Evaluation of a Weaning Protocol for High-Flow Nasal Oxygen Therapy in Patients with De Novo Acute Respiratory Failure: A Multicenter Randomized Controlled Trial

The primary objective of this study is to demonstrate that the implementation of a **weaning protocol** for patients undergoing **High-Flow Nasal Oxygen Therapy** (HFNOT) significantly increases the likelihood of successful weaning by day 7 post-randomization. This is clinically relevant as it addresses the management of patients with **de novo acute respiratory failure**, potentially reducing the duration of HFNOT and associated healthcare resources.

Secondary objectives include:

• To show that the use of a high-flow nasal oxygen weaning protocol increases the probability that the patient will be weaned from high-flow nasal oxygen therapy at day 28 post-randomization.
• Compare the incidence of intubation, use of curative non-invasive ventilation, or death up to day 28.
• Describe the duration of use of high-flow nasal oxygen therapy in patients weaned from high-flow nasal oxygen therapy.
• Study the evolution of the ROX index during the weaning phase.
• Study the evolution of accessory respiratory muscle activation and dyspnea during the weaning phase.
• Compare the length of stay in intensive care and/or continuous care units.
• Compare the duration of stay between admission to the intensive care unit and/or continuous monitoring unit and discharge from the intensive care unit or the ability to be discharged.

The clinical trial focuses on patients experiencing **de novo acute respiratory failure**. The sponsor has not provided information regarding the total number of participants. The study population includes both male and female subjects, aged 18 years and older, who are admitted to an intensive care unit for acute hypoxemic respiratory failure. Participants are required to be treated with high-flow nasal oxygen therapy at a flow rate of at least 50L/min and an inspired oxygen fraction of 0.5 or higher. The trial includes individuals with a stable or improving ROX index, greater than 4.88, within the 6 hours prior to inclusion. Participants must have undergone a gas measurement under high-flow nasal oxygen therapy within 24 hours of inclusion and have been treated with high-flow nasal oxygen for at least 24 hours in an intensive care or continuous care unit. The trial population is selected based on these criteria, and participants must be affiliated with a social security scheme and provide written consent. The study includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the provided data.

The clinical trial is designed to evaluate the efficacy of a weaning protocol for patients undergoing **high-flow nasal oxygen therapy** in the intensive care unit (ICU) due to **de novo acute respiratory failure**. This is a multicenter, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial aims to demonstrate that the protocol increases the probability of successful weaning from high-flow nasal oxygen therapy by day 7 post-randomization. The study is expected to run until October 2026, with recruitment having commenced in September 2023.

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), admission to the ICU for acute hypoxemic respiratory failure, and treatment with high-flow nasal oxygen therapy. The inclusion visit will also assess the stability or improvement of the ROX index and require a gas measurement within 24 hours prior to inclusion. Follow-up visits will be conducted to monitor the primary endpoint, which is the success rate of weaning by day 7, defined as being weaned for more than 48 hours without the need for non-invasive ventilation or intubation, and being alive at day 7. Secondary endpoints include the weaning rate at day 28, time to definitive weaning, and cumulative incidence of intubation and non-invasive ventilation up to day 28. The end-of-study visit will assess the overall outcomes, including mortality rate and length of stay in the ICU.

Participant involvement is expected to last up to 28 days, with the possibility of early termination if the participant experiences significant adverse events or if the study protocol is violated. The trial is categorized as a low-intervention study, with the medicinal product being **oxygen** administered as a cryogenic medicinal gas via inhalation. The maximum daily dose is 60 liters, with a total treatment period not exceeding 28 days. The trial is conducted under the authorization of AIR LIQUIDE SANTE INTERNATIONAL, ensuring compliance with regulatory standards and ethical guidelines.

The clinical trial involves the use of **OXYGENE MEDICINAL LIQUIDE AIR LIQUIDE SANTE FRANCE**, a medicinal gas in cryogenic form, intended for inhalation via a fixed evaporator. The active substance in this experimental medication is **oxygen**, which is chemically derived. The pharmaceutical form is specifically designed for inhalation gas administration. The maximum daily dose is 60 liters, with a total maximum dose of 60 liters over the treatment period. The treatment duration is capped at 28 days. The administration route is through inhalation, ensuring direct delivery to the respiratory system. This product is not a pediatric formulation and is not classified as an orphan drug.

In this study, the experimental treatment is compared against the standard-of-care therapy, which involves the use of high-flow nasal oxygen therapy. The trial aims to evaluate the efficacy of a weaning protocol from high-flow nasal oxygen therapy in the intensive care unit setting. The primary objective is to determine if the protocol increases the likelihood of successful weaning by day 7 post-randomization. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in the clinical trial titled "Weaning protocol for high-flow nasal oxygen therapy in the ICU - Multicenter randomized controlled trial. HiFloWEAN" will be assessed using both primary and secondary endpoints. The primary endpoint is the success rate at Day 7 (D7), defined as "definitive" weaning from high-flow nasal oxygen therapy. Success is characterized by patients being weaned for more than 48 hours without the need for non-invasive ventilation or intubation and being alive at D7.

Secondary endpoints include the weaning rate from high-flow nasal oxygen therapy at Day 28 (D28), time to definitive weaning between randomization and D28, and cumulative incidences of intubation and curative non-invasive ventilation up to D28. Additional secondary endpoints are the mortality rate at D28, the number of days on high-flow nasal oxygen therapy for patients permanently weaned, and the evolution of the **ROX index** during the weaning phase. Other measures include the evolution of accessory respiratory muscle engagement by Patrick score, progression of dyspnoea assessed by the modified Borg scale, length of stay in intensive care, and the duration of stay from admission to discharge or the ability to be discharged from intensive care, assessed through an aptitude assessment grid.