Bronchiectasis: Optimising Azithromycin prevention Treatment to reduce exacerbations (BOAT): A double blind pragmatic randomised controlled trial

Background: Prophylactic azithromycin is recommended to reduce the risk of respiratory exacerbations in people with Bronchiectasis. There is much uncertainty in how to optimally use this valuable treatment. It is unknown if azithromycin is effective beyond one-year of treatment and what happens when azithromycin is discontinued following a period of use.

Aim: To evaluate the benefits/ risks of discontinuation of azithromycin vs continued treatment in bronchiectasis patients already taking azithromycin due to prior exacerbations and assess effects in patient subgroups. Methods

Design: A randomised double-blinded, non-inferiority, pragmatic trial of 2 parallel arms (complete discontinuation vs continued azithromycin as standard of care), to test the strategy of discontinuation of prophylactic azithromycin. Randomisation allocation will be 1:1. Internal pilot to evaluate recruitment will run for 12 months from 1st participant 1st visit (FPFV).

Setting: GP practices, specialist community clinics, hospitals.

Target population: Patients prescribed azithromycin =3 months to reduce risk of bronchiectasis exacerbations (call specifications).

Interventions: Complete discontinuation of azithromycin (matched placebo), vs. continued azithromycin (standard of care).

Trial duration and procedures: 24 months duration for all recruited. Participants will have up to 5 visits face to face over 2-years – baseline, 6, 12 and 18 months, and 24 months, which may coincide with standard of care visits and be in-person or remote depending on participant’s individual preference. Telephone follow-up will be conducted at 1 months and 3 months.

All participants will have active follow up until 24 months, even if primary endpoint met. All remain on trial medication till 24 months unless suffering more than 3 exacerbations/year and/or asking to withdraw.. Secondary outcomes will be collected over the entire trial period and include evaluation both on and off trial medication, providing a long-term perspective of the interventions being assessed.

Outcome measures:

Primary endpoint: Time to first exacerbation (TTFE) necessitating additional treatment with antibiotics and/or oral corticosteroids. Key secondary endpoints (collected over entire trial) 1. Number/rate and severity of exacerbations, length of exacerbation-free status 2. Health related quality of life measured by change in the EuroQol-5 dimension and anxiety/depression score (HADS)

3. Symptoms (QOL-B and CAT respiratory questionnaire) 4. Side effects 5. Mortality 6. Cost effectiveness from NHS perspective.

Sample size: 1000 patients (423 per arm inflated to 500 for drop outs) recruited over 29 months. The sample size is defined by a non-inferiority design. The study requires 423 events per arm needed assuming no loss-to-follow up; exponential time to event; standard arm and intervention arm both have median time to event of 5 months; non-inferiority margin of 1 month.

A 0.025 one-sided type I error rate, 90% power. Each patient is likely reach TTFE within 12 months and thus before the end of the trial. We therefore propose a study of 1000 patients to factor in loss to follow up of ~15% (a conservative estimate as the design and prior experience in bronchiectasis is retention rates of >95% at 6 months).

Pre-specified factors for subgroup analysis include exacerbation history, FEV1 % predicted, Bronchiectasis severity index score, blood eosinophils, Pseudomonas status and smoking status.