Efficacy of Urea in Treating Hyponatremia Associated with Subarachnoid Hemorrhage: A Randomized, Placebo-Controlled Clinical Trial

The primary objective of this study is to **demonstrate the efficacy** of urea therapy in correcting persistent **hyponatremia** despite adequate management during subarachnoid hemorrhage (SAH). This is clinically relevant as hyponatremia is a common and potentially serious complication in patients with SAH, and effective correction is crucial for patient outcomes.

Secondary objectives include:

• Compare the sodium intake required to correct natraemia.
• Study the mechanism of action of urea.
• Assess the impact of treatment on length of stay.
• Evaluate the impact of treatment on neurological outcome at 3 months from inclusion.
• Assessing adverse effects of treatment.
• Evaluate the persistence of natraemia correction 48 hours after discontinuation of treatment.
• Comparison of speed of correction of natraemia.

The clinical trial focuses on patients experiencing **hyponatremia** during subarachnoid hemorrhage. The study population includes both male and female participants aged 18 and over. Participants are selected based on the presence of non-traumatic subarachnoid hemorrhage with hyponatremia, characterized by a natraemia of less than 135 mmol/L and a high natriuresis, greater than 250 mmol/J, despite well-managed salt intake. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **urea** therapy in correcting persistent **hyponatremia** during **subarachnoid hemorrhage**. This study is a randomized, double-blind, controlled trial, conducted over a period of approximately four years and five months, with an estimated end date of March 3, 2025. The trial involves two groups: one receiving the active treatment, **urea**, and the other receiving a placebo, **ergytonyl placebo**. The trial aims to assess the primary endpoint of change in natraemia levels, measured in mmol/L, before and on the day of treatment discontinuation. Secondary endpoints include the comparison of sodium intake required to correct natraemia, the mechanism of action of urea, the impact on the duration of hospital stay, neurological outcomes at three months post-inclusion, adverse effects, persistence of natraemia correction 48 hours after treatment discontinuation, and the speed of natraemia correction.

Participants eligible for the study are adults aged 18 and over, diagnosed with non-traumatic subarachnoid hemorrhage and hyponatremia, defined by a natraemia of less than 135 mmol/L and a high natriuresis greater than 250 mmol/J, despite well-managed salt intake. The trial begins with a screening visit to confirm eligibility based on the inclusion criteria. Following randomization, participants will undergo regular follow-up visits to monitor treatment effects and safety. The end-of-study visit will occur at the conclusion of the treatment period, which is a maximum of five days. The expected length of participant involvement is from the initial screening through the end-of-study visit, with the possibility of early termination if adverse effects are observed or if the participant withdraws consent.

The clinical trial involves the administration of two treatments: **Urea** and **ergytonyl placebo**. **Urea** is the experimental medication used in this study. It is provided in the form of an **oral powder**. The active substance in this formulation is **Urea Ph. Eur.**, which is classified under the Specified Substance Group 3. The maximum daily dose of **Urea** is 4800 mg/kg/h, with a total maximum dose of 24000 mg/kg/h over a treatment period of up to 5 days. The route of administration is oral, and the medication is intended to demonstrate efficacy in correcting persistent hyponatremia in patients with subarachnoid hemorrhage. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The **ergytonyl placebo** serves as the non-experimental treatment in this study. It is administered orally, with a maximum daily dose of 5 ml and a total maximum dose of 25 ml over a 5-day treatment period. The placebo is used to provide a control for comparison against the effects of the experimental **Urea** treatment. The administration of the placebo follows the same oral route and dosing schedule as the experimental treatment to maintain consistency in the trial design. Participant compliance with the placebo regimen is also monitored to ensure the integrity of the study results.

The efficacy of urea treatment in correcting persistent **hyponatremia** in patients with subarachnoid hemorrhage will be assessed through a clinical trial. The primary endpoint for evaluating efficacy is the change in natraemia, measured in mmol/L, before and on the day of treatment discontinuation. Secondary endpoints include comparing the sodium intake required to correct natraemia, studying the mechanism of action of urea, evaluating the impact of treatment on the duration of hospital stay, assessing the neurological outcome three months post-inclusion, evaluating adverse effects, and determining the persistence of natraemia correction 48 hours after treatment discontinuation. Additionally, the speed of natraemia correction will be compared.