Associations between the EQ-5D-5L and exacerbations of chronic obstructive pulmonary disease in the ETHOS trial.

PURPOSE: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with deteriorating health and health-related quality of life (HRQoL) among people with COPD during and after events. HRQoL data are key to evaluating treatment cost-effectiveness and informing reimbursement decisions in COPD. EuroQoL 5-dimension 5-level (EQ-5D-5L) utility scores, based on various HRQoL measures, are used in economic evaluations of pharmacotherapy. These analyses estimated associations between EQ-5D-5L utility scores and exacerbations (new and previous) in patients with moderate-to-very severe COPD. METHODS: Longitudinal mixed models for repeated measures (MMRM), adjusted for time and treatment, were conducted using data from the ETHOS study (NCT02465567); models regressed EQ-5D-5L on current and past exacerbations that occurred during the study, adjusting for other patient reported outcomes and clinical factors. RESULTS: Based on the simplest covariate adjusted model (adjusted for current exacerbations and number of previous exacerbations during the study), a current moderate exacerbation was associated with an EQ-5D-5L disutility of 0.055 (95% confidence interval: 0.048, 0.062) with an additional disutility of 0.035 (0.014, 0.055) if the exacerbation was severe. After resolving, each prior exacerbation was associated with a disutility that persisted for the remainder of the study (moderate exacerbation, 0.014 [0.011, 0.016]; further disutility for severe exacerbation, 0.011 [0.003, 0.018]). CONCLUSION: An EQ-5D-5L disutility of 0.090 was associated with a current severe exacerbation in ETHOS. Our findings suggest incorporating the effects of current, recently resolved, and cumulative exacerbations into economic models when estimating benefits and costs of COPD pharmacotherapy, as exacerbations have both acute and persistent effects.

Relationship between risk, cumulative burden of exacerbations and mortality in patients with COPD: modelling analysis using data from the ETHOS study.

BACKGROUND: The major drivers of cost-effectiveness for chronic obstructive pulmonary disease (COPD) therapies are the occurrence of exacerbations and deaths. Exacerbations, including acute and long-term events, can cause worsening of COPD and lead to an increased risk of further exacerbations, and ultimately may elevate the risk of death. In contrast to this, health economic models are based on COPD severity progression. In this post hoc analysis of the ETHOS study, we focus on the progression of COPD due to exacerbations and deaths. METHODS: We fitted semi-parametric and fully parametric multi-state Markov models with the following five progressive states: State 1, no exacerbation; State 2, 1 moderate exacerbation; State 3, ≥ 2 moderate exacerbations; State 4, ≥ 1 severe exacerbations; State 5, death. The models only allowed a patient to transition to a worsened health state, and transitions did not necessarily have to be to the next adjacent state. We used the multi-state models to analyse data from ETHOS, a phase III, 52-week study assessing the efficacy and safety of triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate in moderate-to-very severe COPD. RESULTS: The Weibull multi-state Markov model showed good fit of the data. In line with clinical evidence, we found a higher mortality risk after a severe exacerbation (11.4-fold relative ratio increase [95% CI, 7.7-17.0], 6.4-fold increase [95% CI, 3.8-10.8] and 5.4-fold increase [95% CI, 2.9-10.3] relative to no exacerbations, 1 moderate exacerbation or ≥ 2 moderate exacerbations, respectively). One moderate exacerbation increased mortality risk 1.8-fold (95% CI, 1.1-2.9) vs no exacerbations. We also found a higher risk of severe exacerbation and mortality following ≥ 2 moderate exacerbations. CONCLUSION: Multi-state modelling of patients with COPD in ETHOS found an acute and chronic effect of severe exacerbations on mortality risk. Risk was also increased after a moderate exacerbation. Clinical management with effective pharmacotherapies should be optimised to avoid even moderate exacerbations. Modelling with exacerbations could be an alternative to current COPD models focused on disease progression. TRIAL REGISTRATION: NCT02465567.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 µg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. METHODS: This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 µg per actuation) radiolabeled with technetium­99­pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. RESULTS: The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). CONCLUSIONS: Radiolabeled BGF 320/18/9.6 µg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids.

