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 (BAIT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Bronchiectasis; Bronchiectasis Adult
• Intervention / Treatment: Other: Standard care; Drug: Itraconazole 65 MG

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 Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 3

Contacts and Locations

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • Chest clinic
    • Contact: Inderpaul S Sehgal, MD,DM; Phone Number: 6823 +91-172275; Email: inderpgi@outlook.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: November 29, 2023
• First Submitted That Met QC Criteria: December 6, 2023
• First Posted (Actual): December 7, 2023

Study Record Updates

• Last Update Posted (Actual): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Diseases; Bronchial Diseases; Bacterial Infections and Mycoses; Mycoses; Bronchiectasis; Aspergillosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole
• Other Study ID Numbers: Study 1291

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: It will be shared after a reasonable request to the corresponding author and obtaining proper ethics approval

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No