Evaluation of Desmopressin Acetate Trihydrate in Preventing Serum Sodium Overcorrection in Patients with Severe Hyponatremia: A Multicenter Randomized Trial

The primary objective of this study is to evaluate whether the systematic administration of **DDAVP** (desmopressin acetate trihydrate) reduces the occurrence of serum sodium concentration (SNa) overcorrection within the first 48 hours post-randomization in patients with severe **hyponatremia**. This is clinically relevant as rapid correction of SNa can lead to serious neurological complications, including osmotic demyelination syndrome.

Secondary objectives include:

• The reversal of acute neurological symptoms in patients with neurological symptoms at inclusion.
• ICU and hospital length of stay.
• Survival rates.
• The occurrence of central pontine myelinolysis diagnosed on clinical and MRI criteria.
• The occurrence of any (pontine or extrapontine) osmotic demyelination as assessed by brain MRI.
• Percentage of patients with neurological symptoms at inclusion reaching the initial goal of rapid partial pre-defined correction of SNa level.
• The urine output and osmolality at various time intervals (H0 to H6, H6 to H12, H12 to H24, and H24 to H48).
• SNa level correction rate and maximal change between H0 and H24, and H0 and H48.
• Amount of hypotonic fluids, sodium, and potassium administered between H0 and H24, and H24 and H48.
• The occurrence of any new neurological sign related to hyponatremia in patients with a normal neurological exam at inclusion or the reappearance of any neurological sign after inclusion.
• The occurrence of excessive re-lowering of sodium.

The clinical trial involves a study population comprising **adults** aged 18 years and older, both male and female, who are currently admitted to the Intensive Care Unit (ICU). Participants are selected based on the presence of **severe hyponatremia**, characterized by a serum sodium concentration (SNa) of less than 120 mmol/L in the presence of neurological symptoms such as seizures, stupor (Glasgow Coma Scale < 12), or signs of brain herniation, or an SNa of less than 115 mmol/L. The trial includes individuals with normal or decreased extracellular fluid volume. The study population is considered vulnerable due to their critical health status. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **desmopressin acetate trihydrate** in preventing serum sodium overcorrection in patients with severe hyponatremia. This is a multicenter, open-label, randomized controlled trial. The primary objective is to determine whether systematic administration of desmopressin decreases the occurrence of serum sodium concentration overcorrection during the first 48 hours post-randomization. The trial is expected to commence on May 13, 2024, and conclude by June 20, 2026.

Participants will be adults admitted to the ICU with severe hyponatremia, defined by serum sodium levels below 120 mmol/L in the presence of neurological symptoms or below 115 mmol/L. The trial will exclude individuals with conditions that could interfere with the study outcomes. The trial will involve a series of study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Randomization will occur following the screening, and participants will be assigned to receive either the investigational product or standard care.

Study visits will include follow-up assessments at specified intervals to monitor serum sodium levels and other clinical parameters. The primary endpoint is the proportion of patients experiencing serum sodium overcorrection within the first 48 hours. Secondary endpoints include the assessment of neurological symptoms, length of ICU and hospital stay, and the occurrence of central pontine myelinolysis. The end-of-study visit will occur at day 15 or earlier if clinically justified, to evaluate the final outcomes and any adverse events.

Participant involvement is expected to last up to 15 days, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants. The study will utilize intravenous administration of the investigational product, with careful monitoring of dosage and treatment duration to mitigate risks associated with overcorrection of serum sodium levels.

The clinical trial involves the administration of **MINIRIN 4 microgrammes/ml**, a **solution for injection** containing **desmopressin acetate trihydrate** as the active substance. This experimental medication is administered intravenously. The maximum daily dose is 20 micrograms, with a total maximum dose of 32 micrograms over a treatment period of up to 2 days. The pharmaceutical form is a solution injectable, and the product is manufactured by FERRING S.A.S. Compliance with the dosing schedule is monitored throughout the trial.

In addition to the experimental treatment, the study utilizes **GLUCOSE 2.5% B. BRAUN**, a **solution for infusion** containing **glucose monohydrate**. This auxiliary treatment is administered intravenously with a maximum daily dose of 250 milliliters and a total maximum dose of 500 milliliters over a 2-day period. The product is provided by B.BRAUN MELSUNGEN AG.

Another auxiliary treatment used in the trial is **CHLORURE DE SODIUM 0.9% AGUETTANT**, a **solution for infusion** containing **sodium chloride**. This solution is administered intravenously with a maximum daily dose of 250 milliliters and a total maximum dose of 250 milliliters over a 2-day period. The product is manufactured by LABORATOIRE AGUETTANT.

The trial also includes the use of **GLUCOSE 5% VIAFLO**, a **solution for infusion** containing **glucose**. This solution is administered intravenously with a maximum daily dose of 250 milliliters and a total maximum dose of 500 milliliters over a 2-day period. The product is supplied by BAXTER SAS.

**GADOTERIC ACID**, containing **meglumine gadoterate**, is used as a test substance in the trial. It is administered intravenously with a maximum daily dose of 0.2 milliliters per kilogram and a total maximum dose of 0.2 milliliters per kilogram over a 1-day period. This product is classified under the ATC code V08CA02.

**CHLORURE DE POTASSIUM B. BRAUN 10%**, a **solution for infusion** containing **potassium chloride**, is also used as an auxiliary treatment. It is administered intravenously with a maximum daily dose of 2.5 millimoles per kilogram and a total maximum dose of 2.5 millimoles per kilogram over a 1-day period. The product is provided by B.BRAUN MELSUNGEN AG.

Lastly, **CHLORURE DE SODIUM HYPERTONIQUE 10% LAVOISIER**, a **solution for injection** containing **sodium chloride**, is used in the trial. This solution is administered intravenously with a maximum daily dose of 45 milliliters and a total maximum dose of 45 milliliters over a 1-day period. The product is manufactured by LABORATOIRES CHAIX ET DU MARAIS and involves an extemporaneous dilution to prepare a 3% NaCl solution.

Efficacy in this clinical trial will be assessed primarily by evaluating the proportion of patients experiencing **serum sodium (SNa)** level overcorrection within the first 48 hours post-randomization. Overcorrection is defined based on the presence or absence of risk factors at the time of randomization, such as chronic alcohol abuse, malnutrition, use of thiazides or antidepressant medications, serum potassium levels below 3.0 mmol/L, or glycaemia above 20 mmol/L. For patients with any risk factor, overcorrection is identified as an SNa increase greater than 6.0 mmol/L in less than 24 hours or greater than 12.0 mmol/L in less than 48 hours. For those without risk factors, it is defined as an SNa increase greater than 10.0 mmol/L in less than 24 hours or greater than 18.0 mmol/L in less than 48 hours.

Secondary efficacy endpoints include the proportion of patients with neurological symptoms at inclusion who achieve a normal Glasgow Coma Scale at 6 hours, length of ICU and hospital stay, time to death post-inclusion, and the occurrence of central pontine myelinolysis diagnosed clinically and via MRI by day 15. Additional assessments involve the proportion of patients with any form of osmotic demyelination, changes in SNa levels, urine output and osmolality at specified intervals, and the total amount of intravenous hypotonic fluids and electrolytes administered. These parameters will be measured and analyzed at various timepoints, including H0, H6, H12, H24, and H48, to provide a comprehensive evaluation of the treatment's efficacy.