Evaluation of Adjunctive Hyperbaric Oxygen Therapy on 30-Day Mortality in Necrotizing Soft-Tissue Infection Patients

The primary objective of the HOT-NSTI trial is to evaluate the **efficacy** of adjunctive hyperbaric oxygen treatment in reducing 30-day all-cause mortality in patients with **necrotizing soft-tissue infection** (NSTI). This trial represents the first randomized clinical trial designed to assess this specific objective, highlighting its clinical relevance in potentially improving survival outcomes for patients suffering from this severe condition.

The clinical trial involves a total of **500 participants** diagnosed with **necrotizing soft-tissue infection** (NSTI). The study population includes both male and female adults aged 18 years and older. Participants were selected based on surgical confirmation of NSTI, characterized by necrotic or deliquescent soft tissue with widespread undermining of the surrounding tissue, as observed perioperatively by a surgeon. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of all participants. The trial aims to evaluate the efficacy of hyperbaric oxygen treatment as an adjunctive therapy in reducing 30-day all-cause mortality among patients with NSTI.

The clinical trial is designed to evaluate the efficacy of **hyperbaric oxygen** treatment as an adjunctive therapy for patients with **necrotizing soft-tissue infection** (NSTI). This trial is structured as a randomized, double-blind, controlled study, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thereby minimizing bias. The trial is categorized as a low-intervention clinical trial, as the investigational product, **Medical Liquid Oxygen**, is already authorized and used in the approved patient population. The trial is expected to commence recruitment on September 1, 2025, and conclude by August 31, 2032.

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 surgically confirmed NSTI. Following randomization, participants will receive the treatment and be monitored for primary and secondary endpoints, including 30-day and 90-day all-cause mortality, amputation rates, quality of life assessments, and other health outcomes. Follow-up visits will be scheduled to assess these endpoints, with the final visit marking the end of the study for each participant. The expected duration of participant involvement is up to 90 days post-randomization, with the possibility of early termination if adverse events occur or if the participant withdraws consent.

The primary endpoint of the trial is the 30-day all-cause mortality rate post-randomization, while secondary endpoints include 90-day all-cause mortality, amputation within 7 days, quality of life at Day 90, days alive and out of hospital within 90 days, ventilator-free days within 7 days, need for renal-replacement therapy, and the incidence of serious adverse events. The trial's low-intervention status is justified by the safety profile of the treatment, with adverse events being rare and mostly mild. The trial will adhere to rigorous safety monitoring and adverse event reporting protocols to ensure participant safety throughout the study.

The clinical trial involves the use of **Medical Liquid Oxygen** as the experimental medication. This product is classified as a **medicinal gas, cryogenic** and is manufactured by AIR LIQUIDE LTD. The active substance in this medication is **oxygen**, which is of chemical origin. The administration route for Medical Liquid Oxygen is via **inhalation**. The dosing regimen allows for a maximum daily dose of 2 units per day, with a total maximum dose of 5 units over the course of the treatment. The maximum treatment period is set at 4 days. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of the adjunctive hyperbaric oxygen treatment in patients with necrotizing soft-tissue infection (NSTI). The trial aims to assess the impact of this treatment on 30-day all-cause mortality in the patient population. Participants' adherence to the treatment protocol will be closely monitored to ensure the integrity of the trial data.

The efficacy of the adjunctive hyperbaric oxygen treatment in the HOT-NSTI trial will be assessed primarily through the evaluation of **30-day all-cause mortality** post-randomization in patients with necrotizing soft-tissue infection (NSTI). This primary endpoint will provide a direct measure of the treatment's impact on patient survival within the first month following intervention.

Secondary endpoints will further elucidate the treatment's efficacy by examining additional parameters, including **90-day all-cause mortality** post-randomization, the incidence of amputation within 7 days, and quality of life at Day 90, which will be evaluated using the 5Q-5D-5L and WHO-DAS questionnaires. Other secondary measures include the number of days patients are alive and out of the hospital within a 90-day period, ventilator-free days within 7 days post-randomization, the need for renal-replacement therapy within 7 days, and the number of subjects experiencing one or more serious adverse events up to 24 hours after the last treatment.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints, ensuring a comprehensive assessment of the treatment's impact over both short and extended periods. The use of validated scales and questionnaires will facilitate the accurate measurement of patient-reported outcomes, contributing to a robust evaluation of the treatment's overall efficacy in improving patient health and quality of life.