Patrick Darken

Background: We evaluated the inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β₂-agonist (ICS/LAMA/LABA) triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual LAMA/LABA and ICS/LABA therapies in patients with chronic obstructive pulmonary disease (COPD) and phenotypic features of asthma (bronchodilator reversibility and elevated blood eosinophils), but no asthma diagnosis, for whom treatment guidelines are limited. Patients and methods: KRONOS (NCT02497001) and ETHOS (NCT02465567) enrolled patients with moderate-to-very-severe COPD, no current asthma diagnosis, and either ≥ 0 (KRONOS) or ≥ 1 (ETHOS) moderate/severe exacerbations in the prior year. This pooled post hoc analysis evaluated trough forced expiratory volume in 1 second (FEV₁) and FEV₁ area under the curve from hours 0 to 4 (AUC_{0– 4}) change from baseline over 12– 24 weeks, moderate/severe exacerbation rates, and St George’s Respiratory Questionnaire (SGRQ) total score over 24 weeks with ICS/LAMA/LABA (BGF 320/14.4/10 μg), LAMA/LABA (glycopyrronium/formoterol fumarate dihydrate [GFF] 14.4/10 μg), and ICS/LABA (budesonide/formoterol fumarate dihydrate [BFF] 320/10 μg) in patients with phenotypic features of asthma defined as reversibility to salbutamol and blood eosinophils ≥ 300 cells/mm³. Analyses were not adjusted for multiplicity. Results: BGF improved trough FEV₁ and FEV₁ AUC_{0– 4} versus GFF (least squares mean [LSM] difference [95% confidence interval (CI)] 125 [39– 211] and 153 [59– 247] mL) and BFF (LSM difference [95% CI] 118 [30– 207] and 146 [49– 243] mL). Exacerbation rates were estimated to be lower with BGF versus GFF and BFF (respective rate ratios [95% CI] 0.28 [0.19– 0.43] and 0.69 [0.45– 1.05]) and SGRQ total score was estimated to be improved with BGF versus GFF and BFF (respective LSM differences [95% CI] – 5.18 [– 8.11 to – 2.24] and – 1.09 [– 4.08 to 1.91]). Conclusion: BGF was estimated to have benefits on lung function, exacerbations, and health-related quality of life versus dual therapies in patients with COPD and phenotypic features of asthma. Trial Registration: ClinicalTrials.gov NCT02497001 and NCT02465567.

Background: High-quality decision-making in the pharmaceutical industry requires accurate assessments of the Probability of Technical Success of clinical trials. Failure to do so will lead to lost opportunities for both patients and investors. Pharmaceutical companies employ different methodologies to determine Probability of Technical Success values. Some companies use power and assurance calculations; others prefer to use industry benchmarks with or without the overlay of subjective modulations. At AstraZeneca, both assurance calculations and industry benchmarks are used, and both methods are combined with modulations. Methods: AstraZeneca has recently implemented a simple algorithm that allows for modulation of a Probability of Technical Success value. The algorithm is based on a set of multiple-choice questions. These questions cover a comprehensive set of issues that have historically been considered by AstraZeneca when subjective modulations to Probability of Technical Success values were made but do so in a much more structured way. Results: A set of 57 phase 3 Probability of Technical Success assessments suggests that AstraZeneca’s historical estimation of Probability of Technical Success has been reasonably accurate. A good correlation between the subjective modulation and the modulation algorithm was found. This latter observation, combined with the finding that historically AstraZeneca has been reasonably accurate in its estimation of Probability of Technical Success, gives confidence in the validity of the novel method. Discussion: Although it is too early to demonstrate whether the method has improved the accuracy of company’s Probability of Technical Success assessments, we present our data and analysis here in the hope that it may assist the pharmaceutical industry in addressing this key challenge. This new methodology, developed for pivotal studies, enables AstraZeneca to develop more consistent Probability of Technical Success assessments with less effort and can be used to adjust benchmarks as well as assurance calculations. Conclusion: The Probability of Technical Success modulation algorithm addresses several concerns generally associated with assurance calculations or benchmark without modulation: selection biases, situations where little relevant prior data are available and the difficulty to model many factors affecting study outcomes. As opposed to using industry benchmarks, the Probability of Technical Success modulation algorithm allows to accommodate project-specific considerations.

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. Graphical Abstract:

Purpose: In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations. We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥ 1 exacerbation in the 12 months prior to the study. Patients and Methods: Patients received BGF MDI 320/18/9.6 μg, GFF MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily. Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study. Results: Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study. BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p=0.0003) and no prior (48%; unadjusted p=0.0001) exacerbations subgroups. The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI. In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI (p=0.0022) and BFF MDI (p=0.0110); excluding the first 30 days of data yielded similar results. The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count. Conclusion: In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations.

