Phase 4 Trial Confirms Endoscopic Sinus Surgery Efficacy for Chronic Rhinosinusitis

A phase 4 trial confirmed the clinical effectiveness of endoscopic sinus surgery in patients with chronic rhinosinusitis, while providing no support for the routine long-term use of low-dose clarithromycin.1

“General practitioners and ear, nose, and throat specialists should be aware of the implications of the present findings for patients with chronic rhinosinusitis who they see and treat,” study investigator Carl Philpott, MD, from Norwich Medical School at the University of East Anglia in the UK, and colleagues, wrote.1 “Patients could be advised of the high potential to benefit from endoscopic sinus surgery in terms of symptom relief when being counselled about how to manage their chronic rhinosinusitis.”

Limited evidence on the effectiveness of endoscopic sinus surgery and antibiotics in chronic rhinosinusitis has led to wide differences in practice, with some clinicians performing surgery more often than others. Clinicians perform endoscopic sinus surgery up to five times more often than they prescribe antibiotics.

Longer-term antibiotic use remains in question after 2 randomized controlled trials reported conflicting results.2,3 While a trial in 2006 supported macrolide in the treatment of chronic rhinosinusitis, a trial in 2011 found that taking azithromycin over 3 months (500 mg for 3 days during the first week, followed by 500 mg per week for the next 11 weeks) provided no significant benefit for chronic rhinosinusitis over placebo.

In MACRO, a pragmatic, 3-arm, randomized, placebo-controlled phase 4 trial, investigators sought to compare the clinical effectiveness of endoscopic sinus surgery or 3 months of clarithromycin alongside intranasal medication in adults with chronic rhinosinusitis with or without nasal polyps.1 The primary outcome was the total score on the 22-item Sino-Nasal Outcome Test (SNOT-22) quality-of-life questionnaire assessed 6 months after randomization, analyzed using an intention-to-treat approach. The study also assessed adverse events in participants taking clarithromycin and placebo, along with severe adverse events in all participants.

The team recruited 514 participants (aged ≥ 18 years; 65% male) with chronic rhinosinusitis (410 with nasal polyps; 104 without) from 20 secondary and tertiary care sites in the UK between November 1, 2018, and October 13, 2023. The study included participants who remained symptomatic after taking intranasal corticosteroids, saline nasal irrigations, and a short course of antibiotics.

Investigators randomized participants 1:1:1 to receive endoscopic sinus surgery (within 6 weeks of randomization, depending on waiting lists; n = 171), clarithromycin (250 mg twice a day for 2 weeks then 250 mg once a day for 10 weeks; n = 172), or placebo (n = 171). Participants in all arms also received intranasal medication, comprised of intranasal corticosteroids and saline irrigations.

The study found that participants receiving endoscopic sinus surgery had significantly lower SNOT-22 scores at 6 months compared to participants receiving clarithromycin (adjusted mean difference, -18.13; 98.33% confidence interval [CI], -24.26 to -11.99]; P <.0001) and placebo (-20.44; 98.33% CI, -26.42 to -14.46; P <.0001). Additionally, at 6 months, SNOT-22 scores did not differ significantly between participants assigned to clarithromycin versus placebo (-3.11; 98.33% CI, -8.56 to 2.33; P = .17).1

Investigators identified 10 serious adverse events in 9 participants: 2 events in 2 participants assigned to clarithromycin, 3 events in 3 participants assigned to endoscopic, and 5 events in 4 participants assigned to endoscopic sinus surgery. No events were fatal.1

“The present findings, if implemented in a care pathway, could reduce unnecessary antibiotic prescriptions and reduce the time taken for patients with chronic rhinosinusitis with nasal polyps to access endoscopic sinus surgery for those wanting surgical intervention, with potential cost-savings from reduced consultations and prescriptions,” investigators concluded.1

References

1. Philpott C, Beard DJ, Saeedi E, 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. doi:10.1016/S0140-6736(25)01248-6

2. Wallwork B, Coman W, Mackay-Sim A, Greiff L, Cervin A. A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Laryngoscope. 2006;116(2):189-193. doi:10.1097/01.mlg.0000191560.53555.08

3. Videler WJ, Badia L, Harvey RJ, et al. Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized controlled trial. Allergy. 2011;66(11):1457-1468. doi:10.1111/j.1398-9995.2011.02693.x