Title: Interferon-gamma immunotherapy in chronic pulmonary aspergillosis: a feasibility study
Funder: Department of Health and Social Care

Abstract: Background: Chronic pulmonary aspergillosis (CPA) is a progressive infection affecting patients with underlying lung disease like COPD or previously treated TB. It causes destruction of lung tissue by slowly enlarging cavities, recurrent secondary infections and poor quality of life. Response to antifungal agents is slow and relapses are common, resulting in prolonged or life-long treatment courses. More effective treatment options are needed. Interferon-gamma (IFN&gamma;) is known to have antifungal properties. When used as salvage therapy in CPA, it resulted in a reduction in exacerbation rates and hospital admissions. Therefore, its use as an adjunct to antifungals merits further investigation. Here, we propose a feasibility study of IFN&gamma; in CPA. Research question: Is a randomised controlled trial (RCT) of immunotherapy with IFN&gamma; in addition to standard of care for the treatment of CPA feasible? Aims and objectives: We aim to assess the feasibility of a future RCT of IFN&gamma; therapy in CPA. A randomised feasibility trial will be performed to confirm tolerability and satisfaction with IFN&gamma; in the CPA patient population, assess retention and inform the design and sample size for a definitive study. Methods: Patients starting antifungals for CPA (n=50) will be randomized 1:1 to IFN&gamma; open-label for 12 weeks or no additional treatment. Safety and efficacy assessments will be performed at weeks 1, 4, 12 and 24. Study procedures will take place in the Manchester Clinical Research Facility, Manchester University NHS Foundation Trust. The chest CT scans before treatment and at 6 months will be reviewed by a thoracic radiologist who will be blinded. The lesions will be described by location, size of cavities, aspergillomas, nodules and pleural thickening. Reduction in cavity wall thickness has been found to correlate with clinical improvement and will be used to test the effect of the intervention. The feasibility assessment for the definitive study will be based on tolerability of IFN&gamma; and recruitment/retention rate. Improvement in a quality-of-life score (St George s Respiratory Questionnaire) and radiology will be used as outcome measures to inform sample size for a definitive RCT. Timelines for delivery: Anticipating two participants per month, total duration of the recruitment period and study procedures will be 33 months. Data analysis, feasibility assessment and sample size calculations will occur in the last 6 months and planning for the application and protocol writing for the definite study will occur in the last 3 months. Anticipated Impact and Dissemination: The proposed definitive trial will be the first large-scale RCT of IFN&gamma; in aspergillosis. If IFN&gamma; demonstrates a synergistic effect with antifungals, response rates in CPA will improve. A short course of antifungals with immunotherapy may obviate the need for long-term antifungals. Encouraging results may generate interest in immunotherapy in other chronic lung infection like mycobacterial disease. A reduction in exacerbation rates and hospital admissions, already observed in our pilot data, may be replicated in patients with other chronic lung disease. Results will be shared through the aspergillus.org website, our established patient community and in scientific meetings attended by Infection, Immunology and Respiratory specialists.

Lay abstract: This study explores the role of treatment with interferon-gamma (IFN&gamma;) to improve outcomes in chronic pulmonary aspergillosis (CPA). CPA is a progressive infection caused by the fungus Aspergillus affecting patients with chronic lung disease like COPD or previously treated TB. It causes gradual destruction of lung tissue by slowly enlarging cavities, frequent secondary infections and poor quality of life. Because of its indolent nature and non-specific x-ray findings, it often remains unrecognised for years. Around 3600 people live with CPA in the UK. Mortality from CPA may be up to 40% in five years. Treatment for CPA relies on antifungals for prolonged periods, but only around 60% of patients improve. It is often long-term or lifelong as the response is slow and some patients experience relapses. In addition, only one class of oral antifungal drugs is licensed for CPA, and they are associated with side effects and high cost. Better treatments are needed for CPA. We do not know why many patients do not respond to treatment. Maybe CPA patients have a weakened immune system and are more susceptible to Aspergillus. Our data suggest that CPA patients produce lower amounts of &Iota;FN&gamma;, a substance that facilitates the immune system s response against Aspergillus. We have also shown that, when given to patients with CPA who have failed to improve on antifungal treatment, IFN&gamma; leads to improvement in important patient-centred outcomes like flares of lung disease or hospital admissions. IFN&gamma; is already in use in the NHS for other indications. Therefore, its use in CPA should be explored. However, CPA is a rare condition and the tolerability of IFN&gamma; is not fully established in these patients. To understand whether a large-scale study is feasible in CPA, we first need preliminary data in smaller numbers of patients. We propose a randomised trial of IFN&gamma; in addition to antifungals in CPA. Patients with CPA starting antifungal treatment will be eligible. Participants (25 per group) will be randomly assigned to IFN&gamma; for 12 weeks (in addition to antifungals) or antifungals only. To test whether the treatment works, we will use measurements of the cavities on chest CT scan and scores on a quality-of-life questionnaire. We will assess for tolerability of treatment at intervals similar to clinical practice. Criteria for progression to the large-scale study will be set based on the proportion of patients willing to participate, and on the proportion who complete the treatment. Data collected on those parameters will allow us to determine the number needed for a definite study. If the large-scale study confirms our observations that IFN&gamma; improves outcomes in CPA, then treatment duration can be shortened and relapses avoided. In addition, IFN&gamma; can then be explored in other chronic lung disease.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION