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
Trial Snapshot
- Phase
- Phase 3
- Status
- Recruiting
- Sponsor
- Enrollment
- 80
- Locations
- 1
- Primary Endpoint
- frequency of bronchiectasis exacerbations during the study period
Study Overview
Brief Summary
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
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?
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 12 Years to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Standard care
Standard care of bronchiectasis
Intervention: Standard care (Other)
Itraconazole arm
Supra-bioavailable- Itraconazole capsule 65 mg
Intervention: Itraconazole 65 MG (Drug)
Itraconazole arm
Supra-bioavailable- Itraconazole capsule 65 mg
Intervention: Standard care (Other)
Outcomes
Primary Outcomes
frequency of bronchiectasis exacerbations during the study period
Time Frame: (12 months [6 months each of intervention and observation])
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
Secondary Outcomes
- change in the quality of life assessed by bronchiectasis health questionnaire(6 months)
- time to first exacerbation(12 months)
- change in the spirometric lung function (FVC)(12 months)
- Adverse events(6 months)
- change in the spirometric lung function ( FEV1)(12 months)
- Change in 6 minute walk distance(6 months)
Investigators
Inderpaul singh
Associate Professor
Post Graduate Institute of Medical Education and Research, Chandigarh