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ToolsPhilpott, Carl, Beard, David J., Saeedi, Elnaz, Cook, Jonathan A., Jones, Stephen, Clarke, Caroline S., Teoh, Lucinda, Thomas, Mike, Little, Paul, Vennik, Jane, Lund, Valerie, Schilder, Anne G. M., Long, Fei, Durham, Stephen, Boardman, James and Hopkins, Claire and on behalf of the MACRO Collaborative (2025) The clinical effectiveness of clarithromycin versus endoscopic sinus surgery for adults with chronic rhinosinusitis with and without nasal polyps (MACRO): A pragmatic, multicentre, three-arm, randomised, placebo-controlled phase 4 trial. The Lancet, 406 (10506). pp. 926-939. ISSN 0140-6736
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Abstract
Background: A paucity of evidence regarding use of endoscopic sinus surgery and antibiotics in managing chronic rhinosinusitis has contributed to a five-times variation in endoscopic sinus surgery rates, as well as variation in the use of antibiotics. The main aim of the present trial was to compare the clinical effectiveness of endoscopic sinus surgery or 3 months of clarithromycin treatment alongside intranasal medication in adults with chronic rhinosinusitis with or without nasal polyps. Methods: In this pragmatic, three-arm, randomised, placebo-controlled phase 4 trial, participants were recruited from 20 secondary and tertiary care sites in the UK. Adults (aged ≥18 years) with chronic rhinosinusitis remaining symptomatic following appropriate medical therapy (intranasal corticosteroids, saline nasal irrigations, and a short course of antibiotics) were randomly assigned (1:1:1) to receive endoscopic sinus surgery (within 6 weeks of randomisation if waiting lists allowed) plus intranasal medication, clarithromycin (250 mg twice a day for 2 weeks then 250 mg once a day for 10 weeks) plus intranasal medication, or placebo plus intranasal medication. Intranasal medication comprised intranasal corticosteroids and saline irrigations. Participants were allocated with an automated, web-based secure randomisation system in permuted blocks of varying size (block sizes of three and six), stratified by the presence of polyps and trial site. Participants and site teams were masked to the clarithromycin and placebo allocations, including for outcome assessment. The primary outcome measure was the total score on the 22-item Sino-Nasal Outcome Test (SNOT-22) quality-of-life questionnaire at 6 months after randomisation, with analysis by intention to treat (ITT; available-case basis). Adverse reactions were assessed in the safety population (clarithromycin and placebo), and serious adverse events in the ITT population (all groups). The trial was registered on the ISRCTN registry, ISRCTN36962030, and EudraCT, 2018-001100-11, and is complete, with optional long-term follow-up ongoing. Findings: Between Nov 1, 2018, and Oct 13, 2023, 514 participants (181 [35%] female and 333 [65%] male), with chronic rhinosinusitis with nasal polyps (n=410) or chronic rhinosinusitis without nasal polyps (n=104), were recruited and randomly assigned to receive endoscopic sinus surgery (n=171), clarithromycin (n=172), or placebo (n=171), all with intranasal medication. SNOT-22 scores at 6 months after randomisation were significantly lower (at the 98·33% confidence level after Bonferroni adjustment) in the endoscopic sinus surgery group than in the clarithromycin group (adjusted mean difference –18·13 [98·33% CI –24·26 to –11·99], p<0·0001) and placebo group (–20·44 [–26·42 to –14·46], p<0·0001). 6-month SNOT-22 scores did not differ significantly between participants randomly assigned to clarithromycin versus placebo (–3·11 [–8·56 to 2·33], p=0·17). Ten serious adverse events occurred in nine participants (two events in two [1%] of 172 participants allocated to clarithromycin, three events in three [2%] of 171 allocated to placebo, and five events in four [2%] of 171 allocated to endoscopic sinus surgery), none of which were fatal. Interpretation: The MACRO trial shows that endoscopic sinus surgery has clinical effectiveness in patients with chronic rhinosinusitis, providing significantly improved disease-specific quality of life at 6 months. Conversely, the trial findings do not support routine long-term use of low-dose clarithromycin. Endoscopic sinus surgery should be recommended if intranasal medication alone is unable to achieve symptom control. Funding: National Institute for Health and Care Research Programme Grants for Applied Research.
| Item Type: | Article |
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| Additional Information: | Acknowledgments: This trial was funded by an NIHR Programme Grant for Applied Research (grant number RP-PG-0614–20011). The views expressed are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. This study has been conducted as part of the portfolio of trials in the registered UKCRC Oxford Clinical Trials Research Unit at the University of Oxford. We thank Steffi le Conte, Edmund Wyatt, Laura Lloyd Jones, and Surjeet Singh from the Oxford Surgical Intervention Trials Unit, wider members of the MACRO Programme Team, NeilMed Pharmaceuticals for provision of the sinus irrigation bottles for the trial, Nikkayla Dixon as sponsor representative for University College London, and Jane Woods and Teresa Ferreira for research nurse feedback on trial set up. |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Respiratory and Airways Group |
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| Depositing User: | LivePure Connector |
| Date Deposited: | 26 Sep 2025 15:30 |
| Last Modified: | 25 Oct 2025 00:08 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/100470 |
| DOI: | 10.1016/S0140-6736(25)01248-6 |
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