Introduction: Cellulitis is a common bacterial skin infection causing significant pain, swelling, and impact on daily activities, frequently leading to emergency department presentations and hospital admissions. While antibiotics are the mainstay of treatment, they do not directly address inflammation, often resulting in persisting or worsening symptoms in the initial days. Corticosteroids, with their potent anti-inflammatory effects, have shown benefit in other acute infections but are not currently standard care for patients with cellulitis. This trial aims to determine if adjunctive oral dexamethasone can reduce pain and improve outcomes in adults with cellulitis presenting to UK urgent secondary care settings.

Methods and analysis: This is a pragmatic, multicentre, double-blind, placebo-controlled, randomised, parallel group, phase 3 superiority trial, with an internal pilot and parallel health economic evaluation. Adult patients (≥16 years) with a clinical diagnosis of cellulitis (at any body site except the orbit) presenting to urgent secondary care will be screened for eligibility. 450 participants will be randomised (1:1) to receive either two 8 mg doses of oral dexamethasone or matched placebo, administered approximately 24 hours apart, in addition to standard antibiotic therapy. The primary outcome is total pain experienced over the first 3 days post-randomisation, calculated using the standardised area under the curve (AUC) from pain scores (Numerical Rating Scale 0-10) across up to seven timepoints. Secondary outcomes include health-related quality of life (EQ-5D-5L), patient global impression of improvement, analgesia and antibiotic usage, hospital (re)admissions, complications, unscheduled healthcare use, cellulitis recurrence, and cost-effectiveness at 90 days. The primary estimand will apply a treatment policy approach to intercurrent events.

Ethics and dissemination The trial has received ethical approval from South Central – Oxford B Research Ethics Committee (reference; 24/SC/0289) and will be conducted in compliance with GCP and applicable regulations. Informed consent will be obtained from all participants. Findings will be disseminated through peer-reviewed publications and conference presentations, and to patient groups and relevant clinical guideline committees.

Trial registration ISRCTN76873478. Current protocol version 5.0, 7th January 2025.

Strengths and limitations of this study

This trial employs a robust double-blind, placebo-controlled design to minimise bias in assessing a subjective primary outcome (patient-reported pain).

The pragmatic nature of the trial, recruiting from diverse urgent secondary care settings, with additional incentives to recruit from minoritised groups, aims to enhance the generalisability of findings to real-world clinical practice.

Comprehensive follow-up to 90 days allows for assessment of both short-term symptom relief and longer-term impacts on healthcare utilisation and recurrence.

The inclusion of a parallel health economic evaluation will provide crucial information on the cost-effectiveness of adjunctive dexamethasone.

Potential variability in’usual care’ antibiotic regimens across sites, while reflecting real-world practice, is a possible limitation, which is accounted for in the pragmatic design.

This trial is funded by the NIHR Health Technology Assessment Programme (NIHR153216). All authors are funded by the NIHR HTA grant for this project, with payments made to employing institutions. As a patient partner, DR receives payment for his time on the project from the grant via North Bristol NHS Trust. MJR is funded by an NIHR Research Professorship (NIHR303123), is in receipt of other NIHR SPCR, HTA and PGfAR grants, is a member of the ERICA trial joint TSC/DMC, chair of ASYMPTOMATIC TSC and co-chair of the primary care dermatology research specialist interest and NIHR SPCR skin and allergy working groups. HEW is in receipt of an NIHR Doctoral Fellowship (NIHR305284), sits on advisory boards for UCB Pharma, Honorarium from Leo, L'Oreal, AbbVie, Dermal, Novartis, UCB Pharma and Eli Lilly, Receives course fees and/or travel expenses from UCB Pharma and Novartis and is a research advisor for AbbVie, Novartis, Incyte and Boehringer Ingelheim. No other competing interests have been declared by the authors. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funder (NIHR) provides research costs but is not responsible for and has no involvement in data analysis, interpretation, or manuscript writing. The trial is sponsored by North Bristol NHS Trust (researchsponsornbt.nhs.uk). The sponsor has overall oversight of the trial but is not actively involved in the trial design, data collection, analysis or manuscript writing. The trial was developed with support from the UK Dermatology Clinical Trials Network (UK DCTN). The UK DCTN is grateful to the British Association of Dermatologists and the University of Nottingham for financial support of the Network. Principal Investigators at each site will be provided with a declaration form as part of the model non-commercial agreement in which any competing interests will be identified. Members of the TSC and DMC have completed conflict of interest forms to declare any competing interests and these have been declared to the NIHR. An independent member of the Trial Steering Committee declares involvement in the design and conduct of the PATCH cellulitis trials and being part of the Trial Management Group for the ongoing COAT cellulitis trial. An independent member of the Data Monitoring Committee declares a role as chair of the UK Dermatology Clinical Trials Network which receives funding from the DEXACELL trial grant. No other conflicts of interest have been reported.

This trial is funded by the NIHR Health Technology Assessment Programme (NIHR153216). All authors are funded by the NIHR HTA grant for this project, with payments made to employing institutions.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

An NHS Research Ethics Committee; South Central, Oxford B Research Ethics Committee (reference; 24/SC/0289) gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors