Iñigo Ojanguren 1,2,3, María Florencia Pilia1 iojanguren@vhebron.net @InigoOjanguren linkedin.com/in/iñigo-ojanguren-arranz-814863a1 Journal club Efficacy and safety of once-daily single-inhaler triple therapy in patients with inadequately controlled asthma: the CAPTAIN trial muscarinic antagonist (LAMA), which acts by blocking Cite as: Ojanguren I, Commentary on: Pilia MF. Efficacy and safety the bronchoconstriction effect of acetylcholine on Lee et al. Efficacy and safety of once-daily of once-daily single-inhaler M3 muscarinic receptors expressed in ASM, to the single-inhaler triple therapy (FF/UMEC/VI) triple therapy in patients ICS/LABA combination has been shown to improve versus FF/VI in patients with inadequately with inadequately controlled lung function and increase the time to first severe asthma: the CAPTAIN trial. controlled asthma (CAPTAIN): a double-blind, exacerbation in adult asthmatics [1]. Breathe 2021; 17: 200279. randomized, phase 3A trial. Lancet Respir Med Despite these advantages, adding the LAMA 2021; 9: 69–84. implies that patients must use two different inhalers with different dose regimens. This is an inconvenience which is not without relevance Context since it has an impact on treatment adherence and hampers the instructions of caregivers. In parallel, Inhaled corticosteroids (ICS) remain the cornerstone there is no study on whether the impact of increasing of treatment in asthmatic patients. In fact, many the ICS dose or adding LAMA varies depending on patients suffering from asthma are able to airway inflammatory status (type 2 or not type 2). achieve good symptom control and avoid asthma Thus, the objectives of the CAPTAIN study were: exacerbations with a combination of moderate dose 1) to analyse the safety and efficacy of single-inhaler ICS and a long-acting β2-agonist (LABA). However, fluticasone furoate (FF) plus umeclidinium (UMEC) a significant number of patients require stepping plus vilanterol (VI) comparted with FF/VI; and 2) to up from moderate dose ICS/LABA to achieve analyse the effects of increasing FF or adding UMEC good asthma control. While LABA are effective on lung function and exacerbations depending on bronchodilators primarily due to their ability to relax the baseline inflammatory status. airway smooth muscle (ASM) by exerting their effects via binding to the active site of β2-airway receptors, the mechanism of action of ICS in asthma is not well Methods known, although they have shown to have a wide range of inhibitory effects on multiple cell types and The CAPTAIN trial was a randomised, double-blind, mediators involved in inflammation and asthmatic 24–52 week, active controlled, parallel group, response. The addition of tiotropium, a long-acting phase 3A study, conducted across 15 countries, @ERSpublications Triple therapy with FF/UMEC/VI improved lung function in patients with moderate or severe uncontrolled asthma on ICS/LABA but did not lead to a reduction in moderate and/or severe exacerbations https://bit.ly/38UnuRW https://doi.org/10.1183/20734735.0279-2020Breathe | 2021 | Volume 17 | No 1 1 Commentary on the CAPTAIN trial encompassing 416 hospitals. Adults (aged UMEC 62.5 μg/VI versus FF/VI (pooled analysis), with ≥18 years) with inadequately controlled asthma rates being lower in the FF 200 μg versus FF 100 μg symptoms (Asthma Control Questionnaire ≥1.5) containing treatment groups (table 2). A higher despite maintenance therapy with daily ICS/LABA dose of FF had an impact on FEV1 and annualised for at least 12 consecutive weeks before pre- the moderate and/or severe exacerbations rate in screening were included. Patients were required patients with a higher baseline blood eosinophil to have a best pre-bronchodilator forced expiratory count and exhaled nitric oxide fraction (FeNO). The volume in 1 s (FEV1) between 30% and 85% of number of adverse events (ranging from 52% predicted normal value and airway reversibility to 63% depending on the treatment group) and (defined as an increase in FEV1 ≥12% and ≥200mL severe adverse events (ranging from <1% to 1% 20–60 min after four inhalations of albuterol or depending on the treatment group) was similar salbutamol) at screening. Patients were randomly across treatment groups with nasopharyngitis, assigned (1:1:1:1:1:1) to one of six treatment headache and upper respiratory tract infection being groups: FF/VI 100/25 μg or 200/25 μg; or FF/ the most commonly reported adverse events. One UMEC/VI 100/31.25/25 μg, 100/62.5/25 μg, death was considered to be related to the study 200/31.25/25 μg or 200/62.5/25 μg. The primary drug (pulmonary embolism) in a patient in the FF/ efficacy end-point was change from baseline FEV1 UMEC/VI 100/31.25/25 μg group. at week 24. The key secondary end-point was the annualised rate of moderate and/or severe asthma exacerbations (up to week 52). Commentary The CAPTAIN trial demonstrated that triple therapy Main results with FF/UMEC/VI improves lung function in patients with moderate or severe uncontrolled asthma on Out of 5185 patients screened, 2439 were ICS/LABA. Compared to FF/VI, FF/UMEC/VI also recruited and randomly assigned to FF/VI improved symptoms and asthma control in a (100/25 μg: n=407; 200/25 μg: n=406) dose-related manner. FF/UMEC/VI did not lead to or FF/UMEC/VI (100/31.25/25 μg: n=405; a significant reduction in moderate and/or severe 100/62.5/25 μg: n=406; 200/31.25/25 μg: exacerbations when added to FF/VI 200/24 μg. n=404; 200/62.5/25 μg: n=408). Baseline High doses of FF were related to fewer exacerbations demographics were similar across all the in patients with a higher baseline blood eosinophil treatment groups. The least squares mean (95% count and FeNO, but this was not observed with the CI) improvement in FEV1 change from baseline addition of UMEC. for FF/UMEC/VI 100/62.5/25 μg versus FF/VI This study provides valuable information to the 100/25 μg was 110mL (66–153 mL; p<0.0001), growing evidence that highlights the benefits of and for 200/62.5/25 μg versus 200/25 μg it was adding a LAMA to asthmatics that are not well- 92mL (49–135; p<0.0001). Adding UMEC 31.25 μg controlled on medium or high doses of ICS plus a to FF/VI produced similar improvements (FF/UMEC/ LABA (table 3). In fact, in line with previous studies VI 100/31.25/25 μg versus FF/VI 100/25 μg: 96mL [1, 2] analysing the benefits of triple therapy in (52–139 mL; p<0.0001); and 200/31.25/25 μg terms of lung function, symptoms and asthma versus 200/25 μg: 82mL (39–125 mL; p: 0.0002)) control, adding UMEC to FF/VI showed a clinically (table 1). No significant reductions in moderate and/ relevant and statistically significant improvement or severe exacerbation rates were observed for FF/ in these outcomes. Table 1 Unpooled analysis of least squares mean change in FEV1 from baseline to week 24 FF/VI 100/25 µg plus FF/VI 200/25 µg plus No UMEC UMEC UMEC No UMEC UMEC UMEC 31.25 µg 62.5 µg 31.25 µg 62.5 µg Subjects n 379 381 390 385 384 391 Changes from baseline 24 (−6–55) 120 (89–151) 134 (104–165) 76 (45–106) 157 (127–188) 168 (137–198) in trough FEV1 mL at week 24 Changes in FEV1 mL Ref. +96 (52–139) +110 (66–153) Ref. +82 (39–125) +92 (49–135) by adding UMEC at p<0.0001 p<0.0001 p<0.0002 p<0.0001 week 24 Data are presented as least squares mean (95% CI), unless otherwise stated. The p-values are not adjusted for multiplicity. 2 Breathe | 2021 | Volume 17 | No 1 Commentary on the CAPTAIN trial  Table 2 Analysis of mean annualised rate of moderate and/or severe exacerbations in the unpooled intention-to-treat population at weeks 1 to 52 FF/VI 100/25 µg plus FF/VI 200/25 µg plus No UMEC UMEC UMEC No UMEC UMEC UMEC 31.25 µg 62.5 µg 31.25 µg 62.5 µg Subjects n 407 405 406 406 404 408 Mean annualised 0.87 0.76 0.68 0.57 0.61 0.55 moderate and/or severe (0.73–1.04) (0.64–0.92) (0.56–0.82) (0.47–0.69) (0.50–0.74) (0.45–0.67) exacerbations rate FF/UMEC/VI versus FF/VI Ref. 1.01 1.07 Ref. 0.98 0.88 (0.72–1.42), (0.76–1.50), (0.66–1.45), (0.60–1.31), p=0.96 p=0.69 p=0.93 p=0.54 Data are presented as rate ratio (95% CI), unless