BACKGROUND: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3. METHODS: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 µg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 µg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. RESULTS: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. CONCLUSIONS: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD. TRIAL REGISTRATION:  ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.

Glycopyrrolate/formoterol fumarate metered dose inhaler for maintenance-naïve patients with chronic obstructive pulmonary disease: a post-hoc analysis of the randomized PINNACLE trials.

BACKGROUND: Glycopyrrolate (GP)/formoterol fumarate (FF; GFF) metered dose inhaler is a fixed-dose combination dual bronchodilator for patients with chronic obstructive pulmonary disease (COPD); however, whether the efficacy in patients without current maintenance treatment is consistent with currently maintenance-treated patients is unclear. METHODS: Data from patients who were not maintenance-treated at screening (NMT) (n = 1943) and patients who were maintenance-treated at screening (MT) patients (n = 3040) receiving GFF, FF, GP, or placebo were pooled from the Phase III PINNACLE studies (NCT01854645, NCT01854658, NCT02343458) for post-hoc analysis. MT patients had received long-acting bronchodilators and/or inhaled corticosteroids in the 30 days prior to screening, and/or prior to randomization. NMT patients had received short-acting bronchodilators or no treatment. Outcomes included forced expiratory volume over 1 s (FEV1), clinically important deterioration (CID), rescue medication use, and safety. RESULTS: GFF provided significant lung function improvements at Week 24 versus placebo, GP, and FF for NMT patients, with pre-dose trough FEV1 treatment differences of 152 (117-188) mL, 73 (45-100) mL, and 56 (29-84) mL, respectively (least squares mean change from baseline versus comparators [95% CI]; all P < 0.0001). GFF reduced the risk of CID by 17-43% in NMT (P ≤ 0.0157) and 18-52% (P ≤ 0.0012) in MT patients compared with monotherapy and placebo, and reduced rescue medication use by 1.5 puffs/day over 24 weeks for both cohorts. Safety profiles for all cohorts were consistent with each other and the parent studies. CONCLUSIONS: NMT patients achieved better lung function with GFF versus monotherapy and placebo, without increased safety risk. Dual bronchodilator therapy may offer better outcomes than monotherapy for COPD patients when administered as first-line treatment.

Benefits of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in improving lung function and reducing exacerbations in patients with moderate-to-very severe COPD: a pooled analysis of the PINNACLE studies.

BACKGROUND: The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4. METHODS: PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed. RESULTS: The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV1 versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59 mL [43, 75]), FF MDI (65 mL [48, 81]), and placebo MDI (146 mL [125, 166]); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals. CONCLUSIONS: This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history. TRIAL REGISTRATION: ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458).

Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

OBJECTIVES: To determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant K trans , in a multicentre trial setting. METHODS: DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated. RESULTS: At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. K trans intra-subject coefficient of variation (N = 14) was 30%. K trans change demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks. CONCLUSION: This demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials. KEY POINTS: • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre.

Improving the power of clinical trials of rheumatoid arthritis by using data on continuous scales when analysing response rates: an application of the augmented binary method.

OBJECTIVE: In clinical trials of RA, it is common to assess effectiveness using end points based upon dichotomized continuous measures of disease activity, which classify patients as responders or non-responders. Although dichotomization generally loses statistical power, there are good clinical reasons to use these end points; for example, to allow for patients receiving rescue therapy to be assigned as non-responders. We adopt a statistical technique called the augmented binary method to make better use of the information provided by these continuous measures and account for how close patients were to being responders. METHODS: We adapted the augmented binary method for use in RA clinical trials. We used a previously published randomized controlled trial (Oral SyK Inhibition in Rheumatoid Arthritis-1) to assess its performance in comparison to a standard method treating patients purely as responders or non-responders. The power and error rate were investigated by sampling from this study. RESULTS: The augmented binary method reached similar conclusions to standard analysis methods but was able to estimate the difference in response rates to a higher degree of precision. Results suggested that CI widths for ACR responder end points could be reduced by at least 15%, which could equate to reducing the sample size of a study by 29% to achieve the same statistical power. For other end points, the gain was even higher. Type I error rates were not inflated. CONCLUSION: The augmented binary method shows considerable promise for RA trials, making more efficient use of patient data whilst still reporting outcomes in terms of recognized response end points.

Linear extrapolation of missing radiographic change scores in clinical trials does not spuriously overestimate group radiographic changes in rheumatoid arthritis.

OBJECTIVE: To assess linear extrapolation (LE) and last observation carried forward (LOCF) as imputation methods for radiographic change in patients with RA. METHODS: The OSKIRA-1 trial enrolled 918 patients with active RA for studying the efficacy of fostamatinib. Radiographs were scheduled for all patients at baseline and week 12, regardless of early escape, and at weeks 24 and 52 for patients who remained in the study. Complete radiographic data for the 24-week follow-up were available for 623 patients and were assessed according to the Sharp/van der Heijde score. From this complete set of data, a random selection of 10% missingness was generated. This was done 1000 times, and for each replicate the missing radiographic change at week 24 was imputed, first by LE, then by LOCF. The mean of the mean and mean of the s.d. across the 1000 replications was calculated. A similar approach was iterated for different proportions of missingness. RESULTS: The mean (s.d.) observed Sharp/van der Heijde score change from baseline to week 24 was 0.36 (2.39). With LE, the mean (s.d.) change was estimated as 0.36 (2.65), 0.35 (2.88), 0.35 (3.17), 0.34 (3.57) and 0.32 (4.45) with 10/20/30/50/90% missingness, respectively. With LOCF, the mean (s.d.) change was estimated as 0.34 (2.39), 0.32 (2.38), 0.30 (2.37), 0.26 (2.36) and 0.18 (2.34) with 10/20/30/50/90% missingness, respectively. CONCLUSION: LE led to stable estimates of progression at the group level, but increasing variability with increasing proportions of missingness. In contrast, LOCF imputation systemically underestimated mean progression with increasing proportions of missingness, with artificially reduced variability estimates.

Guidelines and considerations for conducting experiments using tissue microarrays.

Tissue microarrays (TMAs) represent a powerful method for undertaking large-scale tissue-based biomarker studies. While TMAs offer several advantages, there are a number of issues specific to their use which need to be considered when employing this method. Given the investment in TMA-based research, guidance on design and execution of experiments will be of benefit and should help researchers new to TMA-based studies to avoid known pitfalls. Furthermore, a consensus on quality standards for TMA-based experiments should improve the robustness and reproducibility of studies, thereby increasing the likelihood of identifying clinically useful biomarkers. In order to address these issues, the National Cancer Research Institute Biomarker and Imaging Clinical Studies Group organized a 1-day TMA workshop held in Nottingham in May 2012. The document herein summarizes the conclusions from the workshop. It includes guidance and considerations on all aspects of TMA-based research, including the pre-analytical stages of experimental design, the analytical stages of data acquisition, and the postanalytical stages of data analysis. A checklist is presented which can be used both for planning a TMA experiment and interpreting the results of such an experiment. For studies of cancer biomarkers, this checklist could be used as a supplement to the REMARK guidelines.

Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers.

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. OBJECTIVES: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. METHODS: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. MEASUREMENTS AND MAIN RESULTS: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed "pauciinflammatory." Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1ß, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83­0.95); serum CXCL10, 0.83 (95% CI, 0.70­0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78­0.93), respectively. CONCLUSIONS: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1ß, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.

Defining 'research inspired teaching' and introducing a research inspired online/offline teaching (riot) framework for fostering it using a co-creation approach.

BACKGROUND: There are calls to ensure that evidence-based practice is enabled for every midwife and nurse by means of education, research, leadership and access to evidence. Concurrently, there is a global call for universities to foster 'Research Inspired Teaching'. Yet such teaching must first be defined and may usefully be developed, delivered, and evaluated as part of a framework approach. OBJECTIVE: To co-create a uniform definition of 'Research Inspired Teaching' and a framework for developing, delivering, and evaluating it. DESIGN: A co-creation approach was taken, underpinned by the interpretive framework of communal constructivism. SETTING: United Kingdom. PARTICIPANTS: The sampling strategy was purposive, whereby those who had reportedly actively engaged in 'Research Inspired Teaching' were invited to participate. The resulting multidisciplinary team of co-creators (n = 14) included students, educators, and self-identified facilitators of 'Research Inspired Teaching'. METHODS: The co-creation of outputs was facilitated by two online co-creation workshops. All creative, written, and verbal contributions made by co-creators were collected as data and used to 'co-define', 'co-design' and 'co-refine' outputs. To enhance credibility, triangulation was used throughout. A final review of results presented in this article via all co-creators concluded this process. RESULTS: This article presents a definition of teaching, a definition of research, a founding definition of Research Inspired Teaching and a guiding framework along with 10 core principles for developing, delivering, and evaluating it. CONCLUSIONS: These outputs may be useful for both midwifery and nursing faculties, providing common language for collaboration and inspiring further developments and research. In pursuit of excellence, further international research could usefully investigate how these outputs may further bridge the Research-Teaching Nexus in Higher Education, and partner with other universities looking to cultivate, evidence and promote their own 'Research Inspired Teaching' in practice. In this pursuit, inter-university partnerships would be welcomed.

