A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma

Agarwal, Ritesh; Dhooria, Sahajal; Sehgal, Inderpaul Singh; Aggarwal, Ashutosh N.; Garg, Mandeep; Saikia, Biman; Behera, Digambar; Chakrabarti, Arunaloke

doi:10.1016/j.chest.2018.01.005

Cited by 124 publications

(92 citation statements)

References 26 publications

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“…There have been studies comparing triazole antifungals to steroids for treatment of ABPA. A randomised controlled trial comparing itraconazole to prednisolone for treatment of acute‐stage ABPA revealed that although prednisolone was more effective in inducing response than itraconazole, itraconazole had a better side effect profile and was efficacious in a considerable number . In another randomised controlled trial by the same group, voriconazole monotherapy was found to be effective and safer than glucocorticoids for treatment of ABPA .…”

Section: Discussionmentioning

confidence: 99%

An evaluation of nebulised amphotericin B deoxycholate (Fungizone^®) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre

Otu

Langridge

Denning

2019

Mycoses

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Summary Antifungal treatment options for allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitisation (SAFS) are largely limited to itraconazole based on the outcome of randomised controlled trials. It is unclear if nebulised amphotericin B deoxycholate (Fungizone®) is a viable therapeutic option. We evaluated the safety and efficacy of nebulised Fungizone® in the long‐term treatment of various forms of pulmonary aspergillosis. We assessed the records of 177 patients with various forms of pulmonary aspergillosis attending the National Aspergillosis Centre in Manchester who had received Fungizone®. Patients first received a challenge test with nebulised Fungizone® in hospital with spirometry pre/post‐Fungizone® and nebulised salbutamol given pre‐Fungizone®. Tolerability and changes in Aspergillus IgE, Aspergillus IgG and total IgE were evaluated. Sixty‐six per cent (117/177) were able to tolerate the test dose of Fungizone® and in all cases, the reason for discontinuation of the first test dose was worsening breathlessness. Twenty six (21%) stopped therapy within 4‐6 weeks, and the commonest reason cited for discontinuation of therapy was increased breathlessness, hoarseness and cough. Eighteen (10.2%) patients continued the Fungizone® for >3 months of which 5 (27.8%) recorded an improvement in total IgE, Aspergillus‐specific IgE and Aspergillus IgG. Eleven had ABPA, four had SAFS, two had Aspergillus bronchitis and one had Aspergillus sensitisation with cavitating nodules. Among these 18 patients, sputum fungal culture results went from positive to negative in five patients, became positive in one patient, remained positive in three patients, and remained negative in seven patients. Nebulised Fungizone® appears to be a poorly tolerated treatment for pulmonary Aspergillosis with high dropout rates. There appears to be both clinical and serological benefits following sustained treatment with nebulised Fungizone® in some patients.

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Section: Discussionmentioning

confidence: 99%

An evaluation of nebulised amphotericin B deoxycholate (Fungizone^®) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre

Otu

Langridge

Denning

2019

Mycoses

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“…More recently, a study in treatment-naïve acute ABPA patients showed that oral itraconazole monotherapy improved clinical outcomes and FEV 1 after 6 weeks of therapy. 6 Collectively, these studies illustrate that, despite a variable pharmacokinetic profile, low bioavailability and risks of AEs at higher doses, 9,11,31,32 oral itraconazole can provide clinical benefit in ABPA.…”

Section: Pur1900 Safety and Tolerabilitymentioning

confidence: 94%

“…ABPA management focuses on using oral corticosteroids to suppress inflammation and oral antifungals to attempt to eradicate A. fumigatus from the airways. 3 Itraconazole is the most commonly used antifungal therapy and randomized controlled trials have demonstrated efficacy in treating ABPA either as adjunctive or monotherapy [4][5][6] ; however, oral doses of itraconazole have variable absorption and food interactions, and no correlation is observed between serum and sputum levels. 7 Patients with cystic fibrosis have highly variable pharmacokinetics and steadystate sputum concentrations of itraconazole often fall below the minimum inhibitory concentration (MIC 90 ) for A. fumigatus in most subjects.…”

