Effectiveness of FF/UMEC/VI versus ICS/LABA in Patients with Uncontrolled Asthma Treated in Routine Clinical Practice (PERFORM): A Pragmatic Randomized Controlled Trial

Erika Penz,1,2 Stephen G Noorduyn,3,4 Alison C Moore,5 Hiroyuki Nagase,6 Jodie Crawford,7 Mary Woessner,8 Lydia Demetriou,9 Nicola Brown,10 David Slade,11 Gabriel Garcia,12 Alan P Baptist,13 John J Oppenheimer14 1Department of Medicine, Division of Respirology and Sleep Medicine, University of Saskatchewan, Saskatoon, SK, Canada; 2Respiratory Research Center, University of Saskatchewan, Saskatoon, SK, Canada; 3Global Real-World Evidence, GSK, Mississauga, ON, Canada; 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 5Global Medical Affairs, General Medicines, GSK, London, UK; 6Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan; 7Development Biostatistics, GSK, London, UK; 8GSK, Durham, NC, USA; 9Global Clinical Operations, GSK, London, UK; 10Clinical Sciences, Respiratory, GSK, London, UK; 11Respiratory Clinical Research Unit, GSK, Collegeville, PA, USA; 12Respiratory Research Center, La Plata, Argentina; 13Division of Allergy and Immunology, Henry Ford Health, Detroit, MI, USA; 14University of Medicine and Dentistry of New Jersey-Rutgers, Newark, NJ, USACorrespondence: Stephen G Noorduyn, Global Real-World Evidence, GSK, 100 Milverton Drive, Suite 800, Mississauga, ON, L5R 4H1, Canada, Email [email protected]: Asthma guidelines recommend stepwise escalation of inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy, yet many patients remain uncontrolled. Randomized controlled trials (RCTs) show that single-inhaler triple therapy improves lung function, with varying effects on symptoms and exacerbations. However, highly controlled explanatory RCTs with selective populations may not reflect real-world care. PERFORM evaluated the effectiveness and safety of initiating once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) ELLIPTA versus usual care non-ELLIPTA ICS/LABA in routine clinical practice.Methods: PERFORM (GSK219912/NCT06372496) is a randomized, open-label, active-controlled, 52-week, global pragmatic trial including adults (18– 75 years) with uncontrolled, infrequently exacerbating asthma, previously untreated or treated with non-ELLIPTA ICS or ICS/LABA in the 3-months pre-randomization. Powered primary and secondary endpoints were change from baseline in trough forced expiratory volume in 1 second (FEV1) and asthma control (Asthma Control Questionnaire [ACQ]-7 responder analysis) at Week 24 (W24). Safety was assessed throughout the trial.Results: Overall, 1236 patients (mean age: 48.9 years; 68.6% female) were included in this W24 primary analysis (FF/UMEC/VI: N=619; ICS/LABA: N=617). At baseline mean FEV1%predicted was 85.7; mean ACQ-7 score was 2.46. At W24, FF/UMEC/VI statistically significantly improved trough FEV1 from baseline versus ICS/LABA (least squares mean difference [95% confidence interval]: +68mL [36– 99], P< 0.001). FEV1 improvement from baseline was 178mL (139– 217) with FF/UMEC/VI and 110mL (72– 149) with ICS/LABA. Odds of a clinically meaningful response in ACQ-7 score (≥ 0.5-point improvement from baseline) were significantly greater with FF/UMEC/VI versus ICS/LABA (odds ratio [95% confidence interval]: 1.47 [1.13– 1.92], P< 0.004); 79.0% of patients achieved a response with FF/UMEC/VI and 71.8% with ICS/LABA. Safety profile to W24 aligned with previous studies.Conclusion: This pragmatic RCT demonstrated significant improvements in lung function and asthma control with FF/UMEC/VI versus ICS/LABA in uncontrolled and infrequently exacerbating patients treated in a routine practice setting. These findings further inform the evidence base for optimized use of FF/UMEC/VI.Keywords: asthma control, lung function, real-world setting, single-inhaler triple therapy