Effect of inhaled budesonide/formoterol fumarate dihydrate delivered via two different devices on lung function in patients with COPD and low peak inspiratory flow.

BACKGROUND AND AIMS: Low peak inspiratory flow (PIF) is common following severe exacerbations of chronic obstructive pulmonary disease (COPD). Patients with COPD and low PIF may be at risk of suboptimal delivery of inhaled therapies to the airways, especially when using devices such as dry powder inhalers (DPIs), which require greater inspiratory effort than metered dose inhalers (MDIs). We report the results from a 2-week crossover study evaluating the effects of inhaled dual therapy with budesonide/formoterol fumarate dihydrate with an MDI with a spacer versus a DPI in patients with COPD and low PIF. METHODS: This randomized, open-label, two-period (each 1 week in duration) crossover efficacy and safety study included patients with severe-to-very severe COPD and PIF < 50 L/min (NCT04078126). Patients were randomized 1:1 to twice-daily budesonide/formoterol fumarate dihydrate MDI (BFF MDI) 320/10 µg with a spacer for 1 week followed by twice-daily budesonide/formoterol fumarate dihydrate DPI (BUD/FORM DPI) 320/9 µg for 1 week, or the inverse. The primary endpoint was peak change from baseline in forced expiratory volume in 1 s (FEV1) within 4 h post-dose following 1 week of treatment. Other assessments included pre-dose lung function, pharmacokinetics, and safety, as assessed by adverse events. RESULTS: The modified intention-to-treat analysis set comprised 30 patients (mean age: 66.9 years; mean baseline FEV1: 766 mL; mean COPD assessment test score: 22.20). Following 1 week of treatment, both BFF MDI and BUD/FORM DPI improved mean [95% confidence interval (CI)] peak FEV1 4 h post-dose [256 (190, 322) mL and 274 (208, 340) mL, respectively]. No clinically meaningful difference between treatments was observed for any lung function endpoint. There were no unexpected safety findings. CONCLUSION: Dual therapy with BFF MDI and with BUD/FORM DPI led to improvements in lung function in patients with severe-to-very severe COPD and low PIF.

Relationship between prior inhaled corticosteroid use and benefits ofbudesonide/glycopyrronium/formoterol fumarate dihydrate on exacerbations, symptoms, health-related quality of life, and lung function in patients with chronic obstructive pulmonary disease: Analyses from the ETHOS study.

BACKGROUND: In the Phase III ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid (ICS) doses reduced moderate/severe exacerbation rates and improved symptoms, health-related quality of life (HRQoL), and lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) dual therapy in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD). Here, we assessed whether the benefit for BGF versus GFF was driven by patients who received ICS before randomization to GFF. METHODS: ETHOS was a 52-week, randomized, double-blind, multicenter, parallel-group study in symptomatic patients with COPD and ≥1 moderate/severe exacerbation in the previous year. Patients received BGF 320/14.4/10 µg, BGF 160/14.4/10 µg, GFF 14.4/10 µg, or BFF 320/10 µg twice daily via a single metered dose Aerosphere™ inhaler. In these subgroup analyses, efficacy and safety were assessed in patients with or without prior ICS use in the 30 days before screening. RESULTS: The modified intent-to-treat population comprised 8509 patients (prior ICS use, n = 6810 [80%]; no prior ICS use, n = 1699 [20%]). Moderate/severe exacerbation rates were reduced by 24% and 23% in patients with and without prior ICS use, respectively, with BGF 320 versus GFF. Benefits of BGF 320 versus GFF were also similar in patients with and without prior ICS use across other endpoints relating to exacerbations, symptoms, HRQoL, lung function, and safety. Trends were similar for BGF 160 versus GFF. CONCLUSION: Benefits on exacerbations, symptoms, HRQoL, and lung function with BGF versus GFF were observed, irrespective of prior ICS use in the 30 days before screening.

