- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04824417
A Randomized Controlled Trial to Compare the Clinical Outcomes With Six Months of Therapy With Oral Itraconazole Versus Oral Voriconazole for Management of Treatment naïve Subjects With Chronic Pulmonary Aspergillosis
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Aspergillus is a saprophytic fungus which is present normally in our surroundings and causes a large number of pulmonary diseases spreading through inhalational route. The spectrum of disease caused by aspergillus spp. is wide with the manifestations of the disease being governed primarily by the status of the underlying host immunity, which then determines the nature of the host-aspergillus interaction. Patients with an intact immunity have a more stable and indolent form of disease like aspergilloma whereas with a worsening immune status, the risk of invasive disease increases. Chronic pulmonary aspergillosis (CPA) and allergic bronchopulmonary aspergillosis (ABPA) are two of the commonest pulmonary manifestations seen in non-immunocompromised patients whereas invasive pulmonary aspergillosis being more common in the immunocompromised patients.(1-3) Estimates suggest that CPA affects around 3 million people across the globe, which may still be an under estimated number as the disease co exists with other pulmonary co-morbidities which make accurate diagnosis a pitfall. In India the annual incidence of CPA was estimated in 2011 and varied between 27,000-0.17 million cases, with different estimates. Based on the mortality rate for CPA which was estimated to be 15% annually, the 5-year prevalence of CPA was placed at 290,147 cases with 5-year prevalence rate being 24 per 100,000 in the same year.(4, 5) The disease confers significant morbidity and mortality, making it a significant burden for the society as well as the healthcare. Apart from the respiratory symptoms, CPA causes significant constitutional symptoms as well which adds to the misery of the patient. The diagnosis of CPA is based on presence of chronic symptoms, consistent radiology and demonstration of Aspergillus by direct (culture) or indirect (serological) methods.(1-3) Even though CPA is more of a disease spectrum but overall it is characterized by slowly progressive lung cavitation which may or may not show presence of mycetoma /fungal ball in patients with pre-existing structural lung diseases, even though other patterns have also been identified.
The treatment options majorly consist of medical management with at least 6-month long treatment with antifungal drugs - most significantly the azole groups. Itraconazole is the preferred azole for the treatment of CPA.(6-8) However the response with itraconazole is seen in around 60-75% of the subjects.(9) Moreover, about 30%-50% of the subjects have disease relapse that requires prolonged therapy. The lower response could be because of variable pharmacokinetics and drug absorption of oral itraconazole. Also, itraconazole has many drug interactions. Voriconazole is a third-generation azole and is currently the therapy of choice for invasive aspergillosis due to its lower minimal inhibitory concentration (MIC) values compared to itraconazole. In addition, the pharmacokinetics of voriconazole are not variable and oral form has a good bioavailability (up to 95%). In a previous study, the use of voriconazole resulted in radiological control in 97% of the subjects and a significant improvement in patients' symptoms but global success at six-months was only seen in 32% subjects.(10) However, despite being multicenter the study only included 48 subjects. Moreover, there was no control group and the authors did not use therapeutic dose monitoring. In addition, the study also included subjects with subacute invasive aspergillosis (SAIA). Thus, there is lack of information regarding the role of voriconazole in subjects with CPA. We hypothesize that the use of voriconazole will be associated with better treatment outcomes compared with oral itraconazole in treatment naïve subjects with CPA. In this randomized controlled trial, we compare the clinical outcomes of six months therapy with oral itraconazole with oral voriconazole in treatment naïve subjects with chronic pulmonary aspergillosis.
REFERENCES
- Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2018.
- Patterson TF, Thompson GR, 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60.
- Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. The European respiratory journal. 2016;47(1):45-68.
- Agarwal R, Denning DW, Chakrabarti A. Estimation of the burden of chronic and allergic pulmonary aspergillosis in India. PloS one. 2014;9(12):e114745.
- Agarwal R. Burden and distinctive character of allergic bronchopulmonary aspergillosis in India. Mycopathologia. 2014;178(5-6):447-56.
- Agarwal R, Aggarwal AN, Sehgal IS, Dhooria S, Behera D, Chakrabarti A. Performance of serum galactomannan in patients with allergic bronchopulmonary aspergillosis. Mycoses. 2015;58(7):408-12.
- Agarwal R, Dua D, Choudhary H, Aggarwal AN, Sehgal IS, Dhooria S, et al. Role of Aspergillus fumigatus-specific IgG in diagnosis and monitoring treatment response in allergic bronchopulmonary aspergillosis. Mycoses. 2017;60(1):33-9.
- Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother. 2014;69(5):1162-76.
- Agarwal R, Vishwanath G, Aggarwal AN, Garg M, Gupta D, Chakrabarti A. Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature. Mycoses. 2013;56(5):559-70.
- Cadranel J, Philippe B, Hennequin C, Bergeron A, Bergot E, Bourdin A, et al. Voriconazole for chronic pulmonary aspergillosis: a prospective multicenter trial. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2012;31(11):3231-9.
Study Type
Enrollment (Estimated)
Phase
- Phase 3
Contacts and Locations
Study Locations
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-
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Chandigarh, India, 160012
- Chest clinic
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Chandigarh, India, 160012
- Respiratory ICU, Department of Pulmonary Medicine, PGIMER
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
The cases will include treatment naïve consecutive subjects with chronic cavitary pulmonary aspergillosis (CPA). The diagnosis of CPA will be made by a multidisciplinary team (pulmonary physicians, radiologist and microbiologist) based on composite of clinical, radiological and microbiological criteria.(9, 10) This includes presence of all the following: (i) one or more clinical symptoms (persistent cough, recurrent hemoptysis, weight loss, malaise, fever and dyspnea) for ≥3 months; (ii) slowly progressive or persistent radiological findings (one or more cavities and surrounding fibrosis, infiltrates, consolidation, with or without fungal ball or progressive pleural thickening) on computed tomography (CT) of the thorax; (iii) immunological (A.fumigatus-specific IgG >27 mgA/L or positive Aspergillus precipitins) or microbiological evidence of Aspergillus infection (growth of Aspergillus in respiratory secretions or serum galactomannan index >0.6 or BALF galactomannan index >1.4); and, (iv) exclusion of other pulmonary disorders with similar presentation.
Exclusion Criteria:
Subjects with any of the following will be excluded: (i) failure to provide informed consent; (ii) patients on immunosuppressive drugs, intake of prednisolone (or equivalent) >10 mg for at least 3 weeks or a diagnosis of human immunodeficiency virus syndrome; (iii) intake antifungal azoles for >3 weeks in the preceding six months; (iv) subjects with active pulmonary infection due to mycobacterium tuberculosis or mycobacteria other than tuberculosis (MOTT); (v) subjects with others forms of pulmonary aspergillosis (allergic bronchopulmonary aspergillosis, chronic necrotizing aspergillosis and angio-invasive aspergillosis); and, (vi) pregnancy.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Control
Oral itraconazole
|
Control
|
Experimental: Intervention
Oral voriconazole
|
Comparator
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
proportion of subjects with an overall favourable response at the end of oral itraconazole therapy
Time Frame: six months
|
six months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
number of relapses at six-months after completion of therapy
Time Frame: six months
|
six months
|
adverse events due to itraconazole or voriconazole
Time Frame: six months
|
six months
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Infections
- Respiratory Tract Diseases
- Lung Diseases
- Bacterial Infections and Mycoses
- Mycoses
- Lung Diseases, Fungal
- Aspergillosis
- Pulmonary 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
- Voriconazole
Other Study ID Numbers
- PGI/IEC/2019/002366
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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