otherwise stated. The p-values are not adjusted for multiplicity. A relevant strength of the CAPTAIN study consists in be related to the fact that during the run-in and analysing the influence of baseline type 2 biomarkers stabilisation periods most patients received a lower on response to FF/UMEC/VI. The effect of increasing ICS dose compared to their usual baseline dose. In the FF dose on trough FEV1 values and the rate this context, some patients requiring a higher ICS of moderate and/or severe exacerbations were dose may have experienced exacerbations leading increased with the increasing blood eosinophil count to study withdrawal. As a result, the efficacy of and FeNO. In this context, the proportion of patients higher dose ICS may have been underestimated in on FF 100 μg who had a severe exacerbation was the trial. Finally, it should be noted that no details nearly three-fold higher in patients with baseline were given regarding the proportion of participants blood eosinophils of at least 300 cells·μL−1 and receiving acceptable concomitant medications FeNO >50 ppb compared to patients with baseline such as systemic steroids up to 5 mg·day−1, anti- blood eosinophils <150 cells·μL−1 and FeNO <20 ppb. immunoglobulin E or anti-interleukin 5, and their This type of analysis makes it possible to take a step potential impact on the results. forward towards the implementation of treatable traits in current practice. Other positive aspects related to the CAPTAIN study consist of the 5-week Implications for practice pre-randomisation period during which standardised medication was provided, and both comparators (FF/ Similar to previous triple therapy trials, the CAPTAIN VI and FF/UMEC/VI) were administered with the study certifies that in general terms when asthma same dry powder inhaler. is not well-controlled with ICS/LABA, the ICS/ However, there is an important difference LAMA/LABA combination is able to improve FEV1 between the present study and its predecessors values. It also highlights the differential properties in terms of asthma exacerbations [1–3]. While the of each component of the triple combination. While TRIGGER and TRIMARAN tiotropium studies showed adding LAMA translates into an improvement in reductions in severe exacerbations with the addition FEV1 values, increasing the ICS dose impacts the of LAMA, these effects were not observed with the number of severe exacerbations. These findings addition of UMEC to FF/VI. While adding UMEC favour the treatable treats approach that allows an to FF/VI 100/25 μg reduced moderate/severe individualised treatment strategy depending on the exacerbations, no additional reduction was seen desired outcomes. when added to FF/VI 200/24 μg. It should be kept The CAPTAIN study also highlights the relevance in mind that the disparity in terms of the definitions of biomarker-based outcomes, since increasing the of moderate exacerbations and the differences in ICS dose could specially benefit asthmatics with study populations between studies could justify high type 2 airway inflammation, while UMEC could such discrepancies. In fact, the main limitation of have an important role particularly in patients with the study is related to the low rate of exacerbations low type 2 inflammation. observed with respect to the lower risk population Last but not least, the possibility of offering the than was assumed in the calculations. This combination of ICS/LAMA/LABA in a single inhaler limitation could have had a relevant impact on could improve the low treatment adherence rates the results observed and could, at least partially, observed in asthmatics and could also ameliorate explain the lack of efficacy of UMEC in reducing the inhaler instruction efforts of the caregivers. severe asthma exacerbations when added to high In conclusion, this study could lead to a step- dose FF and VI. Another potential limitation could change in the asthma therapy paradigm in patients Breathe | 2021 | Volume 17 | No 1 3 4 Commentary on the CAPTAIN trial