Benefits of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate on COPD Exacerbations, Lung Function, Symptoms, and Quality of Life Across Blood Eosinophil Ranges: A Post-Hoc Analysis of Data from ETHOS.

Purpose: Blood eosinophil (EOS) count can guide treatment decisions for chronic obstructive pulmonary disease (COPD). In the 52-week ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid doses reduced moderate/severe exacerbation rates and improved lung function, symptoms, and disease-related quality of life (QoL) versus dual therapy with glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) in patients with moderate-to-very severe COPD. This subgroup analysis evaluated treatment benefits in ETHOS by baseline EOS count. Methods: Patients (40-80 years) with a COPD history were randomly assigned 1:1:1:1 to receive BGF 320/14.4/10 µg, BGF 160/14.4/10 µg, GFF 14.4/10 µg, or BFF 320/10 µg via a metered-dose inhaler. This post-hoc analysis assessed endpoints by baseline EOS count using Global Initiative for Obstructive Lung Disease thresholds (<100, ≥100, ≥100-<300, ≥300 cells/mm3), and investigated continuous relationships between treatment effects and EOS count on exacerbations, symptoms, disease-related QoL, lung function, and safety. Results: In the modified intention-to-treat population (n=8509), 82.6% had EOS counts ≥100 cells/mm3. BGF 320 reduced moderate/severe exacerbation rates versus GFF in the ≥100, ≥100-<300, and ≥300 subgroups; treatment differences increased with EOS count. BGF 320 improved rescue medication use and lung-function outcomes across all subgroups, and St George's Respiratory Questionnaire total score, Transition Dyspnea Index focal score, and Exacerbations of Chronic Pulmonary Disease Tool total score in all except the <100 subgroup versus GFF. Benefits of BGF 320 versus BFF were generally consistent across subgroups. Safety data were comparable across subgroups. Conclusion: Benefits of BGF versus GFF were observed across EOS counts, particularly at ≥100 cells/mm³; versus BFF, benefits were largely independent of EOS. These findings confirm that benefits of ICS-containing triple therapy are not restricted to EOS counts ≥300 cells/mm³, supporting recommendations to consider triple therapy in patients with an exacerbation history and EOS counts ≥100 cells/mm³.

Predictive modeling of COPD exacerbation rates using baseline risk factors.

BACKGROUND: Demographic and disease characteristics have been associated with the risk of chronic obstructive pulmonary disease (COPD) exacerbations. Using previously collected multinational clinical trial data, we developed models that use baseline risk factors to predict an individual's rate of moderate/severe exacerbations in the next year on various pharmacological treatments for COPD. METHODS: Exacerbation data from 20,054 patients in the ETHOS, KRONOS, TELOS, SOPHOS, and PINNACLE-1, PINNACLE-2, and PINNACLE-4 studies were pooled. Machine learning was used to identify predictors of moderate/severe exacerbation rates. Important factors were selected for generalized linear modeling, further informed by backward variable selection. An independent test set was held back for validation. RESULTS: Prior exacerbations, eosinophil count, forced expiratory volume in 1 s percent predicted, prior maintenance treatments, reliever medication use, sex, COPD Assessment Test score, smoking status, and region were significant predictors of exacerbation risk, with response to inhaled corticosteroids (ICSs) increasing with higher eosinophil counts, more prior exacerbations, or additional prior treatments. Model fit was similar in the training and test set. Prediction metrics were ~10% better in the full model than in a simplified model based only on eosinophil count, prior exacerbations, and ICS use. CONCLUSION: These models predicting rates of moderate/severe exacerbations can be applied to a broad range of patients with COPD in terms of airway obstruction, eosinophil counts, exacerbation history, symptoms, and treatment history. Understanding the relative and absolute risks related to these factors may be useful for clinicians in evaluating the benefit: risk ratio of various treatment decisions for individual patients.Clinical trials registered with www.clinicaltrials.gov (NCT02465567, NCT02497001, NCT02766608, NCT02727660, NCT01854645, NCT01854658, NCT02343458, NCT03262012, NCT02536508, and NCT01970878).

