MACRO Trial Challenges Long-Standing Chronic Rhinosinusitis Treatment Paradigms
Key Insights
The landmark MACRO trial, the most extensive clinical investigation into chronic rhinosinusitis (search) management to date, demonstrated that endoscopic sinus surgery significantly outperformed both clarithromycin antibiotics and placebo in improving quality of life scores at six months.
The study found no significant benefit from three-month clarithromycin treatment compared to placebo, challenging the routine use of long-term macrolide antibiotics in chronic rhinosinusitis (search) patients.
Results support offering sinus surgery earlier in the treatment pathway without delay if symptoms don't respond to intranasal medications, potentially reducing unnecessary antibiotic prescriptions and associated resistance concerns.
The MACRO trial, a groundbreaking £3.2 million study funded by the UK National Institute of Health Research (search), has delivered definitive evidence challenging established treatment approaches for chronic rhinosinusitis (search) (CRS), a condition affecting millions worldwide with symptoms including nasal discharge, congestion, decreased smell, and facial pressure lasting more than 12 weeks.
Landmark Study Design and Scope
The pragmatic, three-arm randomized, placebo-controlled phase 4 trial recruited 514 adults with CRS from 20 secondary and tertiary care sites across the UK. Participants included 181 females (35%) and 333 males (65%), with 410 having chronic rhinosinusitis (search) with nasal polyps (80%) and 104 without polyps (20%). All remained symptomatic despite appropriate medical therapy comprising intranasal corticosteroids (search), saline irrigation, and short-course antibiotics.
The study compared three treatment approaches: endoscopic sinus surgery within six weeks (n=171), clarithromycin 250mg twice daily for two weeks then once daily for 10 weeks with intranasal medication (n=172), and placebo with intranasal medication (n=171). All participants continued intranasal medication throughout the study period.
Surgery Demonstrates Clear Superiority
At six months, the primary outcome measure—the 22-item Sino-Nasal Outcome Test (SNOT-22) quality-of-life questionnaire—showed significantly lower scores in the endoscopic sinus surgery group compared to both clarithromycin (adjusted mean difference −18.13; 98.33% CI −24.26 to −11.99; p<0.0001) and placebo groups (−20.44; 98.33% CI −26.42 to −14.46; p<0.0001). Lower SNOT-22 scores indicate better sinonasal-related quality of life.
Secondary outcomes reinforced surgery's effectiveness, with significant improvements across multiple measures except peak expiratory flow rate and peak nasal inspiratory flow rate. Regarding olfactory function, the surgical group showed significantly greater increases in TDI scores (assessing threshold, discrimination, and identification) compared to placebo, though only 40% achieved the minimum clinically important difference of 5.5 points.
Antibiotics Show Limited Benefit
Critically, SNOT-22 scores showed no significant difference between clarithromycin and placebo groups (−3.11; CI −8.56 to 2.33; p=0.17), undermining the routine use of long-term macrolide antibiotics. This finding is particularly significant given analysis of general practice data showing nearly one in 10 CRS patients receiving five or more antibiotic courses over five years.
Subgroup analysis revealed surgery proved effective in both main disease endotypes, with stronger effects in type 2 inflammatory disease. While clarithromycin showed no significant SNOT-22 improvement in either subgroup, there was a trend toward significance in non-type 2 CRS participants, though this subgroup was underpowered.
Safety Profile and Adverse Events
Adverse events remained rare across all groups, with 10 serious adverse events in nine participants: two in the clarithromycin group (1%), three in the placebo group (2%), and five in the surgery group (2%). None proved fatal, and all participants were discharged without lasting complications.
Clinical Practice Implications
The trial findings directly challenge current treatment paradigms. As Professor Carl Philpott and Professor Claire Hopkins, the study's joint leaders, noted, the results indicate long-term macrolides should not be used routinely in primary or secondary care, especially when endotype is undetermined.
The researchers propose a new care pathway emphasizing earlier surgical intervention for patients not responding to intranasal treatments. This approach could reduce unnecessary antibiotic prescriptions—a critical consideration given rising antibiotic resistance concerns—while potentially lowering costs related to repeated prescriptions and appointments.
Future Research Directions
The MACRO programme continues monitoring many trial participants annually for five years, with long-term results planned for publication in 2029. Additional research is planned to gather more evidence regarding clarithromycin's effectiveness specifically in non-type 2 CRS subgroups.
The study's comprehensive approach, spanning health informatics, health economics, qualitative research, trial delivery, and consensus-building activities, provides a robust foundation for implementing evidence-based CRS management strategies across healthcare systems.