Evaluation of Goal-Directed Fluid Removal Using Furosemide Versus Placebo in Adult ICU Patients with Moderate to Severe Fluid Overload

The primary objective of this study is to evaluate the **benefits and harms** of goal-directed fluid removal using **furosemide** compared to a placebo in adult intensive care unit (ICU) patients experiencing moderate to severe **fluid overload**. The study aims to determine whether forced fluid removal with furosemide, as opposed to spontaneous fluid excretion with a placebo, will increase the number of days patients are alive and out of the hospital by day 90. This is clinically relevant as fluid overload is a common and serious condition in critically ill patients, and effective management could improve patient outcomes and reduce hospital stays.

The clinical trial involves a total of **150 participants** who are adult patients admitted to the Intensive Care Unit (ICU) with moderate to severe **fluid overload**. The study population includes both male and female subjects, aged 18 years and above, who are clinically stable as assessed by specific medical criteria. Participants were selected based on their acute admission to the ICU and a clinically estimated fluid accumulation of at least 5% of their ideal body weight. The trial population is characterized by a vulnerable group due to their critical health status. Lifestyle considerations such as diet and physical activity are not specified, as the focus is on the medical condition and stability of the participants. The selection criteria ensure that the study targets individuals who are most likely to benefit from the intervention being tested, which is the goal-directed fluid removal with furosemide versus placebo.

The clinical trial is designed to evaluate the efficacy and safety of **furosemide** in comparison to a placebo for the management of fluid overload in critically ill patients. This study is a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thus minimizing bias. The trial is set to run from August 24, 2020, to February 29, 2028, with the recruitment phase having commenced on August 24, 2020.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as acute ICU admission, age of 18 years or above, and clinical stability. The inclusion criteria also require a fluid accumulation of at least 5% of the ideal body weight. Following the inclusion visit, participants will be randomly assigned to receive either furosemide or a placebo, administered via intravenous infusion. The primary endpoint is the number of days alive and out of the hospital at day 90, with secondary endpoints including all-cause mortality and quality of life assessments at one year.

Throughout the trial, participants will attend follow-up visits to monitor their health status and any adverse events. These visits are crucial for assessing the safety and efficacy of the treatment. The end-of-study visit will occur at the conclusion of the participant's involvement, which is expected to last up to 90 days. Conditions that may lead to early termination from the study include significant adverse reactions or withdrawal of consent by the participant.

The trial aims to provide valuable insights into the potential benefits of goal-directed fluid removal using furosemide in ICU patients with fluid overload, contributing to improved patient outcomes and informing future clinical practices.

The clinical trial involves the administration of **furosemide**, a loop diuretic, as the experimental medication. Furosemide is provided in an infusion form and is administered via **intravenous infusion**. The maximum daily dose of furosemide is 1500 mg, with a total maximum dose of 135,000 mg over a treatment period of up to 90 days. The active substance in furosemide is **furosemide Ph. Eur.**, and it is produced by Region Hovedstadens Apotek. The trial aims to evaluate the effects of goal-directed fluid removal in intensive care patients with fluid overload.

The trial also includes a **placebo** treatment, which consists of sodium chloride 0.9% for intravenous infusion. In Denmark and The Netherlands, the placebo is produced by the capital region pharmacy in Denmark, while in Sweden, sodium chloride 0.9% is available with marketing authorization and is prepared on-site for blinding purposes. The placebo serves as a comparator to assess the efficacy of furosemide in the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial is designed to be randomized, blinded, and placebo-controlled to objectively assess the benefits and potential harms of furosemide compared to placebo in the target patient population.

The efficacy of the clinical trial titled "Goal directed fluid removal with furosemide in intensive care patients with fluid overload: a randomised, blinded, placebo-controlled trial (GODIF)" will be assessed using both primary and secondary endpoints. The primary endpoint is the number of days alive and out of hospital at day 90. This measure will provide a direct assessment of the intervention's impact on patient recovery and hospital discharge rates.

Secondary endpoints include several parameters: all-cause mortality at day 90, days alive without life support at day 90, and the number of participants experiencing one or more serious adverse events and serious adverse reactions at day 90. Additionally, long-term outcomes will be evaluated, such as all-cause mortality at 1 year, health-related quality of life at 1 year assessed by the EQ-5D-5L and EQ-VAS scores, participants' subjective assessment of their quality of life at 1 year, and cognitive function after 1 year assessed by the Montreal Cognitive Assessment test (MoCA 5 min).

The trial will involve the administration of **furosemide** or placebo (sodium chloride 0.9% for intravenous infusion) to adult ICU patients with moderate to severe fluid overload. The primary objective is to determine if forced fluid removal with furosemide compared with placebo will increase the number of days alive and out of hospital at day 90. The efficacy assessments will be conducted at specified timepoints, including day 90 and 1 year, to capture both immediate and long-term effects of the treatment.