Chronic rhinosinusitis (CRS) affects approximately 9% of adults worldwide and substantially impairs quality of life. Symptoms include nasal obstruction, discharge, facial pain, anosmia, and sleep disturbance, sometimes more severely than angina or chronic respiratory disease. Acute exacerbations are common, and about one-third of patients attending ENT clinics fail to respond to standard treatments, including intranasal corticosteroids, short-term antibiotics, and saline rinses, making them suitable candidates for endoscopic sinus surgery.
The evidence for long-term antibiotic therapy remains inconsistent, making the treatment challenging. In 2023, 12,090 sinus surgeries were performed in England, while in the United States (U.S.), more than 250,000 sinus surgeries occur annually, with evidence of five-fold variation in surgical rates across regions. The 2020 European Position Paper highlighted the lack of high-quality trials and emphasized the need for comparative studies evaluating surgical compared to medical interventions.
The MACRO trial was designed as a pragmatic, multicenter, randomized, placebo-controlled Phase 4 study conducted across 21 hospitals in the United Kingdom, with 20 active recruitment sites. Adults aged 18 years or older with chronic rhinosinusitis, with or without nasal polyps, who had failed standard medical therapy and reported moderate-to-severe symptoms and met European criteria for diagnosing chronic rhinosinusitis as evidenced by a Sino-Nasal Outcome Test (SNOT-22) of greater than 20.
Recent sinus surgery, long-term macrolide use, severe comorbidities, and clarithromycin contraindications were exclusion criteria. Participants were allowed to continue nasal steroids, saline irrigations, and topical decongestants.
Following consent, participants were randomly assigned on a 1:1:1 basis to either endoscopic sinus surgery with an intranasal medication, clarithromycin with an intranasal medication, or a placebo with an intranasal medication. Randomisation was stratified by centre and polyp status and was centrally allocated and concealed. Participants and clinicians were blinded to the clarithromycin or placebo, but the surgical allocation could not be blinded.
Participants in the clarithromycin group received 250mg twice daily for 2 weeks, followed by a 250mg oral dose once daily for 10 weeks. The placebo group received the same regimen with an identical placebo preparation. Participants in the surgery arm underwent functional endoscopic sinus surgery (FESS) within six weeks of randomization and were performed by consultant rhinologists using standardized methods. All participants continued to use intranasal corticosteroids and saline irrigation during the six-month trial, allowing for the use of additional treatments, such as oral steroids or antibiotics, permitted for acute exacerbations.
Between 2018 and 2023, 514 patients with chronic rhinosinusitis were enrolled, primarily (80%) with nasal polyps, and randomized them to receive clarithromycin, a placebo, or surgery combined with intranasal medication. Most patients (94%) received their assigned treatment, and 39 major protocol violations were reported. In the surgery group, 148 had surgery, with two-thirds receiving complete sinus surgery within six months.
A total of 333 males (65%) and 181 females (35%) were included in the trial population. Of the 296 participants with ethnicity data, 271 (92%) participants identified as White. The three study groups were similar at baseline in terms of socio-demographic and clinical characteristics, medical history, and outcomes. Randomisation distributed trial sites and phenotypes (with polyps and without polyps) evenly among the three groups.
This study demonstrated that endoscopic sinus surgery provided greater improvements in symptoms and quality of life compared to continued medical therapy, with or without intranasal medication. Surgery led to significant improvements in SNOT-22 scores and sinus-specific outcomes with modest but sub-threshold improvements in smell.
Clarithromycin offered no overall benefit; however, it may be beneficial for patients without type 2 disease who may derive some advantage. The trial was underpowered for patients without polyps and did not adequately represent non-white populations. These findings support endoscopic sinus surgery as the preferred option for patients with CRS and persistent symptoms despite standard medical therapy.
References: Philpott C, Ahmed S, et al. 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. Lancet. 2025;406(10506):926-939.
