Optimising azithromycin prevention treatment in COPD to reduce exacerbations (OPACE)

BACKGROUND

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. AIM

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. METHODS

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.

SETTING: GP practices, hospitals, specialist community clinics. TARGET POPULATION: Stable COPD patients prescribed azithromycin>=3 months to reduce risk of COPD exacerbations. INTERVENTIONS ASSESSED

Continued azithromycin (standard of care), complete discontinuation (matched placebo), seasonal discontinuation (azithromycin October-March, matched placebo April-September). TRIAL INVOLVEMENT

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. OUTCOMES Primary endpoint Time to first exacerbation (TTFE) requiring additional treatment with antibiotics and/or corticosteroids.

Secondary endpoints include Number/rate and severity of exacerbations, length of exacerbation-free status Health related quality of life Cost effectiveness from NHS perspective SAMPLE SIZE

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. TIMETABLE

Total trial duration 53 months. Pilot 9 months; recruitment period 29 months; median follow up 31 months. Interim analysis at 18 months. IMPACT

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.