Interferon-gamma as Adjunctive Therapy in Chronic Pulmonary Aspergillosis: a Randomised Feasibility Study (INCAS)

This study explores the role of treatment with interferon-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 Chronic Obstructive Lung Disease (COPD) or previously treated tuberculosis (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 nonspecific x-ray findings, it often remains unrecognised for years. Around 3600 people live with CPA in the United Kingdom. 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 ΙFNγ, 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, interferon-gamma leads to improvement in important patient-centred outcomes like flares of lung disease or hospital admissions. Interferon-gamma is already in use in the National Health Service of the United Kingdom for other indications. Therefore, its use in CPA should be explored. However, CPA is a rare condition and the tolerability of interferon-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 interferon-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 interferon-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 interferon-gamma improves outcomes in CPA, then treatment duration can be shortened and relapses avoided. In addition, interferon-gamma can then be explored in other chronic lung disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Aspergillosis; Chronic Pulmonary Aspergillosis
• Intervention / Treatment: Drug: Antifungals as standard of care; Drug: Interferon Gamma-1B 0.1 MG Per 0.5 ML Injection PLUS antifungals as standard of care

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Chris Kosmidis, MD; Phone Number: 01612915875; Email: chris.kosmidis@manchester.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of CPA
• Started antifungal treatment for CPA within the last 2 weeks and received no antifungals for CPA in the eight weeks prior
• Chest CT scan available within the 6 months prior to enrolment
• Individuals of child bearing potential agree to have pregnancy test an use highly effective contraception

Exclusion Criteria:

• Moderate to severe liver dysfunction (Child-Pugh Class B or C)
• Renal failure (eGFR <30 mL/min)
• Clinically diagnosed active depression
• Active tuberculosis or non-tuberculous mycobacterial (NTM) lung disease
• Acute infection or other event within the preceding 4 weeks which, as assessed by the investigators, might interfere with the assessment of response to treatment
• Use of any interferon formulation within the preceding six months
• Active viral hepatitis infection
• Pregnancy or breastfeeding
• Immunosuppression (>15mg prednisolone/day for at least four weeks or equivalent) within the preceding six months
• Inability to self-administer subcutaneous medications AND lack of a carer who can administer
• Participants lacking capacity to consent

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
Active Comparator: Antifungal; Any oral triazole antifungal as per routine care	Drug: Antifungals as standard of care; Patients starting oral antifungal treatment for chronic pulmonary aspergillosis will be randomised 1:1 to additional interferon-gamma for 3 months or no additional treatment.
Experimental: Antifungal plus inteferon gamma; Any oral triazole antifungal as per routine care plus interferon-gamma three times weekly subcutaneously 50 micrograms/m2 for 3 months	Drug: Interferon Gamma-1B 0.1 MG Per 0.5 ML Injection PLUS antifungals as standard of care; Patients starting oral antifungal treatment for chronic pulmonary aspergillosis will be randomised 1:1 to additional interferon-gamma for 3 months or no additional treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of participants retained in the intervention arm	6 months
Proportion of target sample achieved	3 years
Change in maximum cavity wall thickness on CT scan	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in St George's Respiratory Questionnaire (SGRQ) score	The SGRQ ranges from 0-100 with higher scores indicating worse quality of life	3 and 6 months
Number of exacerbations requiring antibiotics or steroids in the six months before and after starting treatment		1 year

Collaborators and Investigators

• Sponsor: Manchester University NHS Foundation Trust
• Investigators: Principal Investigator: Chris Kosmidis, MD, Manchester University NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: November 29, 2022
• First Submitted That Met QC Criteria: December 13, 2022
• First Posted (Actual): December 16, 2022

Study Record Updates

• Last Update Posted (Actual): October 30, 2023
• Last Update Submitted That Met QC Criteria: October 27, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: immunotherapy; interferon gamma
• 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, Local; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Interferons; Interferon-gamma; Antifungal Agents; Clotrimazole; Miconazole
• Other Study ID Numbers: B01674

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No