The effectiveness, cost consequences, and safety of 5 versus 7 days of oral flucloxacillin for lower limb cellulitis in adults presenting in UK primary care: study protocol for the COAT trial - a pragmatic, multicentre, double-blind, randomised, phase 3 non-inferiority trial

Background Cellulitis is an acute bacterial infection of the dermis and subcutaneous tissue, most commonly affecting the lower limbs. UK guidelines recommend a 5–7-day course of oral flucloxacillin as first-line treatment in primary care. Most patients are prescribed a 7-day course or longer. Evidence supporting shorter regimens is limited and largely derived from hospital-based studies using alternative antimicrobial agents. No trials have evaluated different durations of oral flucloxacillin in primary care. This trial aims to assess the effectiveness, safety, and cost consequences of 5 versus 7 days of oral flucloxacillin for lower limb cellulitis in UK primary care. Methods This is a pragmatic, phase III, multi-centre, randomised, double-blind, non-inferiority trial, with internal pilot and parallel health economic evaluation. Adults (≥18 years) with lower-limb cellulitis will be randomised (1:1) to 5 vs 7 days of oral flucloxacillin, operationalised by providing 500 mg flucloxacillin or matched placebo, four times daily for two days following completion of a 5-day standard-of-care course of open-label flucloxacillin. Participants will be followed up for 28 days using self-reported symptom diaries and at 12 months through medical notes review. The primary outcome is pain over days 6–14 post-baseline, recorded daily on a 0–10 Numerical Rating Scale. Secondary outcomes include total antibiotic and analgesic use, patient-reported wellbeing, health-related quality of life, severity of leg swelling and redness, time to self-reported recovery, healthcare resource use (including hospital admissions, primary care consultations, and medication), recurrent cellulitis episodes, complications, and participant-incurred costs. The primary analysis will compare pain scores between groups using a generalised linear mixed model, adjusting for baseline pain and stratification variables and accounting for clustering of repeated measures within participants. The trial received ethical approval from the North East – Tyne & Wear South Research Ethics Committee on 16 June 2023 (ref: 23/NE/0021). Trial registration ISRCTN27053187, 01/06/2023, https://doi.org/10.1186/ISRCTN27053187