Evaluation of Empagliflozin on Plasma Sodium Levels in Euvolemic and Hypervolemic Hyponatremia: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate whether treatment with **empagliflozin** 25 mg once daily results in a stronger average daily increase in plasma sodium concentration from baseline (day 0) to day 4 and from baseline (day 0) to day 30 in patients with euvolemic or hypervolemic **hyponatremia** compared to placebo. This is clinically relevant as hyponatremia is a common electrolyte disorder that can lead to significant morbidity and mortality if not effectively managed.

Secondary objectives include assessing the impact on other laboratory parameters such as urine sodium, estimated glomerular filtration rate (eGFR), blood and urine osmolality, potassium, creatinine, urea, uric acid, glucose, electrolyte-free water clearance, biomarkers of salt-water balance, and bone markers. Additionally, the study aims to evaluate the influence on the short and long-term course of plasma sodium levels, the impact on hyponatremia-related clinical outcomes including thirst, symptoms of hyponatremia (e.g., headache, vertigo, nausea), general well-being, quality of life, neurocognitive functions, gait stability, grip strength, and the incidence of falls and fractures. Furthermore, the study will investigate the influence on the clinical course, including treatment escalation, length of hospital stay, and readmission.

The clinical trial involves a total of **80 participants** diagnosed with **hyponatremia**, specifically targeting adult patients aged 18 years and older. The study population includes both male and female subjects, ensuring a diverse representation of genders. Participants were selected based on their diagnosis of chronic euvolemic or hypervolemic non-hyperosmolar hyponatremia, characterized by a heparin plasma sodium level of less than 135 mmol/L on the day of inclusion. The trial does not involve a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection criteria focus on the medical condition and age, without additional emphasis on other health status factors.

The clinical trial is designed to evaluate the efficacy of **empagliflozin** in patients with euvolemic and hypervolemic **hyponatremia**. This is a multicentric, randomized, double-blind, placebo-controlled trial. The primary objective is to assess whether treatment with empagliflozin 25 mg once daily results in a stronger average daily increase in plasma sodium concentration from baseline to day 4 and from baseline to day 30 compared to placebo. The trial is expected to conclude by January 31, 2026, with recruitment starting on February 17, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years) and specific hyponatremia characteristics. Following randomization, participants will receive either the active treatment or placebo for a maximum treatment period of 30 days. Study visits will occur on day 0 (baseline), day 1, day 4, and day 30, with additional assessments on days 2 and 3. The end-of-study visit will take place on day 30, with a follow-up visit scheduled approximately 37 days after the baseline.

The expected length of participant involvement is approximately 67 days, including the follow-up period. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or any medical condition that, in the investigator's opinion, warrants discontinuation. The trial will measure primary endpoints such as changes in plasma sodium concentration and secondary endpoints including urine sodium, eGFR, and various biochemical markers. The study will also assess changes in body weight, blood pressure, heart rate, and quality of life, among other parameters.

The clinical trial involves the administration of **Jardiance** 25 mg film-coated tablets, which contain the active substance **empagliflozin**. This medication is provided in the form of a film-coated tablet and is administered orally. The dosage is set at 25 mg once daily, with a maximum treatment period of 4 days. Empagliflozin is a chemical substance, and the product is manufactured by Boehringer Ingelheim International GmbH. The trial aims to evaluate the effect of empagliflozin on plasma sodium concentration in patients with euvolemic or hypervolemic hyponatremia.

In addition to the experimental treatment, a placebo is used as a comparator in this double-blind study. The placebo is provided in the form of **P-Tabletten weiß 10 mm Lichtenstein**, which contains **lactose monohydrate** as the active substance. This tablet is also administered orally, with a dosage of 25 mg once daily, and a maximum treatment period of 30 days. The placebo is manufactured by Winthrop Arzneimittel GmbH. The use of a placebo allows for the assessment of the true efficacy of empagliflozin by comparing the changes in plasma sodium concentration between the treatment and placebo groups.

Both the experimental medication and the placebo are over-encapsulated to maintain blinding. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial is designed to provide robust data on the efficacy of empagliflozin in the specified patient population, with careful monitoring of dosing and administration to maintain the integrity of the study results.

Efficacy in the clinical trial will be assessed by evaluating the impact of the treatment with empagliflozin on plasma sodium concentration in patients with euvolemic or hypervolemic **hyponatremia**. The primary endpoints include the short-term change in the average daily area under the curve (AUC) for plasma sodium concentration from baseline (day 0) to day 4, and the long-term change in plasma sodium concentration from baseline to day 30. Secondary endpoints encompass a range of parameters, including the course of plasma sodium levels on specific days, urine sodium, estimated glomerular filtration rate (eGFR), and various serum and urine biomarkers at baseline, day 4, and day 30.

Additional secondary endpoints involve assessments of daily fluid intake, changes in body weight, blood pressure, heart rate, and symptoms of hyponatremia. Patient-reported outcomes such as general well-being, quality of life, and neurocognitive functions will be measured using validated tools like the visual analogue scale (VAS), EQ-5D-5L questionnaire, MoCA Test, and Trail Making Test A and B. Gait stability and grip strength will be evaluated using the Timed Up and Go Test and a hand dynamometer, respectively. The trial will also monitor the incidence of fractures, rate of ICU admissions, and length of hospital stay. These efficacy parameters will be collected and analyzed at specified timepoints, including baseline, day 4, and day 30, to determine the treatment's effectiveness in normalizing plasma sodium levels and improving patient outcomes.