Compare Oral Itraconazole and Standard Care Versus Standard Care Alone in Patients With Non-cystic Fibrosis Related Bronchiectasis With Chronic Aspergillus Infection in Reducing Bronchiectasis Exacerbations

Study Overview
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Brief Summary
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There is an intricate link between bronchiectasis and fungi. Patients with cystic fibrosis frequently manifest fungal sensitization and fungal colonization with Aspergillus fumigatus.6 Aspergillus species also has a cause-and-effect relationship with non-CF (cystic fibrosis) bronchiectasis.7, 8 In allergic bronchopulmonary aspergillosis (ABPA), Aspergillus is the cause of bronchiectasis. In contrast, in other causes of bronchiectasis, A fumigatus can theoretically promote allergic response, which may result in poor lung function, increase the risk of exacerbations, and even cause ABPA over time.9, 10 In a recent study, we found an overall prevalence of Aspergillus sensitization of 29.5% and the prevalence of chronic aspergillus infection was 76%.11 The prevalence of chronic aspergillus colonization in non-(tuberculosis) TB-non-CF fibrosis was 47.5% (49/103).11 By mechanism similar to chronic bacterial colonization, chronic aspergillus infection or aspergillus sensitization can increase the risk of bronchiectasis exacerbation. Therefore, eradication of A. fumigatus from the airways of patients with bronchiectasis would decrease the future risk of a bronchiectasis exacerbation. Notably, in ABPA, use of itraconazole and voriconazole reduce the exacerbations by reducing the fungal burden in the airways.12, 13 In this randomized trial, we will investigate whether treatment with oral itraconazole for six months would reduce the future risk of bronchiectasis exacerbation in patients with non-CF-non-ABPA bronchiectasis.

Detailed Description
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Bronchiectasis is a chronic lung disease due to irreversible and abnormal dilatation of the bronchi. Bronchiectasis manifest with chronic cough, expectoration, hemoptysis, dyspnea, and others. Bronchiectasis can be broadly classified as genetic (cystic fibrosis [CF], ciliary dyskinesia and others) or acquired (post-infective, tuberculosis (TB), allergic bronchopulmonary aspergillosis [ABPA] and others).1 The natural course of bronchiectasis is associated with recurrent exacerbations that cause further damage and disease progression.2 Most exacerbations are caused by viral or bacterial infections, inflammation and external environment factors. Chronic bacterial infections increase the risk of bronchiectasis exacerbation.2 In a multicentric European study chronic infection with Pseudomonas aeruginosa was associated with an increased risk of exacerbation.3 Notably, change in the interaction between the bacterial microbiome by external inciting events (viral infection or air pollution) increases exacerbation risk.4 Similarly, viral infections by increasing the systemic and airway inflammation induce a bronchiectasis exacerbation.5 Airway inflammation both neutrophilic and eosinophilic are also important causes of bronchiectasis exacerbations.2 Most previous studies in non-CF bronchiectasis have not investigated the role of fungal sensitization or chronic fungal infection in causing bronchiectasis exacerbation. There is an intricate link between bronchiectasis and fungi. Patients with cystic fibrosis frequently manifest fungal sensitization and fungal colonization with Aspergillus fumigatus.6 Aspergillus species also has a cause-and-effect relationship with non-CF bronchiectasis.7, 8 In ABPA, Aspergillus is the cause of bronchiectasis. In contrast, in other causes of bronchiectasis, A fumigatus can theoretically promote allergic response, which may result in poor lung function, increase the risk of exacerbations, and even cause ABPA over time.9, 10 In a recent study, we found an overall prevalence of Aspergillus sensitization of 29.5% and the prevalence of chronic aspergillus infection was 76%.11 The prevalence of chronic aspergillus colonization in non-TB-non-CF fibrosis was 47.5% (49/103).11 By mechanism similar to chronic bacterial colonization, chronic aspergillus infection or aspergillus sensitization can increase the risk of bronchiectasis exacerbation. Therefore, eradication of A. fumigatus from the airways of patients with bronchiectasis would decrease the future risk of a bronchiectasis exacerbation. Notably, in ABPA, use of itraconazole and voriconazole reduce the exacerbations by reducing the fungal burden in the airways.12, 13 In this randomized trial, we will investigate whether treatment with oral itraconazole for six months would reduce the future risk of bronchiectasis exacerbation in patients with non-CF-non-ABPA bronchiectasis. Study question: Does oral itraconazole for six months reduce the bronchiectasis exacerbation in patients with non-cystic fibrosis bronchiectasis?

Official Title
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A Randomized Controlled Trial to Compare Oral Itraconazole and Standard Care Versus Standard Care Alone in Patients With Non-cystic Fibrosis Related Bronchiectasis With Chronic Aspergillus Infection in Reducing Bronchiectasis Exacerbations

Conditions
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Bronchiectasis, Bronchiectasis Adult

Intervention / Treatment
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* Drug: Itraconazole 65 MG
* Other: Standard care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adults subjects (≥13 years) with non-cystic fibrosis bronchiectasis fulfilling all the following criteria: • bronchiectasis on thin-section computed tomography (CT) chronic aspergillus infection defined by the presence of A.fumigatus-specific IgG ≥40 mgA/L clinically stable for at least three months prior to study inclusion Exclusion Criteria: We will exclude subjects with any of the following: allergic bronchopulmonary aspergillosis as the cause of underlying bronchiectasis cystic fibrosis post-tuberculosis bronchiectasis severe asthma current smokers active bacterial, mycobacterial (atypical or typical), or fungal (aspergillosis or mucormycosis) infections use of systemic antifungal drugs in past 3 months previous documented intolerance to itraconazole pregnancy failure to provide informed consent

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard care<br>Standard care of bronchiectasis | Other: Standard care<br>* Standard care for bronchiectasis<br>|
| Experimental: Itraconazole arm<br>Supra-bioavailable- Itraconazole capsule 65 mg | Drug: Itraconazole 65 MG<br>* Two capsules of suba-itraconazole 65 mg twice daily for 6 months<br>Other: Standard care<br>* Standard care for bronchiectasis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| frequency of bronchiectasis exacerbations during the study period | An exacerbation will be defined as clinical deterioration for at least 48 hours and the presence of three or more of the following six features: (1) increase in cough; (2) sputum volume/consistency; (3) sputum purulence; (4) breathlessness or exercise intolerance; (5) fatigue, malaise, or fever; (6) hemoptysis; and change of bronchiectasis treatment by a physician | (12 months [6 months each of intervention and observation]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to first exacerbation | Time taken for the first exacerbation | 12 months | 
| change in the spirometric lung function (FVC) | Spirometry will be done to measure FVC | 12 months | 
| change in the spirometric lung function ( FEV1) | Spirometry will be done to measure FEV1 | 12 months | 
| Change in 6 minute walk distance | 6 minute walk test will be done at baseline and at treatment completion | 6 months | 
| Adverse events | Adverse events during therapy will be assessed | 6 months | 
| change in the quality of life assessed by bronchiectasis health questionnaire | We will use BHQ at baseline and 6 months | 6 months |