search
Back to results

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

Primary Purpose

Chronic Pulmonary Aspergillosis

Status
Recruiting
Phase
Phase 3
Locations
India
Study Type
Interventional
Intervention
Itraconazole 200 mg
Voriconazole 200mg
Sponsored by
Postgraduate Institute of Medical Education and Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Pulmonary Aspergillosis focused on measuring cpa, aspergillosis

Eligibility Criteria

13 Years - 90 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Chest clinicRecruiting
  • Respiratory ICU, Department of Pulmonary Medicine, PGIMERRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Control

Intervention

Arm Description

Oral itraconazole

Oral voriconazole

Outcomes

Primary Outcome Measures

proportion of subjects with an overall favourable response at the end of oral itraconazole therapy

Secondary Outcome Measures

number of relapses at six-months after completion of therapy
adverse events due to itraconazole or voriconazole

Full Information

First Posted
March 27, 2021
Last Updated
April 11, 2023
Sponsor
Postgraduate Institute of Medical Education and Research
search

1. Study Identification

Unique Protocol Identification Number
NCT04824417
Brief Title
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
Official Title
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 Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2021 (Actual)
Primary Completion Date
December 15, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Postgraduate Institute of Medical Education and Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The current initial therapy for CPA is with six months of oral itraconazole. However, the response with six months of therapy has a response rate of 65-70% and has a relapse rate after stopping treatment of up to 50%. Voriconazole is a third-generation azole and a theoretical advantage of lower MICs compared to itraconazole. Also, oral voriconazole has good availability (95%) in fasting state. This is likely to improve the response rate and reduce the chances of relapse of chronic pulmonary aspergillosis. There is no head to head comparison of oral itraconazole with oral voriconazole. In this study we intent 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Pulmonary Aspergillosis
Keywords
cpa, aspergillosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Randomized trial
Masking
ParticipantOutcomes Assessor
Masking Description
Single blinded
Allocation
Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Control
Arm Type
Active Comparator
Arm Description
Oral itraconazole
Arm Title
Intervention
Arm Type
Experimental
Arm Description
Oral voriconazole
Intervention Type
Drug
Intervention Name(s)
Itraconazole 200 mg
Intervention Description
Control
Intervention Type
Drug
Intervention Name(s)
Voriconazole 200mg
Intervention Description
Comparator
Primary Outcome Measure Information:
Title
proportion of subjects with an overall favourable response at the end of oral itraconazole therapy
Time Frame
six months
Secondary Outcome Measure Information:
Title
number of relapses at six-months after completion of therapy
Time Frame
six months
Title
adverse events due to itraconazole or voriconazole
Time Frame
six months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
13 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Chest clinic
City
Chandigarh
ZIP/Postal Code
160012
Country
India
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Inderpaul S Sehgal, MD,DM
Phone
+91-172275
Ext
6823
Email
inderpgi@outlook.com
Facility Name
Respiratory ICU, Department of Pulmonary Medicine, PGIMER
City
Chandigarh
ZIP/Postal Code
160012
Country
India
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Inderpaul S Sehgal, MD,DM
Phone
911275
Ext
6823
Email
inderpgi@outlook.com
First Name & Middle Initial & Last Name & Degree
Ritesh Agarwal, MD,DM
Phone
911275
Ext
6825
Email
agarwal.ritesh@outlook.in

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

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

We'll reach out to this number within 24 hrs