Evaluation of Methylprednisolone Hydrogen Succinate Versus Placebo on Ventilator-Free Days in Severe COPD Exacerbations in ICU Patients

The primary objective of this study is to determine if the systemic administration of **corticosteroids**, specifically methylprednisolone, increases the number of ventilator-free days (VFD) and survival at day 28 in patients with chronic obstructive pulmonary disease (COPD) admitted to an intensive care unit (ICU), step-up unit, or respiratory care unit for acute exacerbations requiring ventilatory support, either invasive or non-invasive. This is clinically relevant as it may improve patient outcomes by reducing the duration of mechanical ventilation and potentially enhancing survival rates.

Secondary objectives include evaluating the effect of corticosteroids compared to placebo on:

• Mechanical ventilation and support
• Side effects of corticosteroids
• Length of stay
• Mortality
• Exacerbations of COPD

The clinical trial involves participants diagnosed with **chronic obstructive pulmonary disease (COPD)**, specifically those experiencing an acute exacerbation requiring ventilatory support. The study population includes both male and female subjects aged 40 years and older. Participants are required to have a strong suspicion or documented diagnosis of COPD, characterized by persistent respiratory symptoms and a history of exposure to risk factors such as tobacco smoke. The trial does not involve a vulnerable population. Participants must be admitted to an ICU, step-up unit, or respiratory care unit within 24 hours of the onset of acute respiratory failure. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, including severe acute exacerbation of COPD and the necessity for mechanical ventilation. Participants' general health status is compromised due to the acute nature of their condition, and they must be affiliated with or benefit from the French health insurance system. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of systemic **corticosteroids** compared to placebo in increasing the number of ventilator-free days and survival at day 28 in patients with severe acute exacerbations of **chronic obstructive pulmonary disease (COPD)** requiring ventilatory support. This is a multicenter, randomized, double-blind, controlled trial. The trial is expected to run from October 25, 2021, to January 31, 2027. Participants will be randomly assigned to receive either **methylprednisolone hydrogen succinate** or a placebo, both administered via intravenous injection. The maximum treatment period is five days.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥ 40 years), documented COPD, and severe acute exacerbation requiring mechanical ventilation. Following the inclusion visit, participants will undergo regular follow-up visits to monitor treatment effects and safety. The primary endpoint is the number of ventilator-free days and survival at day 28. Secondary endpoints include the rate of non-invasive ventilation (NIV) failure, duration of NIV and invasive mechanical ventilation, and various clinical outcomes such as circulatory support-free days, severe hyperglycemia, and ICU-acquired infections.

The expected length of participant involvement is up to 90 days, with assessments continuing until day 90 post-hospital discharge. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial aims to provide robust data on the impact of corticosteroids on ventilatory support duration and survival in COPD patients, contributing to evidence-based management strategies in critical care settings.

The clinical trial involves the administration of **Methylprednisolone Viatris 120 mg**, a **poudre pour solution injectable** intended for **intravenous administration**. The active substance in this experimental medication is **methylprednisolone hydrogen succinate**, a chemical compound classified under the ATC code **H02AB04**. The pharmaceutical form is a **solution for injection**, and the medication is provided by Viatris Sante. The maximum daily dose is set at **1 mg/kg**, with a total maximum dose of **1 mg/kg** over a treatment period not exceeding **5 days**. The administration schedule is designed to ensure compliance, with monitoring protocols in place to assess participant adherence to the dosing regimen.

The comparator treatment in this study is **Sodium Chlorure 0.9% Bioluz**, a **solution injectable** provided in a pouch for **intravenous administration**. The active substance is **sodium chloride**, also a chemical compound, classified under the ATC code **B05XA03**. This solution serves as a placebo in the trial, with a maximum daily dose of **50 ml** and a total maximum dose of **2500 ml** over a **5-day** treatment period. The administration of this solution is also monitored to ensure participant compliance and to maintain the integrity of the trial's blinding process.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the number of ventilator-free days (VFD) and alive at day 28 in patients with severe acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD) admitted to an intensive care unit (ICU), step-up unit, or respiratory care unit. Secondary endpoints include the non-invasive ventilation (NIV) failure rate, defined by intubation, duration of NIV and invasive mechanical ventilation, circulatory support-free days and alive at day 28, severe hyperglycemia requiring intravenous insulin before day 5, and gastrointestinal bleeding requiring intervention. Additional secondary endpoints are uncontrolled arterial hypertension necessitating medication changes, ICU-acquired weakness assessed by MRC-score on day 28 or at ICU discharge, ICU-acquired infections, length of ICU and hospital stay, ICU and hospital mortality, day 28 and day 90 mortality, standardized mortality ratio (SMR), number of new exacerbations or hospitalizations between discharge and day 90, and patient-reported outcomes on dyspnea and comfort at day 90.