Table 3 Summary of the randomised controlled trials (RCTs) analysing triple therapy with LAMA, LABA and ICS in a single inhaler in asthma Breathe | 2021 | Volume 17 | No 1 First author Study design Primary Secondary outcome Results Limitations Adverse events Comments [ref.] outcome Kerstjens [1] Two replicates, Change from Peak and trough FEV1 Addition of tiotropium Inconsistency in the Most events were mild RCTs baseline FEV1 at and FVC at each significantly results between two Dry mouth (<2% week 24 treatment visit increased the time trials all patients, but Time to first Time to the first to the first severe was reported more severe asthma asthma exacerbation exacerbation frequently in the exacerbation and provided tiotropium group than modest sustained in the placebo group) bronchodilation Virchow [2] Two parallel- Change from Change from baseline in Addition of a LAMA Much lower Similar across group, pre-dose FEV1 peak FEV1 at week 26 (glycopyrronium) rate of severe treatment groups double-blind, at week 26 Average morning PEF improves lung exacerbations Most events were mild randomised, Annualised rate over the first 26 weeks function and reduces observed during active-controlled, of moderate/ in each study exacerbations the studies phase 3 trials severe Rate of severe than reported in (TRIMARAN and exacerbations exacerbations historical data TRIGGER) over 52 weeks Lee [3] Double-blind, Change from the Annualised rate of Adding UMEC Low rate of Similar across Post-hoc and randomised, baseline FEV1 at moderate and/ improved lung exacerbations treatment groups (dry prespecified parallel-group, week 24 or severe asthma function but did not compared to other mouth/drying of the subgroup phase 3A study exacerbations lead to a significant studies airway secretions) analyses by (CAPTAIN) Change from baseline reduction in Most patients Most events were mild biomarkers in SGRQ moderate and/or received a lower ICS of type 2 Change from baseline severe exacerbations dose compared to inflammation in ACQ-7 total score their usual baseline dose during run-in/ stabilisation period FVC: forced vital capacity; PEF: peak expiratory flow; SGRQ: St George’s Respiratory Questionnaire; ACQ: Asthma Control Questionnaire. Commentary on the CAPTAIN trial  on LABA/ICS based on the different properties of discrepancy of recent trials on whether the addition LABA, LAMA and ICS. While higher doses of ICS of LAMA to LAMA/ICS reduces exacerbations in this should be considered for exacerbating patients, subgroup of patients, further studies are needed to LAMA should be added for those experiencing clarify these uncertainties. asthma symptoms. Nonetheless, given the Affiliations Iñigo Ojanguren1,2,3, María Florencia Pilia1 1Serveide Pneumología, Hospital Universitari Vall d´Hebron, Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 2Institut de Recerca (VHIR), Barcelona, Spain. 3CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain. Acknowledgements I. Ojanguren is a researcher supported by the Pla Estratègic de Recerca i Innovació en salut (PERIS) 2016–2020 (SLT008/18/00108; G60594009). Conflict of interest I. Ojanguren reports personal fees from AstraZeneca, BIAL, Boehringer Ingelheim, MSD, Chiesi, GSK, Novartis and TEVA, grants from Menarini, grants and personal fees from Mundipharma, outside the submitted work. M.F. Pilia has nothing to disclose. References 1. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma 3. Lee LA, Bailes Z, Barnes N, et al. Efficacy and safety of once- poorly controlled with standard combination therapy. N Engl daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI J Med 2012; 367: 1198–1207. in patients with inadequately controlled asthma (CAPTAIN): 2. Virchow JC, Kuna P, Paggiaro P, et al. Single inhaler extrafine a double-blind, randomized, phase 3A trial. Lancet Respir Med triple therapy in uncontrolled asthma (TRIMARAN and 2021; 9: 69–84. TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Lancet 2019; 394: 1737–1749. Breathe | 2021 | Volume 17 | No 1 5