Monotherapy of Itraconazole Versus Prednisolone in Allergic Bronchopulmonary Aspergillosis (MIPA)

The purpose of this study is to evaluate the efficacy and safety of itraconazole monotherapy in patients with ABPA.

Study Overview

• Status: Completed
• Conditions: Allergic Bronchopulmonary Aspergillosis
• Intervention / Treatment: Drug: Itraconazole; Drug: Glucocorticoids

Detailed Description

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder caused by a complex hypersensitivity response to antigens released by the fungus Aspergillus fumigatus. The clinical entity was first described by Hinson et al in 1952, and the clinical and immunologic significance of Aspergillus fumigatus in the sputum were reported by Pepys and coworkers in 1959. The prevalence of ABPA in bronchial asthma is fairly high and a recent meta-analysis suggested the prevalence of ABPA in asthma clinics to be as high as 13 percent. Diagnostic criteria for ABPA have been laid and generally include the following eight major criteria: (a) history of asthma; (b) transient or fixed pulmonary infiltrates; (c) immediate cutaneous hyperreactivity to A fumigatus antigen; (d) absolute eosinophil count > 1000/µL; (e) serum precipitins against A fumigatus; (f) total IgE levels > 1000 IU/mL; (g) central bronchiectasis on high-resolution computed tomography (HRCT); and, (h) raised A fumigatus specific IgE or IgG levels. However, none of these are specific for ABPA,and there is still no consensus on the number of criteria needed for diagnosis, and patients in different stages of ABPA may not fulfill all these criteria. Also, there is no established definition for remission of ABPA. The most widely followed criteria are clinical and radiological improvement with at least 35 percent decline in total serum IgE levels. However, in a recent study the investigators demonstrated that a 35% decline in serum IgE levels at six weeks is not seen in all patients with ABPA, and the decline is slower in patients with baseline IgE levels < 2500 IU/mL. Moreover, the quantum decline in serum IgE levels did not predict clinical outcome. The disorder is highly prevalent in India. The investigators have previously reported our experience with screening stable outpatients with bronchial asthma and acute severe asthma for ABPA. The investigators have also recently reported the prognostic factors associated with clinical outcomes in patients with ABPA.

Oral corticosteroids are currently the treatment of choice for ABPA associated with bronchial asthma. They not only suppress the immune hyperfunction but are also anti-inflammatory. However, there is no data to guide the dose and duration of glucocorticoids and different regimens of glucocorticoids have been used in literature. Itraconazole, an oral triazole with relatively low toxicity, is active against Aspergillus spp. in vitro and in vivo. The activity of itraconazole against Aspergillus spp. is more than that of ketoconazole. The administration of itraconazole can eliminate Aspergillus in the airways and can theoretically reduce the allergic responses in ABPA. The aim of this prospective randomized controlled trial (RCT) is to evaluate the efficacy and safety of itraconazole monotherapy in patients with ABPA.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• India
  • UT
    • Chandigarh, UT, India, 160012
      • Postgraduate Institute of Medical Education and Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: Patients will be included in the study if they meet the criteria for ABPA defined by

Presence of all the following three criteria:

• immediate cutaneous hyperreactivity on aspergillus skin test
• elevated total IgE levels > 1000 IU/mL
• A fumigatus specific IgE levels > 0.35 kU/L

Two of the following criteria:

• presence of serum precipitating antibodies against A fumigatus
• fixed or transient radiographic pulmonary opacities
• absolute eosinophil count > 1000/µL
• central bronchiectasis on HRCT.

Exclusion Criteria:

• if they have taken glucocorticoids for more than three weeks in the preceding six months
• failure to give informed consent
• enrollment in another trial of ABPA

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
Experimental: Itraconazole group; Itraconazole 200 mg BD for 4 months along with inhaled formoterol/fluticasone (6/125 mcg) 2 puffs twice daily by MDI and as needed as per the SMART approach	Drug: Itraconazole; Itraconazole 200 mg BD for 6 months along with inhaled formoterol/fluticasone (6/125 mcg) 2 puffs twice daily by MDI and as needed as per the SMART approach; Other Names: Azole
Active Comparator: Glucocorticoid group; Prednisolone 0.5 mg/kg/day for 4 weeks; 0.25 mg/kg/day for 4 weeks; 0.125 mg/kg/day for 4 weeks. Then taper by 5 mg every 2 weeks and discontinue. Patients will also receive inhaled formoterol/fluticasone (6/125 mcg) as needed as per the SMART approach for control of asthma	Drug: Glucocorticoids; Prednisolone 0.5 mg/kg/day for 4 weeks; 0.25 mg/kg/day for 4 weeks; 0.125 mg/kg/day for 4 weeks. Then taper by 5 mg every 2 weeks and discontinue. Patients will also receive inhaled formoterol/fluticasone (6/125 mcg) as needed as per the SMART approach for control of asthma; Other Names: Prednisolone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission rates in the two groups at six weeks and three months	Remission - if the IgE levels decline by >=25% and there is clinical improvement with partial/total clearance of chest radiographic lesions after three months of glucocorticoids (if previously present pulmonary opacities)	6 weeks, 3 months
Percentage decline in IgE levels at six weeks and three months	IgE levels will be noted at baseline six weeks and three months after glucocorticoid therapy and percentage decline will be calculated as: (baseline IgE levels minus IgE levels after six weeks of treatment) divided by baseline IgE levels	6 weeks, 3 months
Complete remission rates in the two groups	No ABPA exacerbations over the next 3 months after stopping therapy	3 months, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse rates in the two groups at six and 12 months after completion of treatment	Relapse - doubling of the baseline IgE levels irrespective of the patient's symptoms or appearance of radiologic infiltrates	6 months, 12 months
Treatment related adverse effects in the two groups		Every 6 weeks

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Ritesh Agarwal, MD, DM, PGIMER, Chandigarh

Publications and helpful links

General Publications

• Agarwal R, Dhooria S, Singh Sehgal I, Aggarwal AN, Garg M, Saikia B, Behera D, Chakrabarti A. A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma. Chest. 2018 Mar;153(3):656-664. doi: 10.1016/j.chest.2018.01.005. Epub 2018 Jan 11.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: March 23, 2011
• First Submitted That Met QC Criteria: March 23, 2011
• First Posted (Estimate): March 24, 2011

Study Record Updates

• Last Update Posted (Actual): March 16, 2017
• Last Update Submitted That Met QC Criteria: March 15, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: ABPA
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bacterial Infections and Mycoses; Respiratory Hypersensitivity; Hypersensitivity; Mycoses; Lung Diseases, Fungal; Aspergillosis; Pulmonary Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Prednisolone; Itraconazole; Glucocorticoids
• Other Study ID Numbers: IGCST; MS/1398/Res/1838 (Other Identifier: PGIMER)