Title: Optimising azithromycin prevention treatment in COPD to reduce exacerbations (OPACE)
Funder: Department of Health and Social Care

Abstract: BACKGROUND _x000D_ Chronic obstructive pulmonary disease (COPD) is a common long-term lung condition affecting about 1.2 million people in the UK, causing approximately 30,000 deaths per year. Symptoms include shortness of breath, cough and wheezing. People living with COPD often experience a sudden worsening of symptoms; called exacerbations or flare-ups. These are debilitating and frightening and can shorten life expectancy. Azithromycin is an antibiotic that is also anti-inflammatory and is prescribed as a long-term prevention to reduce the risk of flare-ups. However, side effects of azithromycin may affect some people. Antibiotic resistance is another concern, especially when using azithromycin for prevention rather than to treat active infection._x000D_ WHY THIS TRIAL IS NEEDED_x000D_ We don’t know how effective azithromycin is after 1 year of treatment at reducing flare-ups, or whether to stop taking it once COPD has stabilised or stop it over the summer when fewer flare-ups happen. We also don’t know if the effectiveness of azithromycin differs between people depending on factors like how bad their COPD is. Given these uncertainties, it is challenging to know how best to use azithromycin in managing COPD. Azithromycin is a valuable antibiotic, and we want to prescribe it only where it has benefit, to avoid unnecessary side effects and reduce the chances of bacteria becoming resistant to it. _x000D_ _x000D_ AIM _x000D_ To establish the effects of stopping azithromycin prevention in people with stable COPD, who have been taking it for at least 3 months. We will compare continuing azithromycin with stopping it completely or stopping over the summer. We will compare the effects on flare-ups, symptoms and quality of life and also find out what factors may affect how patients’ respond to these interventions. _x000D_ _x000D_ HOW THE TRIAL WILL BE RUN _x000D_ This study is a randomised trial. This means participants will be randomised (‘by chance’) to one of the 3 trial medication arms: 1) Azithromycin. 2) Dummy placebo pills matched in appearance and taste to azithromycin. 3) A combination of azithromycin over winter and dummy pills over the summer. The participants and trial team will not know which trial medication participants are randomised to. We will recruit about 1300 people with COPD, stable in their condition, prescribed azithromycin prevention, from GP practices and hospitals across the UK. _x000D_ _x000D_ WHAT IS INVOLVED?_x000D_ Participants will be in the trial for 31 months. The trial will have 4 visits which can be in person or by phone depending on participant’s preference and 4 further follow up phone calls. Assessments include questionnaires. Participants will stay on their allocated trial medication, unless they experience more than 3 flare-ups/ per year, in which case it will be stopped. Participants can restart their usual azithromycin prescription, if advised by their doctor. If a participant has stopped taking their trial medication, they will still remain in the trial for ongoing follow up._x000D_ _x000D_ PATIENT INVOLVEMENT _x000D_ People living with COPD have been involved in designing and developing this trial and will be involved in all stages of the project._x000D_ _x000D_ IMPACT_x000D_ This trial will help us find out what affects patients’ response to azithromycin and decide whether stopping azithromycin prevention completely, seasonally over the summer, or continuing it is best for individuals. The trial will help us know how best to use azithromycin in people with COPD at high risk of flare-ups

Lay abstract: BACKGROUND _x000D_ Prophylactic azithromycin is recommended as a treatment to reduce the risk of COPD exacerbations in people with COPD, at high risk of exacerbations. There is much uncertainty in how to use this valuable treatment in managing COPD. It is unknown whether azithromycin is effective beyond one-year of treatment or what happens when azithromycin is discontinued following a period of use, or temporarily stopped over the summer when there are fewer exacerbations. Whether there are differences in treatment responsiveness between subgroups of people with COPD is uncertain._x000D_ AIM_x000D_ To evaluate benefits and risks of azithromycin prophylaxis vs complete or seasonal discontinuation in people with stable COPD at high risk of exacerbations and assess these effects in patient subgroups._x000D_ METHODS_x000D_ DESIGN: Randomised double-blind, non-inferiority, adaptive-design trial of 3 parallel arms (continued azithromycin prophylaxis as standard of care vs complete discontinuation, vs seasonal discontinuation) in patients with stable COPD at high risk of exacerbations. Internal pilot to evaluate recruitment will run for 9 months. Randomisation allocation will be 1:1:1. Adaptive design means a treatment arm can be dropped if futile at interim analysis, but remaining arms continue. _x000D_ SETTING: GP practices, hospitals, specialist community clinics._x000D_ TARGET POPULATION: Stable COPD patients prescribed azithromycin>=3 months to reduce risk of COPD exacerbations._x000D_ INTERVENTIONS ASSESSED_x000D_ Continued azithromycin (standard of care), complete discontinuation (matched placebo), seasonal discontinuation (azithromycin October-March, matched placebo April-September)._x000D_ TRIAL INVOLVEMENT _x000D_ Median follow up of 31 months, 24 months minimum for last participant recruited. Participants will have 4 visits (in person or remote, depending on participant’s preference) and 4 phone calls. Participants will have active follow up till completed their visits and will remain on trial medication unless experience >3 exacerbations/year. Participants can restart their regular azithromycin prescription after stopping trial medication if advised by their GP/specialist. Secondary outcomes will be collected over the entire trial providing long-term perspective of interventions. _x000D_ OUTCOMES_x000D_ Primary endpoint_x000D_ Time to first exacerbation (TTFE) requiring additional treatment with antibiotics and/or corticosteroids._x000D_ Secondary endpoints include_x000D_ Number/rate and severity of exacerbations, length of exacerbation-free status _x000D_ Health related quality of life _x000D_ Cost effectiveness from NHS perspective_x000D_ SAMPLE SIZE_x000D_ 1311 patients (437 per arm) to be recruited. Assuming a median TTFE of 150 days and non-inferiority threshold of 30 days shorter, this equates to the threshold on the hazard ratio scale of 1.25. Sample size is based on 90% power for two non-inferiority comparisons (seasonal and placebo compared with continuous as standard treatment), at 2.7% significance using a Cox proportional hazards model. Pre-specified subgroup analysis includes exacerbations history, FEV1%, smoking, CAT score, blood eosinophils. _x000D_ TIMETABLE_x000D_ Total trial duration 53 months. Pilot 9 months; recruitment period 29 months; median follow up 31 months. Interim analysis at 18 months._x000D_ IMPACT _x000D_ This trial will provide evidence to shape guidelines and change current practice. It will enable a precision medicine approach; optimising azithromycin use in COPD care. Results will be shared with patients, clinicians, and stakeholders.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY