Abstract
Introduction
Prospective, randomized evidence for clinical remission, an ambitious treatment goal relevant for all patients with asthma, with single-inhaler triple therapy (SITT) in routine care is lacking. Significant improvement in lung function and asthma control with SITT versus inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) was demonstrated in PERFORM at week 24.
Methods
PERFORM (GSK 219912/NCT06372496), a randomized, open-label, active-controlled, global pragmatic trial, evaluated the effectiveness and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus usual care ICS/LABA in adults (18–75 years) with uncontrolled, infrequently exacerbating asthma. Secondary outcomes related to clinical remission (no oral corticosteroid use, no severe exacerbations, optimized lung function [change from baseline (CFB) in forced expiratory volume in 1 second (FEV1) ≥ 100 mL], asthma control [Asthma Control Questionnaire total score < 1.50]) were assessed at week 52, following prespecified analysis plans. Alternative clinical remission definitions using stabilized lung function (CFB FEV1 ≥ 0 mL) and those within Japanese guidelines were also assessed. Clinical remission responder analyses are presented as multiplicity-adjusted odds ratios. Safety was assessed throughout.
Results
Overall, 1236 participants (mean age 48.9 years; 68.6% [n = 848/1236] female) were included (FF/UMEC/VI: N = 619/1236; ICS/LABA: N = 617/1236). Participants receiving FF/UMEC/VI had statistically significantly greater odds of achieving clinical remission (including optimized lung function) at week 52 versus usual care ICS/LABA (adjusted odds ratio [95% confidence interval] 2.13 [1.54, 2.94], P < 0.0001). Similar results were observed for alternative definitions. Week 52 safety profile aligned with previous studies.
Conclusions
In a broad patient population with uncontrolled asthma, treatment with FF/UMEC/VI resulted in statistically significantly greater odds of achieving clinical remission versus usual care ICS/LABA in a setting reflecting routine practice, a secondary outcome of PERFORM. These findings were consistent irrespective of clinical remission definitions and provide evidence informing the use of FF/UMEC/VI in an underserved group of symptomatic patients with infrequent exacerbations and minimal lung function impairment.
Trial Registration
GSK 219912/NCT06372496.
Graphical Abstract
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03721-1.
Keywords: Asthma control, Clinical remission, Lung function, Routine practice setting, Single-inhaler triple therapy, Pragmatic randomized controlled trial
Video 1 (MP4 217347 KB)
Key Summary Points
| Why carry out this study? |
| A large proportion of patients with asthma experience a daily burden of uncontrolled symptoms despite infrequent exacerbations and preserved lung function. |
| PERFORM was a randomized, controlled, pragmatic trial evaluating the effectiveness and safety of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus usual care inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) in participants with uncontrolled asthma in a setting reflecting routine practice. |
| Clinical remission is an ambitious treatment goal in asthma, measured over at least 52 weeks, with core components including lung function, asthma control, no systemic corticosteroid use, and no exacerbations. |
| What was learned from this study? |
| In PERFORM, participants receiving FF/UMEC/VI had statistically significantly greater odds of achieving clinical remission versus usual care ICS/LABA in routine practice, which was consistent across multiple definitions of this endpoint. |
| These findings support the clinical concept of targeting clinical remission through FF/UMEC/VI single-inhaler triple therapy intervention in an underserved group of symptomatic patients with infrequent exacerbations and minimal lung function impairment. |
Digital Features
This article is published with digital features, including a video and graphical abstract, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.32824451.
Introduction
Current asthma treatment guidelines recommend inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy for patients whose symptoms are uncontrolled with low-dose maintenance ICS [1]. However, approximately 80% of patients with asthma report weekly symptoms and 70% remain uncontrolled even when adherent to high-dose ICS/LABA [2–4]. Triple therapy is recommended for patients who remain uncontrolled despite medium-to-high dose ICS/LABA and who are at risk of exacerbating [1]. Nonetheless, there remains an unmet need for patients with asthma treated with ICS/LABA who continue to experience a persistent burden of daily symptoms despite infrequent exacerbations and preserved lung function.
Explanatory phase 3 randomized controlled trials (RCTs) are the accepted standard for establishing treatment efficacy, requiring strict eligibility criteria and controlled treatment conditions. The phase 3a CAPTAIN RCT demonstrated the efficacy and safety of once-daily single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus matched-dose FF/VI in a controlled trial setting. CAPTAIN and RCTs of other single-inhaler triple therapies (SITTs) demonstrated significant improvements in lung function with SITT versus dose- and formulation-matched ICS/LABA. However, the observed impact of SITT on symptom control and exacerbations in explanatory RCTs has been inconsistent [5–8] and real-world studies have shown that SITT is associated with significant improvements in exacerbations and oral corticosteroid (OCS) use [9, 10]. There is therefore a need for pragmatic randomized studies evaluating clinical outcomes with SITT in participants with symptomatic asthma.
In the PERFORM trial, participants with uncontrolled, infrequently exacerbating asthma were randomized to receive either FF/UMEC/VI (administered via ELLIPTA) or non-ELLIPTA ICS/LABA usual care [11]. At week 24, statistically significant improvements in lung function and asthma control were observed with FF/UMEC/VI SITT versus usual care ICS/LABA, providing the first pragmatic randomized evidence of the benefit of a SITT in these patient profiles [12].
Clinical remission, assessed over at least 52 weeks, is an ambitious and achievable treatment goal in asthma that should be considered relevant for all patients [1, 13, 14]. Various guidelines and expert groups have positions on clinical remission, and nearly all include the core components of lung function, asthma control, systemic corticosteroid (SCS) use, and occurrence of exacerbations [1, 13, 14]. Notably, Japanese guidelines have two definitions of clinical remission, differing on the inclusion of the lung function component [15, 16]. The 2024 Japanese Guidelines for Adult Asthma (JGL), aimed at specialists, define clinical remission based on the same four components and measures symptom control with an Asthma Control Test (ACT) score ≥ 23. In contrast, the Practical Guidelines for Asthma Management (PGAM), intended for primary care providers, exclude lung function as it is not always measured in clinical practice.
Prior assessments of FF/UMEC/VI versus FF/VI dual therapy for clinical remission included post hoc analyses of the phase 3a CAPTAIN RCT. These analyses showed that 31–36% of participants receiving FF/UMEC/VI 100/62.5/25 µg or 200/62.5/25 µg met a composite endpoint reflecting the components of clinical remission at 24 weeks, specifically no SCS use, no severe exacerbations, asthma control (Asthma Control Questionnaire-5 [ACQ-5] < 1.50), optimized lung function (change from baseline [CFB] in trough forced expiratory volume in 1 s [FEV1] ≥ 100 mL), compared with 19% for FF/VI 100/25 µg and 26% for FF/VI 200/25 µg dual therapy [17]. A similar proportion (30–38% vs 21–24%) achieved a clinical remission composite endpoint (herein clinical remission) with FF/UMEC/VI versus FF/VI at 52 weeks; consistent findings were reported when stabilized lung function (CFB in trough FEV1 ≥ 0 mL) was used in place of optimized lung function [17]. In the PERFORM trial, 33.9% versus 19.0% of participants met a composite endpoint reflecting the same four components and optimized lung function for FF/UMEC/VI versus usual care ICS/LABA at 24 weeks [12]. This evidence provides an early indication of the attainability of key clinical outcomes within a clinical remission endpoint, as 24-week treatment data have been found to be potentially predictive of clinical remission achievement at 52 weeks [17]. Currently, there is a lack of prospective, randomized evidence for clinical remission with SITT, particularly in patients with uncontrolled, infrequently exacerbating asthma.
Here we present results from the week 52 analysis of the PERFORM trial, evaluating the effectiveness and safety of FF/UMEC/VI SITT versus usual care ICS/LABA, with the aim of reporting the first prospective, randomized evidence on clinical remission and exploring various clinical remission definitions. Please see Video 1 in the online/HTML version of the manuscript for a video summary of this study or follow the digital features link above.
Methods
Trial Design and Population
The PERFORM trial (GSK 219912/NCT06372496) was a 52-week, stratified, randomized, open-label, active-controlled, pragmatic trial conducted across seven countries [11]. Eligible participants were 18–75 years of age with uncontrolled asthma (ACQ-6 score ≥ 1.5 at randomization), had ≤ 1 severe exacerbation in the previous 12 months, and were either untreated (i.e., had not received any ICS-containing therapy within the 3 months prior to randomization) or had received non-ELLIPTA ICS or ICS/LABA maintenance therapy for ≥ 3 months prior to randomization [11]. Further details of the PERFORM trial design and population have been published previously [11, 12].
Participants were randomized 1:1 to receive either FF/UMEC/VI delivered via the ELLIPTA dry-powder inhaler or to any licensed non-ELLIPTA ICS/LABA therapy prescribed as usual care. Non-ELLIPTA ICS/LABA usual care was selected at the treating physician’s discretion, according to local guidelines and availability. While more participants were prescribed FF/UMEC/VI 100/62.5/25 µg or low-dose ICS/LABA, ICS escalation to FF/UMEC/VI 200/62.5/25 µg or high-dose ICS/LABA, respectively, was permitted at any time during the trial in the event of worsening asthma control at the discretion of the treating physician [11]. To reflect routine clinical practice, participants only attended in-clinic visits at screening (visit 1), randomization (visit 2), week 24 (visit 3), and week 52 (or early withdrawal; visit 4). A telephone safety follow-up was conducted 7 days post discontinuation [11].
Trial Oversight
The PERFORM trial was sponsored by GSK (219912/NCT06372496) and conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice, as well as applicable local regulations. Trial documents and protocol amendments received approval by relevant local institutional review boards and/or independent ethics committees (Table S1) [11]. All participants provided physically or digitally signed, informed consent.
Outcomes
Effectiveness
The primary endpoint of the PERFORM trial was CFB in trough FEV1 at week 24. The key secondary endpoint was achieving a response in ACQ-7 total score (defined as an improvement [decrease] from baseline beyond the 0.5-point minimum clinically important difference [18]) at week 24. Results for both the primary and key secondary endpoints have been published [12]. A step-down closed testing approach accounted for multiplicity across selected prespecified endpoints, with the primary and key secondary endpoints occurring first and second, respectively, in the statistical hierarchy [11].
The composite endpoint of clinical remission at week 52 was third in the testing hierarchy. This 52-week endpoint was defined as achieving the following four components: no OCS use since baseline, no severe exacerbations since baseline, controlled asthma (ACQ-5 total score < 1.50), and optimized lung function (CFB in trough FEV1 ≥ 100 mL). A severe exacerbation was defined as the deterioration of asthma requiring the use of SCS (tablets, suspension, or injection) or an increase from a stable maintenance dose of SCS for ≥ 3 days, or an inpatient hospitalization or emergency department visit because of asthma requiring SCS [11]. The proportions of participants achieving the clinical remission endpoint and achieving its individual components at week 52 were assessed and presented. Similar data were also collected for a clinical remission endpoint with stabilized lung function (i.e., CFB in trough FEV1 ≥ 0 mL at week 52) [11].
Exploratory analyses were carried out to assess the proportion of participants achieving clinical remission using alternative definitions. The four-component definition endorsed by the JGL replaced the asthma control measure (ACQ-5 total score < 1.50) with the ACT total score ≥ 23. The three-component definition adopted by the PGAM further removed the lung function component (no OCS use since baseline, no severe exacerbations since baseline, and an ACT total score ≥ 23) [15, 16].
Safety Profile
Safety endpoints included incidence of trial intervention/treatment-related treatment-emergent adverse events (TEAEs) and serious TEAEs, assessed to week 52.
Statistical Analyses
A prespecified step-down closed testing approach was used to control the family-wise type I error rate at alpha = 0.05 from multiple testing the primary and key secondary endpoints [11, 12]. These endpoints were met; therefore, the testing strategy proceeded to the third endpoint in the hierarchy, namely the clinical remission secondary endpoint. Endpoints not included in the step-down approach (including individual components of the clinical remission endpoint and alternative definitions of clinical remission) were not adjusted for multiplicity and should be considered as descriptive. Details of sample size calculations, analysis sets, and analysis methods for the primary and key secondary endpoints have been reported previously [11, 12]. Briefly, effectiveness and safety analyses included randomized participants who received ≥ 1 prescription of FF/UMEC/VI or ICS/LABA. Effectiveness analyses (modified full analysis set 1 [FAS-Modified-1]) were assessed according to randomized trial intervention and safety analyses (modified safety analysis set 1 [SAF-Modified-1]) were assessed according to actual treatment prescribed. Responder analyses (clinical remission endpoint) were assessed using a generalized linear mixed model using a logit link function with covariates of treatment, treatment-by-visit interaction, sex, region, actual pre-trial asthma maintenance therapy (untreated, ICS alone, ICS/LABA), pre-trial ICS dose (high, low), age, baseline trough FEV1, baseline ACQ-5 total score, trough FEV1-by-visit interaction, and ACQ-5 total score-by-visit interaction. Data from both week 24 and week 52 were included in the model for adjusted analyses. For unadjusted analyses (post hoc), data from week 24 and week 52 were analyzed separately with a generalized linear model for binary response with the binary composite treatment responder as the dependent variable and treatment as a covariate. The number and percentage of responders and non-responders at week 52 are presented; treatment comparisons are reported as adjusted odds ratios (ORs) with 95% confidence intervals (CIs), with absolute risk difference, number needed to treat, and unadjusted odds ratios also presented in the Supplement. Responders were defined as participants who achieved all four components of the clinical remission endpoint at the timepoint of interest, and non-responders were defined as participants who did not achieve all four components at the timepoint of interest. Participants with missing data (including those who withdrew) for one or more components of the clinical remission endpoint at the timepoint of interest were considered non-responders. Statistical analyses were performed in SAS v9.4 or higher (SAS Institute, Cary, NC).
Baseline characteristics and safety data were summarized using descriptive statistics.
Intercurrent events (trial intervention discontinuation, use of prohibited medications, ICS dose escalation) were handled using a treatment policy approach and all observed data were included in the analysis regardless of the intercurrent event.
Results
Trial Population
Overall, 1236 participants (FF/UMEC/VI: N = 619; ICS/LABA: N = 617) were randomized, received ≥ 1 prescription of FF/UMEC/VI or ICS/LABA and were included in the primary effectiveness analyses (FAS-Modified-1); 1041 completed the trial, with 1016 completing 52 weeks of trial intervention (Fig. S1). In the 3 months pre-randomization, 63.3% (n = 783/1236) of participants were treated with ICS/LABA and 31.9% (n = 394/1236) received no prior ICS-containing maintenance therapy. Most participants who were randomized to ICS/LABA were prescribed budesonide/formoterol (43.2% [n = 261/604]), fluticasone propionate/salmeterol (33.1% [n = 200/604]) or fluticasone propionate/formoterol (16.7% [n = 101/604]) (SAF-Modified-1).
Baseline characteristics are reported in Table 1 and have been described previously [12]. Mean (standard deviation [SD]) age was 48.9 (15.1) years, most participants were female (68.6% [n = 848/1236]), and 7% (n = 87/1236) were current smokers. Most participants were of White (61.1% [n = 755/1236]) or Asian (31.1% [n = 384/1236]) ethnicity. Participants had a mean (SD) FEV1 % predicted of 85.73 (19.55) and mean [SD] ACQ-7 total score of 2.46 (0.76). In the 12 months pre-randomization, 17.9% (n = 221/1236) had one severe exacerbation.
Table 1.
Baseline participant characteristics (FAS-Modified-1)
| Overall populationa | |||
|---|---|---|---|
| FF/UMEC/VI (N = 619) |
ICS/LABA (N = 617) |
Overall (N = 1236) |
|
| n/619 (%) | n/617 (%) | n/1236 (%) | |
| Sex | |||
| Female | 429 (69.3) | 419 (67.9) | 848 (68.6) |
| Male | 190 (30.7) | 198 (32.1) | 388 (31.4) |
| Country | |||
| Argentina | 216 (34.9) | 204 (33.1) | 420 (34.0) |
| USA | 182 (29.4) | 186 (30.1) | 368 (29.8) |
| Japan | 165 (26.7) | 161 (26.1) | 326 (26.4) |
| Australia | 29 (4.7) | 39 (6.3) | 68 (5.5) |
| Canada | 10 (1.6) | 14 (2.3) | 24 (1.9) |
| Taiwan | 8 (1.3) | 10 (1.6) | 18 (1.5) |
| South Korea | 9 (1.5) | 3 (0.5) | 12 (1.0) |
| Ethnicity | |||
| White | 376 (60.7) | 379 (61.4) | 755 (61.1) |
| Asian | 193 (31.2) | 191 (31.0) | 384 (31.1) |
| Black or African American | 41 (6.6) | 38 (6.2) | 79 (6.4) |
| Native Hawaiian or Other Pacific Islander | 4 (0.6) | 2 (0.3) | 6 (0.5) |
| Multiple | 2 (0.3) | 4 (0.6) | 6 (0.5) |
| Native American or Native Alaskanb | 2 (0.3) | 3 (0.5) | 5 (0.4) |
| Not reported/unknown | 1 (0.2) | 0 | 1 (0.1) |
| Smoking status | |||
| Current smoker | 42 (6.8) | 45 (7.3) | 87 (7.0) |
| Former smoker | 112 (18.1) | 120 (19.4) | 232 (18.8) |
| Never smoker | 465 (75.1) | 452 (73.3) | 917 (74.2) |
| Pre-trial asthma maintenance therapy | |||
| ICS/LABA | 392 (63.3) | 391 (63.4) | 783 (63.3) |
| Untreated | 199 (32.1) | 195 (31.6) | 394 (31.9) |
| ICS alone | 28 (4.5) | 31 (5.1) | 59 (4.8) |
| Pre-trial ICS dose | |||
| Low | 230 (37.2) | 230 (37.3) | 460 (37.2) |
| High | 190 (30.7) | 192 (31.1) | 382 (30.9) |
| Participants taking OCS at baseline | 0 | 2 (0.3) | 2 (0.2) |
| Participants with a severe asthma exacerbation during the 12 months pre-randomization | 107 (17.3) | 114 (18.5) | 221 (17.9) |
| Mean (SD) | |||
|---|---|---|---|
| Age, years | 48.7 (15.01) | 49.1 (15.17) | 48.9 (15.09) |
| Smoking pack years |
n = 150 11.4 (12.78) |
n = 164 11.9 (14.51) |
n = 314 11.6 (13.69) |
| Time since asthma diagnosis at randomization, yearsc |
n = 617 20.50 (18.57) |
n = 617 21.98 (19.25) |
n = 1234 21.24 (18.92) |
| Trough FEV1, mL | 2449 (800.5) | 2504 (785.3) | 2476 (793.1) |
| FEV1 % predicted | 85.11 (19.86) | 86.36 (19.24) | 85.73 (19.55) |
| FVC, mL | 3361 (936.9) | 3451 (968.4) | 3406 (953.4) |
| ACQ-5 total score | 2.79 (0.79) | 2.80 (0.81) | 2.80 (0.80) |
| ACQ-6 total score | 2.55 (0.78) | 2.56 (0.78) | 2.56 (0.78) |
| ACQ-7 total score | 2.46 (0.77) | 2.46 (0.76) | 2.46 (0.76) |
| ACT total score | 14.7 (4.12) | 14.7 (4.07) | 14.7 (4.09) |
ACQ Asthma Control Questionnaire, ACT Asthma Control Test, eCRF electronic Case Report Form, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, FVC forced vital capacity, ICS inhaled corticosteroid, LABA long-acting β2-agonist, OCS oral corticosteroid, SD standard deviation, UMEC umeclidinium, VI vilanterol
aParticipants who were randomized and received ≥ 1 prescription of FF/UMEC/VI or ICS/LABA
bData were collected as “American Indian or Alaska Native” in the eCRF
cFF/UMEC/VI: n = 617; ICS/LABA: n = 617; Overall: n = 1234. Baseline characteristics from week 24 have previously been reported [12]; baseline data for a few participants were updated between week 24 and week 52 database locks
Effectiveness
Clinical Remission Endpoint
A greater proportion of participants in the FF/UMEC/VI arm (29.7%; n = 184/619) achieved clinical remission (optimized lung function) at week 52 than the ICS/LABA arm (17.0%; n = 105/617) (Table 2). The odds of achieving clinical remission at week 52 were statistically significantly greater for FF/UMEC/VI compared with ICS/LABA (adjusted OR [95% CI] 2.13 [1.54, 2.94], P < 0.0001; Fig. 1).
Table 2.
Participants achieving clinical remission at week 52 (FAS-Modified-1)
| FF/UMEC/VI (N = 619) |
ICS/LABA (N = 617) |
|
|---|---|---|
| Composite endpoint using optimized lung function (CFB in trough FEV1 ≥ 100 mL) | ||
| n/619 (%) | n/617 (%) | |
| Responders | 184 (29.7) | 105 (17.0) |
| No OCS use since baseline | 551 (89.0) | 533 (86.4) |
| No severe asthma exacerbations since baseline | 541 (87.4) | 533 (86.4) |
| ACQ-5 total score < 1.50 | 423 (68.3) | 384 (62.2) |
| CFB in trough FEV1 ≥ 100 mL | 253 (40.9) | 167 (27.1) |
| Non-responders | 435 (70.3) | 512 (83.0) |
| Non-responder due to missing dataa | 94 (21.6) | 104 (20.3) |
| Adjusted OR (95% CI), P value | 2.13 (1.54, 2.94), P < 0.0001 | |
| Composite endpoint using stabilized lung function (CFB in trough FEV1 ≥ 0 mL) | ||
|---|---|---|
| n/619 (%) | n/617 (%) | |
| Responders | 256 (41.4) | 173 (28.0) |
| No OCS use since baseline | 551 (89.0) | 533 (86.4) |
| No severe asthma exacerbations since baseline | 541 (87.4) | 533 (86.4) |
| ACQ-5 total score < 1.50 | 423 (68.3) | 384 (62.2) |
| CFB in trough FEV1 ≥ 0 mL | 351 (56.7) | 262 (42.5) |
| Non-responders | 363 (58.6) | 444 (72.0) |
| Non-responder due to missing dataa | 94 (25.9) | 104 (23.4) |
| Adjusted OR (95% CI), P value | 1.85 (1.40, 2.45), P < 0.0001b | |
ACQ Asthma Control Questionnaire, CFB change from baseline, CI confidence interval, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, ICS inhaled corticosteroid, LABA long-acting β2-agonist, OCS oral corticosteroid, OR odds ratio, UMEC umeclidinium, VI vilanterol
aPercentages based on the number of non-responders
bP value was not adjusted for multiplicity and is considered descriptive
Fig. 1.
Odds of achieving clinical remission across alternative definitions (FAS-Modified-1). aOptimized lung function defined as CFB in trough FEV1 ≥ 100 mL; bStabilized lung function defined as CFB in trough FEV1 ≥ 0 mL; cP value was not adjusted for multiplicity and is considered descriptive. CFB change from baseline, CI confidence interval, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, ICS inhaled corticosteroid, JGL Japanese Guidelines for Adult Asthma, LABA long-acting β2-agonist, PGAM Practical Guidelines for Asthma Management, UMEC umeclidinium, VI vilanterol
Achievement of individual clinical remission components was consistently higher with FF/UMEC/VI versus ICS/LABA across all four criteria, with the largest treatment difference observed for CFB in trough FEV1 ≥ 100 mL (40.9% vs 27.1%); full data are presented in Table 2. Unadjusted data are presented in Table S2.
Additional Clinical Remission Endpoints (Not Multiplicity Adjusted)
The clinical response as measured by the proportion of participants achieving clinical remission was consistently observed across the different definitions (Table 2; Fig. 1). The odds of achieving the clinical remission exploratory endpoint with stabilized lung function (CFB in trough FEV1 ≥ 0 mL) at week 52 were greater with FF/UMEC/VI versus ICS/LABA (adjusted OR [95% CI] 1.85 [1.40, 2.45], P < 0.0001; Fig. 1) and the proportion of responders was 41.4% (n = 256/619) with FF/UMEC/VI versus 28.0% (n = 173/617) with ICS/LABA (Table 2). Unadjusted data are presented in Table S2.
Clinical remission was also assessed according to definitions established by JGL and PGAM in 2024 [15, 16]. For the JGL definition including the optimized lung function component (no OCS use, no severe exacerbations, ACT total score ≥ 23, CFB in trough FEV1 ≥ 100 mL), the odds of achieving the endpoint were greater with FF/UMEC/VI versus ICS/LABA (adjusted OR [95% CI] 2.21 (1.52, 3.23), P < 0.0001) (Fig. 1). The proportion of participants achieving the JGL composite endpoint with optimized lung function was 19.9% (n = 123/619) with FF/UMEC/VI versus 10.4% (n = 64/617) with ICS/LABA (Table 3). For the alternative JGL composite endpoint with stabilized lung function (no OCS use, no severe exacerbations, ACT total score ≥ 23, CFB in trough FEV1 ≥ 0 mL), the odds of achieving the endpoint were again greater with FF/UMEC/VI versus ICS/LABA (adjusted OR [95% CI] 2.16 [1.56, 3.00], P < 0.0001; Fig. 1) and the proportion of responders was 27.3% (n = 169/619) with FF/UMEC/VI versus 15.7% (n = 97/617) with ICS/LABA (Table 3). For the PGAM definition (no OCS use, no severe asthma exacerbations, and ACT total score ≥ 23) the odds of achieving clinical remission were greater with FF/UMEC/VI versus ICS/LABA (adjusted OR [95% CI] 1.49 [1.10, 2.02], P = 0.0100; Fig. 1) and the proportion of responders was 36.7% (n = 227/619) with FF/UMEC/VI versus 29.7% (n = 183/617) with ICS/LABA (Table 3). Unadjusted data are presented in Table S3.
Table 3.
Participants achieving clinical remission at week 52 as defined by JGL (four-component) and PGAM (three-component) (FAS-Modified-1)
| FF/UMEC/VI (N = 619) |
ICS/LABA (N = 617) |
|
|---|---|---|
| JGL 2024 definition using optimized lung function (CFB in trough FEV1 ≥ 100 mL) | ||
| n/619 (%) | n/617 (%) | |
| Responders | 123 (19.9) | 64 (10.4) |
| No OCS use since baseline | 551 (89.0) | 533 (86.4) |
| No severe asthma exacerbations since baseline | 541 (87.4) | 533 (86.4) |
| ACT total score ≥ 23 | 256 (41.4) | 204 (33.1) |
| CFB in trough FEV1 ≥ 100 mL | 253 (40.9) | 167 (27.1) |
| Non-responders | 496 (80.1) | 553 (89.6) |
| Non-responder due to missing dataa | 94 (19.0) | 104 (18.8) |
| Adjusted OR (95% CI), P value | 2.21 (1.52, 3.23), P < 0.0001b | |
| JGL 2024 definition using stabilized lung function (CFB in trough FEV1 ≥ 0 mL) | ||
|---|---|---|
| n/619 (%) | n/617 (%) | |
| Responders | 169 (27.3) | 97 (15.7) |
| No OCS use since baseline | 551 (89.0) | 533 (86.4) |
| No severe asthma exacerbations since baseline | 541 (87.4) | 533 (86.4) |
| ACT total score ≥ 23 | 256 (41.4) | 204 (33.1) |
| CFB in trough FEV1 ≥ 0 mL | 351 (56.7) | 262 (42.5) |
| Non-responders | 450 (72.7) | 520 (84.3) |
| Non-responder due to missing dataa | 94 (20.9) | 104 (20.0) |
| Adjusted OR (95% CI), P value | 2.16 (1.56, 3.00), P < 0.0001b | |
| PGAM 2024 definition | ||
|---|---|---|
| n/619 (%) | n/617 (%) | |
| Responders | 227 (36.7) | 183 (29.7) |
| No OCS use since baseline | 551 (89.0) | 533 (86.4) |
| No severe asthma exacerbations since baseline | 541 (87.4) | 533 (86.4) |
| ACT total score ≥ 23 | 256 (41.4) | 204 (33.1) |
| Non-responders | 392 (63.3) | 434 (70.3) |
| Non-responder due to missing dataa | 90 (23.0) | 99 (22.8) |
| Adjusted OR (95% CI), P value | 1.49 (1.10, 2.02), P = 0.0100b | |
ACT Asthma Control Test, CFB change from baseline, CI confidence interval, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, ICS inhaled corticosteroid, JGL Japanese Guidelines for Adult Asthma, LABA long-acting β2-agonist, OCS oral corticosteroid, OR odds ratio, PGAM Practical Guidelines for Asthma Management, UMEC umeclidinium, VI vilanterol
aPercentages based on the number of non-responders
bP value was not adjusted for multiplicity and is considered descriptive
Safety Profile
The safety profile for the 52-week treatment period was similar between treatment groups (Table 4). Overall, the proportion of participants with on-treatment AEs related to trial intervention, as assessed by the investigator, was 6.6% (n = 42/632) of participants with FF/UMEC/VI and 2.5% (n = 15/604) with ICS/LABA. The most frequently reported TEAEs by system organ class (SOC) were in the respiratory, thoracic, and mediastinal disorders SOC, reported in 4.4% (n = 28/632) of participants with FF/UMEC/VI and 1.5% (n = 9/604) with ICS/LABA. Within this SOC, dysphonia was the most commonly reported preferred term (FF/UMEC/VI: 3.2% (n = 20/632); ICS/LABA: 0.8% (n = 5/604), with other events occurring in ≤ 0.5% in either group. Serious TEAEs occurred in 3.5% (n = 22/632) of participants with FF/UMEC/VI and 2.6% (n = 16/604) with ICS/LABA.
Table 4.
Treatment-emergent adverse events during the 52-week treatment period (SAF-Modified-1)
| Participantsa | FF/UMEC/VI (N = 632) |
ICS/LABA (N = 604) |
Overall population (N = 1236) |
|---|---|---|---|
| n/632 (%) | n/604 (%) | n/1236 (%) | |
| Any TEAEb | 58 (9.2) | 31 (5.1) | 89 (7.2) |
| Respiratory, thoracic, and mediastinal disorders | 28 (4.4) | 9 (1.5) | 37 (3.0) |
| Infections and infestations | 12 (1.9) | 3 (0.5) | 15 (1.2) |
| Neoplasms benign, malignant, and unspecified (including cysts and polyps) | 7 (1.1) | 4 (0.7) | 11 (0.9) |
| Gastrointestinal disorders | 5 (0.8) | 2 (0.3) | 7 (0.6) |
| General disorders and administration site conditions | 2 (0.3) | 2 (0.3) | 4 (0.3) |
| Hepatobiliary disorders | 2 (0.3) | 0 | 2 (0.2) |
| Musculoskeletal and connective tissue disorders | 2 (0.3) | 0 | 2 (0.2) |
| Nervous system disorders | 2 (0.3) | 2 (0.3) | 4 (0.3) |
| Blood and lymphatic system disorders | 1 (0.2) | 0 | 1 (0.1) |
| Cardiac disorders | 1 (0.2) | 2 (0.3) | 3 (0.2) |
| Injury, poisoning, and procedural complications | 1 (0.2) | 3 (0.5) | 4 (0.3) |
| Investigations—sputum abnormal | 1 (0.2) | 0 | 1 (0.1) |
| Pregnancy, puerperium, and perinatal conditions | 1 (0.2) | 1 (0.2) | 2 (0.2) |
| Psychiatric disorders | 1 (0.2) | 1 (0.2) | 2 (0.2) |
| Skin and subcutaneous tissue disorders | 1 (0.2) | 1 (0.2) | 2 (0.2) |
| Congenital, familial, and genetic disorders | 0 | 1 (0.2) | 1 (0.1) |
| Any trial intervention/treatment-related TEAEc | 42 (6.6) | 15 (2.5) | 57 (4.6) |
| Respiratory, thoracic, and mediastinal disorders | 24 (3.8) | 8 (1.3) | 32 (2.6) |
| Infections and infestations | 9 (1.4) | 1 (0.2) | 10 (0.8) |
| Gastrointestinal disorders | 4 (0.6) | 0 | 4 (0.3) |
| General disorders and administration site conditions | 2 (0.3) | 1 (0.2) | 3 (0.2) |
| Nervous system disorders | 2 (0.3) | 2 (0.3) | 4 (0.3) |
| Injury, poisoning, and procedural complications | 1 (0.2) | 0 | 1 (0.1) |
| Investigations—sputum abnormal | 1 (0.2) | 0 | 1 (0.1) |
| Psychiatric disorders | 1 (0.2) | 0 | 1 (0.1) |
| Skin and subcutaneous tissue disorders | 1 (0.2) | 1 (0.2) | 2 (0.2) |
| Cardiac disorders | 0 | 2 (0.3) | 2 (0.2) |
| Any serious TEAE | 22 (3.5) | 16 (2.6) | 38 (3.1) |
| Neoplasms benign, malignant, and unspecified (including cysts and polyps) | 7 (1.1) | 4 (0.7) | 11 (0.9) |
| Infections and infestations | 4 (0.6) | 2 (0.3) | 6 (0.5) |
| Respiratory, thoracic, and mediastinal disorders | 4 (0.6) | 1 (0.2) | 5 (0.4) |
| Hepatobiliary disorders | 2 (0.3) | 0 | 2 (0.2) |
| Musculoskeletal and connective tissue disorders | 2 (0.3) | 0 | 2 (0.2) |
| Blood and lymphatic system disorders | 1 (0.2) | 0 | 1 (0.1) |
| Cardiac disorders | 1 (0.2) | 0 | 1 (0.1) |
| Gastrointestinal disorders | 1 (0.2) | 2 (0.3) | 3 (0.2) |
| Pregnancy, puerperium, and perinatal conditions | 1 (0.2) | 1 (0.2) | 2 (0.2) |
| Congenital, familial, and genetic disorders | 0 | 1 (0.2) | 1 (0.1) |
| General disorders and administration site conditions | 0 | 1 (0.2) | 1 (0.1) |
| Injury, poisoning, and procedural complications | 0 | 3 (0.5) | 3 (0.2) |
| Psychiatric disorders | 0 | 1 (0.2) | 1 (0.1) |
| Any trial intervention/treatment-related serious TEAE | 1 (0.2) | 0 | 1 (0.1) |
| Infections and infestations | 1 (0.2) | 0 | 1 (0.1) |
| Any CV event | 6 (0.9) | 0 | 6 (0.5) |
| TEAEs leading to trial intervention withdrawal/interruption | 21 (3.3) | 5 (0.8) | 26 (2.1) |
| TEAEs leading to death | 1 (0.2) | 2 (0.3) | 3 (0.2) |
AE adverse event, CV cardiovascular, FF fluticasone furoate, ICS inhaled corticosteroid, LABA long-acting β2-agonist, SAE serious adverse event, TEAE treatment-emergent adverse event, UMEC umeclidinium, VI vilanterol
aAll randomized participants who received ≥ 1 prescription of FF/UMEC/VI or ICS/LABA assessed according to actual trial intervention prescribed (primary safety analysis)
bDefined as any AE (trial intervention/treatment-related AEs and all SAEs) with onset dates on or after the start of the trial intervention and up to 7 days after the last dose of trial intervention
cIncluding trial intervention/treatment-related AEs and trial intervention/treatment-related SAEs
Discussion
The primary endpoint for the PERFORM trial of CFB in trough FEV1 at week 24 was statistically significantly greater with FF/UMEC/VI versus usual care ICS/LABA (least squares mean treatment difference [95% CI] 68 mL [36, 99], P < 0.001) [12]. In addition, the odds of achieving a clinically meaningful improvement in ACQ-7 total score at week 24 were also statistically significantly greater with FF/UMEC/VI versus usual care ICS/LABA (adjusted OR [95% CI] 1.47 [1.13, 1.92], P = 0.004) [12].
These 52-week results from the PERFORM trial represent the first prospective randomized evidence assessing clinical remission (optimized) with inhaled triple therapy in asthma, with statistically significantly greater odds of achieving this endpoint with FF/UMEC/VI versus usual care ICS/LABA (adjusted OR [95% CI] 2.13 [1.54, 2.94], P < 0.0001). The proportion of participants achieving clinical remission was 29.7% (n = 184/619) with FF/UMEC/VI versus 17.0% (n = 105/617) with usual care ICS/LABA.
A recently published single-arm observational registry also reported the achievability of clinical remission with another SITT and a four-component composite endpoint defined as no SCS use, no exacerbations, ACT score ≥ 20, and stable lung function (improvement in FEV1 or decline ≤ 5% of predicted value compared with baseline) at 12 months post initiation of SITT [19]. In the PERFORM trial, 41.4% of participants with FF/UMEC/VI achieved clinical remission with a similar definition incorporating stabilized lung function (CFB in trough FEV1 ≥ 0 mL) and comparable asthma symptom threshold. Results presented here also build on other previous evidence of the achievability of clinical remission in asthma with inhaled therapies [20–23]. Thus, clinical remission is an achievable goal with SITT therapy and evidence from a real-world setting is consistent with post hoc analyses of clinical trials.
There is a paradigm shift in the approach to asthma management towards earlier treatment intervention to prevent airway remodeling, reduce steroid burden, and improve quality of life [24, 25]. As part of this shift, clinical remission is an emerging ambitious treatment goal for routine clinical practice that is endorsed by the Global Initiative for Asthma as a means of achieving best possible long-term outcomes for each patient, irrespective of their asthma severity [1, 17]. Treating to a target of clinical remission requires a focus on proactive disease management with the ultimate goal of reversing airway remodeling. Previously published data from the ETHA mechanistic study demonstrated anatomical and biological features consistent with the reversal of airway remodeling in participants with moderate–severe asthma who achieved clinical response on treatment with FF/UMEC/VI [26]. Whether these mechanistic improvements in airway markers are achieved in participants treated with FF/UMEC/VI achieving clinical remission remains to be seen.
The safety profile of FF/UMEC/VI was consistent with previous reports [6, 27–29], with no new safety signals identified over 52 weeks. Rates of TEAEs were low, with slightly higher rates reported from participants receiving FF/UMEC/VI (6.6%) versus those receiving ICS/LABA (2.5%).
The relevance of the PERFORM trial data is particularly supported by its closer reflection of real-world clinical practice and enrollment of a broader population of patients than explanatory RCTs. In addition, the findings from the PERFORM trial also include data from participants who were previously untreated with ICS-containing maintenance therapy in the prior 3 months, demonstrating applicability beyond treatment-experienced patients.
PERFORM is the first pragmatic RCT evaluating a SITT in asthma, as well as the first prospective, randomized assessment of clinical remission with FF/UMEC/VI. A key strength of the PERFORM trial was its pragmatic design, which meant that recruitment and trial delivery was not restricted by the rigid controls of explanatory RCTs. As such, the open-label prescribing and minimal trial intervention, such as lack of adherence reminders and minimal clinic visits, closely reflects a real-world clinical practice setting. However, these elements also warrant consideration for limitations. Open-label comparator arms were employed across different countries and approval labels, and consequently the pharmacologic effect of add-on long-acting muscarinic antagonists cannot be distinguished from device/dosing heterogeneity. However, this approach mirrors real-world clinical decision-making, where physicians evaluate the combined effect of therapeutic agent, device, and dosing strategy on real-world effectiveness. Also, as reversibility is often omitted in clinical practice settings—particularly those where routine spirometry is unavailable—reversibility was not required as an asthma diagnosis criterion. Any potential bias arising from the inclusion of participants without reversibility can be assumed to be equal across treatment arms due to participant randomization. Finally, as only outcomes included in the statistical testing hierarchy were adjusted for multiplicity, type I errors are possible for other outcomes reported.
Conclusion
The 52-week pragmatic randomized PERFORM trial demonstrates statistically greater odds of achieving clinical remission with FF/UMEC/VI compared with usual care ICS/LABA in participants with uncontrolled, infrequently exacerbating asthma, including participants naïve to maintenance therapy or stepping up from ICS containing mono/dual therapy. These findings show that clinical remission is an ambitious treatment goal and it is achievable in routine clinical practice. In conjunction with significantly improved lung function and asthma control at week 24 [12], these results provide evidence informing the use of FF/UMEC/VI SITT in an underserved group of symptomatic patients with infrequent exacerbations and minimal lung function impairment.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the participating patients and physicians of the PERFORM trial. We thank Lydia Demetriou for her early and impactful contribution to study operations.
Medical Writing/Editorial Assistance
Editorial support (in the form of writing assistance, including preparation of the draft manuscript under the direction and guidance of the authors, collating, and incorporating authors’ comments for each draft, assembling tables and figures, grammatical editing, and referencing) was provided by Shelley Morris, MSc, MPhil, Catherine Widnall, PhD, and Jonnie Plumb, PhD, of Fishawack Indicia Ltd, UK, part of Avalere Health, and was funded by GSK.
Author Contributions
Stephen G Noorduyn, John J Oppenheimer, Alison C Moore, Hiroyuki Nagase, Jodie Crawford, Amila Poddar, Victoria Boon, Nicola Brown, David Slade, Gabriel Garcia, Alan P Baptist, and Erika Penz made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work, in line with ICMJE guidelines.
Funding
This trial was funded by GSK (219912/NCT06372496). The trial sponsor oversaw the design and conduct of the trial, was involved in the acquisition and analysis of data, and reviewed the manuscript. The journal’s Rapid Service Fee was funded by GSK. The Open Access fee was also funded by GSK.
Data Availability
Anonymized subject-level data and trial documents will be made available to researchers for a maximum of 18 months following trial completion, following approval of proposed use. Please refer to GSK weblink to access GSK’s data sharing policies and as applicable seek anonymized subject level data via the link https://www.gsk-studyregister.com/en/.
Declarations
Conflict of Interest
Stephen G Noorduyn, Alison C Moore, Jodie Crawford, Amila Poddar, Nicola Brown, and David Slade are employed by GSK and hold financial equities in GSK. Stephen G Noorduyn is a PhD candidate at McMaster University, Hamilton, ON, Canada. John J Oppenheimer has served on adjudication committees or data and safety monitoring boards for AstraZeneca, GSK, Novartis, and Sanofi-Regeneron; received consultancy fees from AstraZeneca, Amgen, Regeneron, ARS, Aquestive, GSK, and Sanofi; and received grants and personal fees from GSK. Hiroyuki Nagase has received speaker and consultation fees from AstraZeneca and GSK, and speaker fees from Kyorin Pharmaceutical, and Sanofi. Victoria Boon is an employee of GSK. Gabriel Garcia has participated in advisory boards for GSK, AstraZeneca, Sanofi, Novartis, and Boehringer Ingelheim; he has received honoraria for speaking at sponsored meetings from GSK, Boehringer Ingelheim, AstraZeneca, Sanofi, Phoenix, and Novartis; and is a principal investigator in trials sponsored by GSK, Boehringer Ingelheim, AstraZeneca, Novartis, Sanofi, PPD, Zambon, Parexel, Covance, IQVIA, and Chiesi. Alan P Baptist reports grant support from GSK, AstraZeneca, Genentech, and Teva. Erika Penz has grant funding from the Canadian Institute Health Research, Lung Saskatchewan, Saskatchewan Health Research Foundation, AstraZeneca, GSK, and Sanofi; has served as a consultant for AstraZeneca, GSK, Roche, Sanofi, and Saskatchewan Cancer Agency; has received speaker honoraria from AstraZeneca, Boehringer Ingelheim, Canadian Thoracic Society, Covis Pharma, GSK, Lung Saskatchewan, Sanofi-Genzyme, and Valeo Pharma; serves as the Past-President of the Canadian Thoracic Society and is a board member of the Canadian Institutes of Health Research- Institute for Cancer Research; has served as co-chair of the COPD Assembly for the Canadian Thoracic Society; and her institution has previously received equipment from AstraZeneca. She is Associate Editor of the COPD section of the CHEST Journal and has received honoraria and travel expenses from CHEST journal.
Ethical Approval
PERFORM was sponsored by GSK (219912/NCT06372496) and conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice, as well as applicable local regulations. Trial documents and protocol amendments received approval by relevant local institutional review boards and/or independent ethics committees. All participants provided physically or digitally signed, informed consent.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Anonymized subject-level data and trial documents will be made available to researchers for a maximum of 18 months following trial completion, following approval of proposed use. Please refer to GSK weblink to access GSK’s data sharing policies and as applicable seek anonymized subject level data via the link https://www.gsk-studyregister.com/en/.