Comparative Efficacy of Itraconazole and Nebulised Amphotericin B in Non-Immunocompromised Chronic Pulmonary Aspergillosis Patients

The primary objective of this study is to compare the **therapeutic efficacy** of a six-month treatment regimen involving itraconazole and nebulised Ambisome® against a treatment with itraconazole alone in patients with **Chronic Pulmonary Aspergillosis** who are non- or mildly-immunocompromised, excluding those with a single aspergilloma. This comparison is clinically relevant as it aims to determine the most effective treatment strategy for managing this chronic fungal infection, potentially improving patient outcomes and guiding clinical practice.

Secondary objectives include: - Comparing both treatment strategies regarding clinical and/or radiological evolution after 3 and 6 months. - Evaluating major events during the follow-up period from month 6 to month 30. - Assessing relapse rates between month 6 and month 30. - Comparing mycological response after 3 and 6 months. - Analyzing the number of medical consultations or hospitalizations for respiratory symptoms. - Evaluating clinical and biological tolerance. - Assessing improvement in quality of life using the VQ-11 Questionnaire. - Estimating concordance for CPA diagnosis and evolution under treatment between clinical, radiological, mycological, and serological parameters.

The clinical trial involves participants diagnosed with **Chronic Pulmonary Aspergillosis**, excluding those with a single aspergilloma. The study population comprises both male and female subjects aged 18 years and older, who are non- or mildly immunocompromised. Participants are required to have an Aspergillus bronchopulmonary infection, confirmed by thoracic CT-scan images, and meet specific serological or microbiological criteria. The trial does not include a vulnerable population. Participants must be legally independent and affiliated with France's Health Care Regime. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified in the trial data.

The clinical trial is designed to evaluate the therapeutic efficacy of a six-month treatment regimen involving **itraconazole** and nebulised **AmBisome** compared to itraconazole alone in patients with **chronic pulmonary aspergillosis**. This study is a prospective, randomized, single-blind trial, excluding patients with a single aspergilloma. The trial aims to assess both clinical and radiological outcomes over a six-month period, with a primary endpoint focusing on therapeutic efficacy defined by clinical improvement or stability and radiological improvement. Secondary endpoints include clinical and radiological evolution at three and six months, major events, and relapse during a 24-month follow-up period post-treatment, as well as mycological response, quality of life, and clinical and biological tolerance.

Participants will be involved in the study for a total duration of 30 months, which includes a six-month treatment phase followed by a 24-month follow-up period. The trial will commence with an inclusion visit, where eligibility criteria such as age, documented **Aspergillus** bronchopulmonary infection, and informed consent will be confirmed. Subsequent study visits will occur at three-month intervals during the treatment phase to monitor clinical and radiological progress. The end-of-study visit will take place at 30 months to evaluate long-term outcomes and any major events or relapses.

Participants are expected to adhere to the study protocol for the entire duration unless specific conditions necessitate early termination. These conditions include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is anticipated to conclude by June 2029, with recruitment having started in December 2018. The study is not classified as low intervention and is categorized as a Phase III clinical trial, focusing on non- or mildly-immunocompromised patients with chronic pulmonary aspergillosis.

The clinical trial involves the administration of several treatments to evaluate their efficacy in patients with **Chronic Pulmonary Aspergillosis**. The primary experimental medication is **AmBisome liposomal 50 mg**, a dispersion for infusion containing the active substance **amphotericine B, liposome**. This medication is administered via oropharyngeal use, with a maximum daily dose of 50 mg and a total dose of 2400 mg over a six-month period. The administration method has been modified for this trial, with the medication being inhaled rather than intravenously infused.

Another key treatment in the trial is **SPORANOX 100 mg capsule rigide**, containing the active substance **itraconazole**. This medication is provided in capsule form for oral use, with a maximum daily dose of 400 mg and a total dose of 67200 mg over the six-month treatment period. This treatment serves as a comparator in the study.

Additional comparator treatments include **VFEND 200 mg film-coated tablets** and **Noxafil 100 mg gastro-resistant tablets**, containing the active substances **voriconazole** and **posaconazole**, respectively. Both are administered orally, with VFEND having a maximum daily dose of 400 mg and Noxafil 300 mg, each over a six-month period.

**CHLORURE DE SODIUM PROAMP 0.9%**, a solution for injection containing **sodium chloride**, is used as an auxiliary treatment. It is administered via oropharyngeal use, with a maximum daily dose of 12 ml and a total dose of 1152 ml over the study duration.

Lastly, **SALBUTAMOL**, a nebuliser solution, is included as an auxiliary treatment. It is administered via oropharyngeal use, with a maximum daily dose of 2.5 mg and a total dose of 120 mg over the six-month period.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial is designed to compare the therapeutic efficacy of the combined treatment of itraconazole and nebulised AmBisome against itraconazole alone in the specified patient population.

The efficacy of the clinical trial will be assessed through a combination of clinical and radiological parameters. The primary endpoint is defined as the therapeutic efficacy at 6 months, which is a composite criterion involving both clinical improvement or stability and radiological improvement. Secondary endpoints include clinical and radiological evolution after 3 and 6 months, where patients will be classified into categories of improvement, stability, or deterioration. Additionally, the trial will monitor major events and relapse during a 24-month follow-up period post-treatment, from month 6 to month 30.

Mycological response will be evaluated after 3 and 6 months of treatment. The number of medical consultations or hospitalizations for respiratory symptoms will be recorded during the 6-month treatment period and the subsequent 24-month follow-up. Clinical and biological tolerance will also be assessed. Quality of life improvements will be measured using the VQ-11 Questionnaire. Furthermore, an evaluation of concordance between parameters for Chronic Pulmonary Aspergillosis (CPA) diagnosis and evolution will be conducted as part of an ancillary project.