Evaluation of Methylprednisolone and Isavuconazonium Sulfate in Immunocompromised Patients with Acute Respiratory Failure of Undetermined Etiology

The primary objective of this study is to evaluate the efficacy of **steroids** ± isavuconazole in reducing 90-day mortality in immunocompromised patients with acute respiratory failure (ARF) from undetermined etiology by day 3. This is clinically relevant as it addresses the high mortality risk associated with ARF in this vulnerable patient population, potentially offering a therapeutic strategy to improve survival outcomes.

Secondary objectives include:

• Assessing how early empirical therapy impacts ICU, hospital, and day-28 mortality.
• Determining whether steroids increase the incidence of ICU-acquired microbiologically documented bacterial infections within 3 months post-randomization.
• Evaluating the proportion of patients developing invasive fungal infections within 3 months post-randomization.
• Investigating the reactivation rates of HSV, VZV, or CMV within 3 months post-randomization.
• Exploring whether steroids are associated with severe hypokalemia, newly acquired or decompensated diabetes, or severe or newly acquired hypertension.
• Examining if isavuconazole promotes the emergence of infections with Aspergillus or mucorale species with reduced sensitivity to the drug.
• Monitoring the occurrence of **Candida** infections.
• Analyzing the impact of steroids on psychiatric symptoms such as Post-traumatic Stress Disorder, anxiety, and depression at 6 months.
• Evaluating how early intervention can improve quality of life at 6 months.

The clinical trial involves **patients with acute respiratory failure** from undetermined etiology, specifically targeting an immunocompromised population. The study includes both male and female participants, aged between 18 and 90 years. The trial population is selected based on specific criteria, including the use of immunosuppressive drugs, history of solid organ transplant, presence of solid tumors, hematological malignancies, or primary immune deficiency. Participants are required to have been admitted to the ICU for acute respiratory failure, characterized by symptoms such as respiratory distress, tachypnea, cyanosis, labored breathing, and a need for significant oxygen support. The trial focuses on a vulnerable population, and informed consent is obtained from the patient or a representative. The sponsor has not provided the total number of participants involved in the study.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study with a 2x2 factorial design, aimed at evaluating the impact of **methylprednisolone** and **isavuconazonium sulfate** on reducing 90-day mortality in immunocompromised patients with acute respiratory failure of undetermined etiology. The trial will involve the administration of these interventions for a maximum period of 14 days or until the patient is discharged from the ICU. The study is expected to run from February 18, 2021, to August 18, 2024, with the primary endpoint being mortality at day 90. Secondary endpoints include ICU mortality, hospital mortality, and the incidence of various infections and conditions within three months following randomization.

Participants will be involved in the study for a period of up to 14 days, with the possibility of early termination if they are discharged from the ICU or if any exclusion criteria are met post-enrollment. The study will commence with a screening visit to confirm eligibility based on criteria such as age, immunocompromised status, and the presence of acute respiratory failure without a known etiology. Following successful screening, participants will be randomized to receive either the active treatment or placebo. Study visits will include regular monitoring and assessments to evaluate the safety and efficacy of the interventions. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, during which final assessments will be conducted to gather data on the primary and secondary endpoints.

Inclusion criteria for the trial require participants to be aged between 18 and 90 years, have a history of immunosuppression, and be admitted to the ICU for acute respiratory failure characterized by specific clinical signs. Exclusion criteria are not explicitly detailed in the provided data. The trial's design ensures that neither the participants nor the investigators are aware of the treatment allocations, maintaining the integrity of the double-blind methodology. The study aims to provide valuable insights into the management of acute respiratory failure in immunocompromised patients, with a focus on improving survival outcomes and understanding the potential risks associated with the interventions.

The clinical trial involves the administration of **Methylprednisolone**, a chemical compound used as an experimental medication. It is provided in the form of a **powder for solution for injection**. The administration route is **intravenous infusion**, with a dosage of 2 mg/kg per day, not exceeding a total dose of 2025 mg over a maximum treatment period of 14 days. The medication is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

**CRESEMBA** (Isavuconazonium sulfate) is another experimental medication used in this trial. It is supplied as a **200 mg powder for concentrate for solution for infusion**. The administration is conducted via **intravenous infusion**, with a maximum daily dose of 600 mg and a total dose not exceeding 2600 mg over a 14-day period. This medication is also not intended for pediatric use. Compliance with the dosing regimen will be closely monitored to ensure adherence to the protocol.

The trial also includes the use of a **placebo** for both Methylprednisolone and CRESEMBA. The placebo for CRESEMBA is administered in a manner consistent with the active drug to maintain the double-blind nature of the study. Similarly, the placebo for Methylprednisolone is used to ensure the integrity of the trial's blinding process. These placebos are designed to mimic the appearance and administration route of their respective active medications, although they contain no active substances.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the reduction in **mortality at day 90** among immunocompromised patients with acute respiratory failure (ARF) of undetermined etiology. Secondary endpoints include ICU mortality, hospital mortality, day 28 mortality, and the proportion of patients with ICU-acquired microbiologically documented bacterial infections. Additional secondary endpoints involve the proportion of patients with invasive fungal infections within three months following randomization, the occurrence of severe hypokalemia, decompensated diabetes, severe or newly acquired hypertension, and the emergence of Aspergillus species with decreased sensitivity to isavuconazole. The incidence of Candida infection, post-traumatic stress disorder, anxiety, and depression at six months, as well as quality of life at six months, will also be evaluated.

The trial will employ a multicenter, double-blind, randomized controlled design with a 2x2 factorial approach. The intervention involves the administration of steroids with or without isavuconazole for a maximum of 14 days or until ICU discharge. Efficacy parameters will be collected and analyzed at specified time points, including day 28, day 90, and six months post-randomization. The tools and instruments for efficacy assessments include validated scales for post-traumatic stress disorder (IES-R), anxiety and depression (HADS), and quality of life (SF36). The trial aims to provide comprehensive data on the impact of the intervention on mortality and other health outcomes in the specified patient population.