Background: In the Phase III, 52-week ETHOS study (NCT02465567), BGF MDI triple fixed-dose combination, reduced moderate/severe COPD exacerbation rate vs dual therapies; however, rates are known to vary by season. Objective: To assess exacerbation rates by season in ETHOS. Methods: Patients with moderate-to-very severe COPD and ≥1 moderate/severe exacerbation in the prior year received BGF MDI 320/14.4/10 μg or 160/14.4/10 μg, glycopyrronium/formoterol (GFF) MDI 14.4/10 μg or budesonide/formoterol (BFF) MDI 320/10 μg twice-daily via a single Aerosphere inhaler. Annualised exacerbation rates were assessed using negative binomial regression. Results: In the mITT population (n=8509), 56.5% of patients had ≥2 exacerbations in the previous year. BGF MDI 320/14.4/10 µg and 160/14.4/10 µg reduced exacerbation rate vs GFF MDI and BFF MDI (Figure); rate ratios vs GFF MDI for winter, spring, summer and fall were 0.83, 0.77, 0.71, 0.77 and 0.82, 0.82, 0.81, 0.66, respectively (all p<0.02 [unadjusted]); and vs BFF MDI were 0.88, 0.95, 0.80, 0.89 and 0.87, 1.01, 0.92, 0.77, respectively. Conclusions: In patients with moderate-to-very severe COPD and an exacerbation history, seasonal variation in exacerbation rate occurred in each treatment group. A reduction in exacerbation rate was generally observed across all seasons for BGF MDI (both dose levels) vs LAMA/LABA and ICS/LABA.

Summary: The term “intercurrent events” has recently been used to describe events in clinical trials that may complicate the definition and calculation of the treatment effect estimand. This paper focuses on the use of an attributable estimand to address intercurrent events. Those events that are considered to be adversely related to randomized treatment (eg, discontinuation due to adverse events or lack of efficacy) are considered attributable and handled with a composite estimand strategy, while a hypothetical estimand strategy is used for intercurrent events not considered to be related to randomized treatment (eg, unrelated adverse events). We explore several options for how to implement this approach and compare them to hypothetical “efficacy” and treatment policy estimand strategies through a series of simulation studies whose design is inspired by recent trials in chronic obstructive pulmonary disease (COPD), and we illustrate through an analysis of a recently completed COPD trial.

Rationale: In the Phase 3 KRONOS study, budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a fixed-dose combination triple therapy, significantly reduced the moderate/severe chronic COPD exacerbation rate vs. glycopyrrolate/formoterol fumarate (GFF) MDI, with numerical improvements vs. budesonide/formoterol fumarate (BFF) MDI. We conducted a post-hoc analysis for seasonal variation of exacerbation rates. Methods: KRONOS was a randomized, double-blind, multicenter, 24-week study (NCT02497001) including patients with symptomatic moderate-to-very severe COPD (CAT-score ≥ 10) despite ≥ 2 inhaled maintenance therapies. We analyzed data from the modified intent-to-treat population receiving BGF MDI 320/18/9.6 μg (n = 639), GFF MDI 18/9.6 μg (n = 625), BFF MDI 320/9.6 μg (n = 314), or open-label budesonide/formoterol dry powder inhaler 400/12 μg (BUD/FORM DPI; n = 318). Of these patients, 74% had not experienced an exacerbation in the previous year. Annualized rate of moderate/severe COPD exacerbations was analyzed using negative binomial regression, adjusting for baseline post-bronchodilator % predicted FEV1, baseline eosinophil count, treatment, season, treatment by season interaction, baseline COPD exacerbation history, country, and ICS use at screening. Seasons were defined as: winter, December−February; spring, March−May; summer, June−August; fall, September−November. Results: Adjusted annualized rates of moderate/severe COPD exacerbations were highest in winter (0.83, 1.60, 0.89, 0.94 for BGF MDI, GFF MDI, BFF MDI, and BUD/FORM DPI, respectively) and lowest in summer (0.25, 0.60, 0.38, 0.44). BGF MDI reduced exacerbations rates vs. GFF MDI regardless of season (treatment incidence rate ratios 0.52, 0.51, 0.42, 0.45 for winter, spring, summer, and fall, respectively; all p < 0.01). Conclusion: In this population of patients with moderate-to-very severe COPD without a requirement for an exacerbation history in the previous year, seasonal variation in exacerbation rates occurred within each treatment group. The significant reduction in annualized exacerbation rates with BGF MDI vs. GFF MDI was consistently observed across all four seasons, indicating that the 6-month study duration provided a robust assessment of COPD exacerbation rates.