremia. The effect of empagliflozin (Jardiance)® without additional fluid restriction is however not yet known. Large randomized controlled trials have shown that SGLT2 inhibitors reduced hospitalization for heart failure in patients with, and more recently without type 2 diabetes. No studies have investigated the effect of SGLT2 inhibitors in hypervolemic hyponatremia.

To evaluate the effect of empagliflozin (Jardiance)® in eu- and hypervolemic hyponatremia, a randomized placebo-controlled study is needed.


Condition or disease Intervention/treatment Phase
Hyponatremia SIADH Liver Failure Kidney Failure Drug: Empagliflozin 25 MG Drug: Placebo Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 172 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicentric prospective randomized double-blind placebo-controlled study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of the SGLT2 Inhibitor Empagliflozin in Patients With Euvolemic and Hypervolemic Hyponatremia - a Multicentric Randomized Double-blind Placebo-controlled Trial (the EMPOWER Study)
Actual Study Start Date : February 4, 2021
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Empagliflozin
Empagliflozin (Jardiance)® 25mg per os once daily for 30 days
 Drug: Empagliflozin 25 MG
Empagliflozin 25mg per os once daily for 30 days
Placebo Comparator: Placebo
Placebo (Lactose tablet) per os once daily for 30 days
 Drug: Placebo
Placebo per os once daily for 30 days


Outcome Measures
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Primary Outcome Measures :
  1. Change in average daily area under curve (AUC) for serum sodium concentration [ Time Frame: 4 days ]
    Change in average daily AUC for serum sodium concentration

  2. Long-term serum sodium change (before/after treatment) [ Time Frame: 30 days ]
    Absolute change in serum sodium concentration from baseline to end of treatment


Secondary Outcome Measures :
  1. Impact intervention on bodyweight [ Time Frame: 30 days ]
    change of bodyweight

  2. Impact intervention on blood pressure [ Time Frame: 30 days ]
    change of blood pressure

  3. Course of serum sodium level [ Time Frame: 30 days ]
    Course of serum sodium level

  4. Change of plasma osmolality [ Time Frame: 30 days ]
    Change of plasma osmolality

  5. Change of urinary osmolality [ Time Frame: 30 days ]
    Change of urinary osmolality

  6. Change of plasma urea [ Time Frame: 30 days ]
    Change of plasma urea

  7. Change of urinary urea [ Time Frame: 30 days ]
    Change of urinary urea

  8. Change of plasma uric acid [ Time Frame: 30 days ]
    Change of plasma uric acid

  9. Change of urinary uric acid [ Time Frame: 30 days ]
    Change of urinary uric acid

  10. Change of plasma creatinin [ Time Frame: 30 days ]
    Change of plasma creatinin

  11. Change of urinary creatinin [ Time Frame: 30 days ]
    Change of urinary creatinin

  12. Change of plasma potassium [ Time Frame: 30 days ]
    Change of plasma potassium

  13. Change of urinary potassium [ Time Frame: 30 days ]
    Change of urinary potassium

  14. Change in plasma copeptin [ Time Frame: 30 days ]
    Change in plasma copeptin

  15. Change in plasma aldosterone [ Time Frame: 30 days ]
    Change in plasma aldosterone

  16. Change in plasma renin [ Time Frame: 30 days ]
    Change in plasma renin

  17. Change in plasma MR-proANP [ Time Frame: 30 days ]
    Change in plasma MR-proANP

  18. Change in plasma NT-proBNP [ Time Frame: 30 days ]
    Change in plasma NT-proBNP

  19. Change in plasma CTX [ Time Frame: 30 days ]
    Change in plasma CTX

  20. Change in plasma P1NP [ Time Frame: 30 days ]
    Change in plasma P1NP

  21. Occurence of thirst [ Time Frame: 30 days ]
    Occurence of thirst

  22. Occurence of headache [ Time Frame: 30 days ]
    Occurence of headache

  23. Occurence of vertigo [ Time Frame: 30 days ]
    Occurence of vertigo

  24. Occurence of nausea [ Time Frame: 30 days ]
    Occurence of nausea

  25. Change in general well-being [ Time Frame: 30 days ]
    Change in general well-being according to visual analogue scale