An adaptive seamless phase II/III design for oncology trials with subpopulation selection using correlated survival endpoints.

Although the statistical methods enabling efficient adaptive seamless designs are increasingly well established, it is important to continue to use the endpoints and specifications that best suit the therapy area and stage of development concerned when conducting such a trial. Approaches exist that allow adaptive designs to continue seamlessly either in a subpopulation of patients or in the whole population on the basis of data obtained from the first stage of a phase II/III design: our proposed design adds extra flexibility by also allowing the trial to continue in all patients but with both the subgroup and the full population as co-primary populations. Further, methodology is presented which controls the Type-I error rate at less than 2.5% when the phase II and III endpoints are different but correlated time-to-event endpoints. The operating characteristics of the design are described along with a discussion of the practical aspects in an oncology setting.

A statistician's perspective on biomarkers in drug development.

Biomarkers play an increasingly important role in many aspects of pharmaceutical discovery and development, including personalized medicine and the assessment of safety data, with heavy reliance being placed on their delivery. Statisticians have a fundamental role to play in ensuring that biomarkers and the data they generate are used appropriately and to address relevant objectives such as the estimation of biological effects or the forecast of outcomes so that claims of predictivity or surrogacy are only made based upon sound scientific arguments. This includes ensuring that studies are designed to answer specific and pertinent questions, that the analyses performed account for all levels and sources of variability and that the conclusions drawn are robust in the presence of multiplicity and confounding factors, especially as many biomarkers are multidimensional or may be an indirect measure of the clinical outcome. In all of these areas, as in any area of drug development, statistical best practice incorporating both scientific rigor and a practical understanding of the situation should be followed. This article is intended as an introduction for statisticians embarking upon biomarker-based work and discusses these issues from a practising statistician's perspective with reference to examples.

Consistent Pulmonary Drug Delivery with Whole Lung Deposition Using the Aerosphere Inhaler: A Review of the Evidence.

Metered dose inhalers (MDIs) are one of the most common device types for delivering inhaled therapies. However, there are several technical challenges in development and drug delivery of these medications. In particular, suspension-based MDIs are susceptible to suspension heterogeneity, in vitro drug-drug interactions, and patient handling errors, which may all affect drug delivery. To overcome these challenges, new formulation approaches are required. The AerosphereTM inhaler, formulated using co-suspension delivery technology, combines drug crystals with porous phospholipid particles to create stable, homogenous suspensions that dissolve once they reach the airways. Two combination therapies using this technology have been developed for the treatment of COPD: glycopyrrolate/formoterol fumarate (GFF MDI; dual combination) and budesonide/glycopyrrolate/formoterol fumarate (BGF MDI; triple combination). Here, we review the evidence with a focus on studies assessing dose delivery, lung deposition, and effects on airway geometry. In vitro assessments have demonstrated that the Aerosphere inhaler provides consistent dose delivery, even in the presence of simulated patient handling errors. Combination therapies delivered with this technology also show a consistent fine particle fraction (FPF) and an optimal particle size distribution for delivery to the central and peripheral airways even when multiple drugs are delivered via the same inhaler. Studies using gamma scintigraphy and functional respiratory imaging have demonstrated that GFF MDI is effectively deposited in the central and peripheral airways, and provides clinically meaningful benefits on airway volume and resistance throughout the lung. Overall, studies suggest that the Aerosphere inhaler, formulated using co-suspension delivery technology, may offer advantages over traditional formulations, including consistent delivery of multiple components across patient handling conditions, optimal particle size and FPF, and effective delivery to the central and peripheral airways. Future studies may provide additional evidence to further characterize the clinical benefits of these technical improvements in MDI drug delivery.

Efficacy and Safety of Budesonide/Glycopyrronium/Formoterol Fumarate versus Other Triple Combinations in COPD: A Systematic Literature Review and Network Meta-analysis.

In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 µg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.