Section: Introductionmentioning

confidence: 99%

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

Hava

Tan²,

Johnson³

et al. 2020

Brit J Clinical Pharma

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Aims Oral itraconazole has variable pharmacokinetics and risks of adverse events associated with high plasma exposure. An inhalation formulation of itraconazole (PUR1900) is being developed to treat allergic bronchopulmonary aspergillosis, an allergic inflammatory disease occurring in asthmatics and patients with cystic fibrosis. Methods A 3‐part, open‐label Phase 1 study was conducted to evaluate safety, tolerability and pharmacokinetics of PUR1900. Healthy volunteers (n = 5–6/cohort) received either single (Part 1) or multiple (Part 2) ascending doses of PUR1900 for up to 14 days. In Part 3 stable, adult asthmatics received a single dose of 20 mg PUR1900 or 200 mg of oral Sporanox (itraconazole oral solution) in a 2‐period randomized cross‐over design. Itraconazole plasma and sputum concentrations were evaluated. Results None of the adverse events considered as at least possibly related to study treatment were moderate or severe, and none were classed as serious. The most common was the infrequent occurrence of mild cough. Itraconazole plasma exposure increased with increasing doses of PUR1900. After 14 days, PUR1900 resulted in plasma exposure (area under the concentration–time curve up to 24 h) 106‐ to 400‐fold lower across doses tested (10–35 mg) than steady‐state exposure reported for oral Sporanox 200 mg. In asthmatics, PUR1900 geometric mean maximum sputum concentrations were 70‐fold higher and geometric mean plasma concentrations were 66‐fold lower than with oral Sporanox. Conclusion PUR1900 was safe and well‐tolerated under the study conditions. Compared to oral dosing, PUR1900 achieved higher lung and lower plasma exposure. The pharmacokinetic profile of PUR1900 suggests the potential to improve upon the efficacy and safety profile observed with oral itraconazole.

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“…The participants in both the groups received oral prednisolone 0.5 mg/kg/d for 4 weeks, followed by 0.25 mg/kg/d and 0.125 mg/kg/d for 4 weeks each. Prednisolone was then tapered by 5 mg every 2 weeks and discontinued subsequently . The total duration of prednisolone was 4 months.…”

Section: Methodsmentioning

confidence: 99%

“…Prednisolone was then tapered by 5 mg every 2 weeks and discontinued subsequently. [17][18][19] The total duration of prednisolone was 4 months. The subjects randomised to the intervention arm additionally received vitamin D supplementation (oral capsule of cholecalciferol 60 000 IU) once weekly for 8 weeks.…”

Section: Interventionmentioning

confidence: 99%

A randomised trial of vitamin D in acute‐stage allergic bronchopulmonary aspergillosis complicating asthma

Dodamani

Muthu

Thakur

et al. 2019

Mycoses

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Summary Vitamin D has been demonstrated to have an immunomodulatory role in cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA). Herein, we evaluate supplemental vitamin D in acute‐stage ABPA complicating asthma. Thirty subjects were randomised to receive either prednisolone (n = 15, control) or prednisolone and oral vitamin D (n = 15, intervention arm). Serum vitamin D levels were significantly higher in the intervention versus the control arm, following therapy. The mean decline in total IgE at 2 months (primary outcome) was 10% higher in the intervention arm than the control arm; however, this was not statistically significant (48.6% vs 38.1%, P = 0.27). The percentage decline in total IgE after 4 and 6 months of randomisation was also similar in the two arms. There was no difference in asthma exacerbations (0 vs 2, intervention vs control; P = 0.16). No ABPA exacerbation occurred in either arm. The other outcomes including the Th2 (IL‐4, IL‐6 and IL‐10) and Th17 (IL‐17) cytokine levels were similar in the two groups. None of the participants experienced hypervitaminosis D. There was no significant improvement in the clinical or immunological outcomes following vitamin D supplementation. A larger trial is required to ascertain the role of vitamin D in ABPA complicating asthma [Clinicaltrials.gov: NCT03133299].

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A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma

Cited by 124 publications

References 26 publications

An evaluation of nebulised amphotericin B deoxycholate (Fungizone^®) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre

An evaluation of nebulised amphotericin B deoxycholate (Fungizone^®) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

A randomised trial of vitamin D in acute‐stage allergic bronchopulmonary aspergillosis complicating asthma

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A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma

Cited by 124 publications

References 26 publications

An evaluation of nebulised amphotericin B deoxycholate (Fungizone®) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre

An evaluation of nebulised amphotericin B deoxycholate (Fungizone®) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

A randomised trial of vitamin D in acute‐stage allergic bronchopulmonary aspergillosis complicating asthma

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An evaluation of nebulised amphotericin B deoxycholate (Fungizone^®) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre

An evaluation of nebulised amphotericin B deoxycholate (Fungizone^®) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre