Introduction

The efficacy of topical nasal corticosteroids and nasal saline irrigations in patients with chronic rhinosinusitis (CRS) has been demonstrated by previous Cochrane systematic reviews. However, there is lack of evidence on the long-term use of macrolide antibiotics. A substantial proportion of patients do not exhibit adequate response to intranasal corticosteroids, short-term antibiotic therapy and saline irrigations and hence endoscopic sinus surgery is recommended for this group of patients. The evidence comparing the efficacy of surgery vs medical treatment in CRS patients with nasal polyps is of very low quality. As no firm conclusions can be drawn from the current studies, further research is warranted as CRS adversely impacts the quality of life of these patients.

Aim

This MACRO trial compared the clinical efficacy of endoscopic sinus surgery vs 3-month course of clarithromycin, in addition to the standard intranasal corticosteroids in chronic rhinosinusitis patients with or without nasal polpys.

Method

Study Design

• Pragmatic, three-arm, randomised, placebo-controlled phase 4 study

Patient Inclusion Criteria

• Patients aged >18 years diagnosed with CRS based on European guidelines (history of <12 weeks of >2 symptoms, one of which was nasal obstruction, nasal blockage, nasal congestion and/or nasal discharge in addition to facial pain or pressure and/or reduction or loss of smell)
• Underwent nasal endoscopy within the past 3 months to determine the phenotype
• Underwent CT scan to determine the Lund-Mackay score
• Having 22-item Sino-Nasal Outcome Test (SNOT-22) score of atleast 20 within the previous 3 months
• Did not have adequate response to intranasal corticosteroids, saline irrigations and a short course of antibiotics (<3 weeks)

Treatment Strategy

• Patients were randomised into 3 groups
  • Endoscopic sinus surgery group: who were to receive endoscopic sinus surgery (within 6 weeks of randomisation if waiting lists allowed) plus intranasal medication
  • Clarithromycin group: to receive clarithromycin 250 mg twice a day for 2 weeks then 250 mg once a day for 10 weeks plus intranasal medication
  • Placebo group: to receive placebo capsules twice daily for 2 weeks followed by once daily for 10 weeks plus intranasal medication
• All participants received intranasal medication that included intranasal corticosteroids and saline irrigations throughout 6 months
• Participants were assigned using a secure, automated web-based randomisation system that employed permuted blocks of varying sizes (three and six), with stratification based on the presence of polyps and trial site
• Both participants and site teams were blinded to the treatment allocation—whether clarithromycin or placebo—including during outcome assessments

Endpoints

Primary Endpoint

• The total score on the SNOT-22 quality-of-life questionnaire at 6 months

Safety Endpoints

• Adverse reactions in the safety population (clarithromycin and placebo groups)
• Serious adverse events in the intent-to-treat (ITT) population (all groups)

Results

• Cohort comprised 514 participants; of which 80% had CRS with nasal polpys (n= 410) and 20% had CRS without nasal polyps (n=104) and 65% were males
• Participants were randomised to receive endoscopic sinus surgery (n=171), clarithromycin (n=172), or placebo (n=171), all with intranasal medication
• Endoscopic sinus surgery was associated with significantly lower SNOT-22 scores at 6 months after randomisation as compared to clarithromycin group (adjusted mean difference –18.13; p<0.0001) and placebo group (–20.44; p<0.0001)

Figure 1. Comparison of SNOT-22 scores at 6 months

• The difference in the 6-month SNOT-22 scores was not significant between clarithromycin vs placebo (–3.11; p=0.17)
• Ten serious adverse events occurred in nine participants; the incidence of AEs was 2%, 1% and 2% in the endoscopic sinus surgery, clarithromycin and placebo groups respectively; however, none of them were fatal

Conclusion

• Endoscopic sinus surgery resulted in significant improvement in disease-specific quality of life at 6 months in patients with chronic rhinosinusitis, suggesting it as a good option in cases where adequate symptom control is not achieved with intranasal medication alone.
• The results of this MACRO trial do not support routine long-term use of low-dose clarithromycin.

Lancet. 2025 Aug 30;406(10506):926-939. Doi: 10.1016/S0140-6736(25)01248-6.