  26. Change in quality of life [ Time Frame: 30 days ]
    change in quality of life according to EQ-5D-5L questionnaire

  27. Change in cognitive impairment [ Time Frame: 30 days ]
    Change in cognitive impairment measured with the MoCa test

  28. Change in visual attention [ Time Frame: 30 days ]
    Change in visual attention measured with the trail making test

  29. Change in neuromuscular impairment [ Time Frame: 30 days ]
    Change in neuromuscular impairment measured with the timed up and go test

  30. Change in grip strength [ Time Frame: 30 days ]
    Change in grip strength measured with a hand dynamometer

  31. Occurence of falls [ Time Frame: 30 days ]
    Occurence of falls

  32. Occurence of fractures [ Time Frame: 30 days ]
    Occurence of fractures

  33. Length of hospital stay [ Time Frame: 30 days ]
    Length of hospital stay


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- chronic eu- OR hypervolemic non hyperosmolar (<300 mOsm/kg) hyponatremia (heparin plasma sodium <135 mmol/L on day of inclusion)

Exclusion Criteria:

  • known hypersensitivity or allergy to class of drugs or the investigational product,
  • severe symptomatic hyponatremia in need of treatment with 3% NaCl-solution or in need of intensive/intermediate care treatment at time of inclusion
  • clinical hypovolemia
  • Severe reduction of eGFR <20 mL/min/1,73 m2 (KDIGO G4 and G5) or end stage renal disease
  • Chronic liver insufficiency with Child Pugh Score ≥10 or decompensated liver cirrhosis (jaundice, hepatorenal syndrome, encephalopathy, bleeding, …)
  • Hepatic impairment defined as aspartate transaminase (AST) or alanine transaminase (ALT) >3x the upper limit of normal (ULN); or total bilirubin >2x ULN at time of enrolment
  • uncontrolled hypothyroidism
  • uncontrolled adrenal insufficiency
  • systolic blood pressure <90mmHg
  • contraindication for lowering blood pressure
  • diabetes mellitus type 1 or pancreatic diabetes mellitus
  • treatment with SGLT2 inhibitors, lithium chloride, vaptans, demeclocycline or urea on inclusion day
  • severe immunosuppression (leucocytes <2 G/l)
  • peripheral arterial disease stage III-IV of the Fontaine Classification
  • fasting or other reasons preventing medication intake
  • previous enrolment into the current study
  • participation in another intervention study
  • pregnancy, breastfeeding, intention to become pregnant during the course of the study or lack of safe contraception.
  • end of life care
Contacts and Locations
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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): NCT04447911


Contacts
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Contact: Mirjam Christ-Crain, Prof +41 61 328 70 80 Mirjam.Christ-Crain@usb.ch

Locations
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Switzerland
Centre Hospitalier Universitaire Vaudois (CHUV) Recruiting
Lausanne, Vaud, Switzerland, 1011
Contact: Anne Zanchi, MD    +41 21 314 11 11    anne.zanchi@chuv.ch   
University Hospital Basel Recruiting
Basel, Switzerland, 4031
Contact: Sophie Monnerat, MD    0041 61 328 76 08    sophie.monnerat@usb.ch   
Kantonsspital Luzern Recruiting
Luzern, Switzerland, 6000
Contact: Stefan Fischli, MD    + 41 41 205 51 03    stefan.fischli@luks.ch   
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Luzerner Kantonsspital
Centre Hospitalier Universitaire Vaudois
Investigators
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Principal Investigator: Julie Refardt, MD University Hospital, Basel, Switzerland
More Information
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Responsible Party: University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT04447911    
Other Study ID Numbers: EMPOWER study
First Posted: June 25, 2020    Key Record Dates
Last Update Posted: September 9, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Failure
Renal Insufficiency
Hyponatremia
Kidney Diseases
Urologic Diseases
Hepatic Insufficiency
Liver Diseases
Digestive System Diseases
 Water-Electrolyte Imbalance
Metabolic Diseases
Empagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs