Evaluation of the Safety and Efficacy of Nebulized Opelconazole Combined with Systemic Antifungal Therapy in Refractory Invasive Pulmonary Aspergillosis

The primary objective of this study is to evaluate the **efficacy** of nebulized PC945, also known as opelconazole, when combined with systemic antifungal therapy for the treatment of refractory **invasive pulmonary aspergillosis** (IPA). This is clinically relevant as refractory IPA is a severe condition with limited treatment options, and improving therapeutic outcomes could significantly impact patient prognosis.

Secondary objectives include assessing the **safety** and **tolerability** of nebulized PC945 in combination with systemic antifungal therapy for the treatment of refractory IPA. Understanding the safety profile is crucial for determining the feasibility of this treatment regimen in clinical practice.

The clinical trial involves a total of **77 participants** diagnosed with **Refractory Invasive Pulmonary Aspergillosis**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific criteria, including a proven or probable diagnosis of the condition according to established consensus definitions, and a lack of response to adequate antifungal therapy. The trial population includes individuals from a vulnerable population, indicating a need for careful consideration of their health status. Lifestyle factors such as diet, physical activity, and habits were not specified by the sponsor. The selection process ensures that the participants meet the necessary inclusion criteria to assess the efficacy of nebulized PC945 in combination with systemic antifungal therapy.

The clinical trial is designed to evaluate the **safety** and **efficacy** of nebulized PC945, containing the active substance **opelconazole**, in combination with systemic antifungal therapy for the treatment of **refractory invasive pulmonary aspergillosis**. This is a Phase III, double-blind, randomized, placebo-controlled study. The trial aims to assess the efficacy of the investigational product over a period of 12 weeks, with the primary endpoint being the number of participants achieving a complete or partial overall response by Day 84. Secondary endpoints include the time to complete or partial overall clinical response within the same timeframe.

Participants will be randomly assigned to receive either the investigational product or a placebo, both administered via inhalation. The trial will commence with a screening visit to confirm eligibility based on criteria such as proven or probable invasive pulmonary aspergillosis that has not responded to adequate antifungal therapy. Following randomization, participants will undergo regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments of clinical response and any adverse events. The end-of-study visit will occur at the conclusion of the 12-week treatment period.

The expected duration of participant involvement in the trial is approximately 12 weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial is estimated to conclude by April 2025, with recruitment having started in April 2022. Participants will be closely monitored throughout the study to ensure adherence to the protocol and to evaluate the therapeutic potential of the investigational product in this patient population.

The clinical trial involves the administration of **PC945**, an investigational medication formulated as a **nebuliser suspension**. The active substance in PC945 is **opelconazole**, a chemical compound developed by Pulmocide Ltd. The medication is administered via **inhalation use**. The dosing regimen for PC945 includes a maximum daily dose of 29.6 mg/g and a total maximum dose of 2486.40 mg/g over a treatment period of up to 84 days. The primary objective of the trial is to evaluate the efficacy of nebulized PC945 in combination with systemic antifungal therapy for the treatment of refractory invasive pulmonary aspergillosis.

In addition to the experimental treatment, the study employs a **placebo** control, referred to as PC945 Placebo Nebuliser Liquid. This placebo is designed to match the pharmaceutical form of the active treatment, ensuring blinding in the double-blind, randomized, placebo-controlled study design. The placebo is administered in the same manner as the active treatment, via inhalation, to maintain consistency in the administration process. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The efficacy of nebulized PC945 in combination with systemic antifungal therapy for the treatment of refractory **invasive pulmonary aspergillosis** (IPA) will be assessed in a double-blind, randomized, placebo-controlled study. The primary endpoint for evaluating efficacy is the number of participants with complete or partial overall response up to 12 weeks (Day 84). Additionally, a secondary endpoint will measure the time to complete or partial overall clinical response within the same timeframe. These endpoints will be used to determine the effectiveness of the treatment regimen in achieving clinical improvement in participants with refractory IPA.