A factorial randomised controlled trial to evaluate efficacy and safety of adding aspirin plus omega-3 or colchicine as repurposed treatments to enhance chronic obstructive pulmonary disease (COPD) exacerbation resolution and reduce recurrent exacerbations.

QUESTION: Can licensed drugs be repurposed to improve recovery from a COPD exacerbation, improve disease stability and avoid the sequelae of recurrent exacerbations, increased cardiovascular risk and mortality.

BACKGROUND: Patients with COPD who experience an exacerbation are at increased risk of repeat exacerbations, cardiovascular events and mortality, particularly in the subsequent three months. Aspirin plus omega-3, and colchicine are therapies that may provide benefits after an exacerbation. Aspirin and omega-3 enhance upregulation of pro-resolution pathways, and given together, may have synergistic resolution and cardioprotective effects. Observational studies suggest aspirin reduces rates of COPD exacerbations.

Colchicine reduces neutrophil mediated inflammation and reduced neutrophil elastase in bronchoalveolar lavage samples of ex-smokers with COPD. Colchicine is beneficial following myocardial infarction in reducing systemic inflammation and cardiovascular risk.

AIM: To assess if low dose aspirin plus omega-3 supplementation or low dose colchicine in addition to standard of care COPD exacerbation treatment reduces risk of subsequent COPD exacerbation and facilitates recovery. METHODS:

DESIGN: A factorial randomised placebo-controlled double-blind trial to assess efficacy and safety of addition of low dose aspirin plus omega-3, or low dose colchicine to standard of care treatment following a COPD exacerbation. Internal pilot will run for 6 months. SETTING: GP practices and hospitals in the UK, PIC sites. POPULATION: Patients with a COPD exacerbation.

INTERVENTIONS ASSESSED:

Participants will be randomised to one of four trial arms, all participants receive standard of care treatments: 1) placebos control arm (current standard of care treatment of an exacerbation), or 2) addition of aspirin plus omega-3, or 3) addition of colchicine, or 4) addition of aspirin plus omega-3 and colchicine. Participants will be on trial treatment for 3 months. Placebos to aspirin, omega-3 and colchicine will be used.

TRIAL ASSESSMENTS:

Trial duration for participants: 6 months, 3 months active treatment. Three trial visits: baseline, 1 and 3 months, telephone follow up at 2 weeks, and 6 months. An additional further telephone follow up at 12 months if able to. Assessments: Participants will complete a diary for up to 3 months, questionnaire at follow ups. Research blood, oral rinse and nasopharyngeal samples will be taken in a proportion of patients.

OUTCOMES: PRIMARY ENDPOINT: Treatment failure assessed at 3 months.

SECONDARY: Time to first and number of COPD CompEx event (composite of symptoms, peak flow and/or exacerbations, and reliever medication use), blood vascular biomarkers and lipid mediators, and oral and nasopharyngeal microbiome to assess intervention effects. Exacerbations, symptoms, hospital admissions, cardiovascular events, mortality.

SAMPLE SIZE: A sample size of 436 (218 per experimental treatment, 109/arm), inclusive of 5% dropout, has over 90% power, 5% significance to detect an absolute 15% reduction in treatment failure in the two experimental treatment arm(s) to 20% (from 35% in matched placebo/control).

TIMETABLE: Trial duration: 30 months: internal pilot 6 months, 24 months recruitment period, 6 months follow up for last participant recruited. IMPACT: Demonstrated efficacy in this trial will be important for clinical practice and future effectiveness evaluation.