Clinical trial NCT04447911: Effects of the SGLT2 Inhibitor Empagliflozin in Patients With Euvolemic and Hypervolemic Hyponatremia
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hyponatremia
SIADH
Liver Failure
Kidney Failure
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: Luzerner Kantonsspital
name: Centre Hospitalier Universitaire Vaudois
First posted: 2020-06-25
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentric prospective randomized double-blind placebo-controlled study
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Change in average daily area under curve (AUC) for serum sodium concentration
timeFrame: 4 days
measure: Long-term serum sodium change (before/after treatment)
timeFrame: 30 days
Secondary outcomes:
measure: Impact intervention on bodyweight
timeFrame: 30 days
measure: Impact intervention on blood pressure
timeFrame: 30 days
measure: Course of serum sodium level
timeFrame: 30 days
measure: Change of plasma osmolality
timeFrame: 30 days
measure: Change of urinary osmolality
timeFrame: 30 days
measure: Change of plasma urea
timeFrame: 30 days
measure: Change of urinary urea
timeFrame: 30 days
measure: Change of plasma uric acid
timeFrame: 30 days
measure: Change of urinary uric acid
timeFrame: 30 days
measure: Change of plasma creatinin
timeFrame: 30 days
measure: Change of urinary creatinin
timeFrame: 30 days
measure: Change of plasma potassium
timeFrame: 30 days
measure: Change of urinary potassium
timeFrame: 30 days
measure: Change in plasma copeptin
timeFrame: 30 days
measure: Change in plasma aldosterone
timeFrame: 30 days
measure: Change in plasma renin
timeFrame: 30 days
measure: Change in plasma MR-proANP
timeFrame: 30 days
measure: Change in plasma NT-proBNP
timeFrame: 30 days
measure: Change in plasma CTX
timeFrame: 30 days
measure: Change in plasma P1NP
timeFrame: 30 days
measure: Occurence of thirst
timeFrame: 30 days
measure: Occurence of headache
timeFrame: 30 days
measure: Occurence of vertigo
timeFrame: 30 days
measure: Occurence of nausea
timeFrame: 30 days
measure: Change in general well-being
timeFrame: 30 days
measure: Change in quality of life
timeFrame: 30 days
measure: Change in cognitive impairment
timeFrame: 30 days
measure: Change in visual attention
timeFrame: 30 days
measure: Change in neuromuscular impairment
timeFrame: 30 days
measure: Change in grip strength
timeFrame: 30 days
measure: Occurence of falls
timeFrame: 30 days
measure: Occurence of fractures
timeFrame: 30 days
measure: Length of hospital stay
timeFrame: 30 days
Other outcomes:
Locations:
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois (CHUV)
state: Vaud
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Luzern
country: Switzerland
facility: Kantonsspital Luzern
Study officials:
affiliation: University Hospital, Basel, Switzerland
name: Julie Refardt, MD
role: PRINCIPAL_INVESTIGATOR
References: