The effect of exacerbation history on outcomes in the IMPACT trial

David M G Halpin, Mark T Dransfield, MeiLan K Han, C Elaine Jones, Sally Kilbride, Peter Lange, David A Lipson, David A Lomas, Fernando J Martinez, Steve Pascoe, Dave Singh, Robert Wise, Gerard J Criner, David M G Halpin, Mark T Dransfield, MeiLan K Han, C Elaine Jones, Sally Kilbride, Peter Lange, David A Lipson, David A Lomas, Fernando J Martinez, Steve Pascoe, Dave Singh, Robert Wise, Gerard J Criner

Abstract

IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI or UMEC/VI in patients with symptomatic COPD and a history of exacerbations.Subgroup analyses assessed whether the efficacy of FF/UMEC/VI versus FF/VI or UMEC/VI and UMEC/VI versus FF/VI varies according to prior exacerbation history, and the combined effects of exacerbation history and blood eosinophil counts. Three subgroups were defined: single moderate (1 moderate/no severe; n=3056 (30%)), frequent moderate (≥2 moderate/no severe; n=4628 (45%)) and severe (≥1 severe/any moderate; n=2671 (26%)). End-points included annual on-treatment moderate/severe exacerbation rate (pre-specified), lung function and health status (both post-hoc).Moderate/severe exacerbation rates (reduction % (95% CI)) were reduced in the FF/UMEC/VI group versus FF/VI (single moderate 20% (10-29), frequent moderate 11% (2-19), severe 17% (7-26)) and versus UMEC/VI (single moderate 18% (5-29), frequent moderate 29% (21-37), severe 26% (14-35)). Moderate/severe exacerbation rates were reduced in the FF/VI group versus UMEC/VI in the frequent moderate subgroup; a numerical reduction was observed in the severe subgroup (single moderate 2% (-12-18), frequent moderate 21% (11-29), severe 11% (-3-22)). Moderate/severe exacerbation rates were lower in the FF/VI group compared with UMEC/VI in patients with higher eosinophil counts. FF/UMEC/VI improved lung function and health status versus both dual therapies irrespective of exacerbation subgroup. UMEC/VI improved lung function versus FF/VI in all subgroups.Triple therapy was more effective than dual regardless of exacerbation history, consistent with results in the intent-to-treat population. Comparisons between dual therapies were influenced by prior exacerbation history and eosinophil counts.

Trial registration: ClinicalTrials.gov NCT02164513.

Conflict of interest statement

Conflict of interest: D.M.G. Halpin reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from AstraZeneca, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees from Pfizer, outside the submitted work. Conflict of interest: M.T. Dransfield reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; grants from Department of Defense, personal fees and other from Boehringer Ingelheim, personal fees and other from GlaxoSmithKline, other from Novartis, personal fees and other from AstraZeneca, other from Yungjin, personal fees and other from PneumRx/BTG, other from Pulmonx, personal fees from Genentech, other from Boston Scientific, personal fees from Quark Pharmaceuticals, grants from NIH, personal fees from Mereo, grants from American Lung Association, grants from NIH, outside the submitted work. Conflict of interest: M.K. Han reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, other from Novartis, other from Sunovion, personal fees from Mylan, outside the submitted work. Conflict of interest: E. Jones reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: S. Kilbride reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: P. Lange reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; grants and personal fees from GlaxoSmithKline, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, outside the submitted work. Conflict of interest: D.A. Lipson reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: D.A. Lomas reports personal fees and other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; grants from GlaxoSmithKline, personal fees and other from GlaxoSmithKline, personal fees from Grifols, outside the submitted work. Conflict of interest: F.J. Martinez reports grants, personal fees and non-financial support from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees and non-financial support from American College of Chest Physicians, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Boehringer Ingelheim, non-financial support from ProterrixBio, personal fees from Columbia University, personal fees and non-financial support from ConCert, personal fees and non-financial support from Genentech, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax Health System, personal fees from Integritas, personal fees from MD Magazine, personal fees from Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communicatinos, personal fees and non-financial support from National Association for Continuing Education, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Pearl Pharmaceuticals, personal fees and non-financial support from PeerView Communications, personal fees and non-financial support from Prime Communications, personal fees and non-financial support from Puerto Rican Respiratory Society, personal fees and non-financial support from Chiesi, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Theravance, personal fees from UpToDate, personal fees from WebMD/MedScape, personal fees from Western Connecticut Health Network, other from Afferent/Merck, non-financial support from Gilead, non-financial support from Nitto, personal fees from Patara/Respivant, personal fees from PlatformIQ, personal fees and non-financial support from Potomac, other from Biogen, personal fees and non-financial support from University of Alabama Birmingham, other from Veracyte, non-financial support from Zambon, personal fees from American Thoracic Society, grants from NIH, personal fees and non-financial support from Physicians Education Resource, personal fees from Rockpointe, other from Prometic, personal fees from Rare Disease Healthcare Communications, other from Bayer, other from Bridge Biotherapeutics, personal fees and non-financial support from Canadian Respiratory Network, other from ProMedior, personal fees and non-financial support from Teva, personal fees from France Foundation, personal fees and non-financial support from Dartmouth, outside the submitted work. Conflict of interest: S. Pascoe reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: D. Singh reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Chiesi, personal fees from Cipla, personal fees from Genentech, grants and personal fees from Glenmark, grants and personal fees from Menarini, grants and personal fees from Mundipharma, grants and personal fees from Novartis, personal fees from Peptinnovate, grants and personal fees from Pfizer, grants and personal fees from Pulmatrix, grants and personal fees from Therevance, grants and personal fees from Verona, outside the submitted work. Conflict of interest: R. Wise reports personal fees, non-financial support and other from GlaxoSmithKline, during the conduct of the study; grants and personal fees from AstraZeneca / Medimmune / Pearl, grants and personal fees from Boehringer Ingelheim, personal fees from Contrafect, personal fees from Pulmonx, personal fees from Roche, personal fees from Spiration, personal fees from Sunovion, grants from Pearl Therapeutics, personal fees from Merck, personal fees from Circassia, personal fees from Pneuma, personal fees from Verona, personal fees from Mylan/Theravance, personal fees from Propeller Health, grants from Sanofi-Aventis, personal fees from AbbVie, grants and personal fees from GSK, outside the submitted work. Conflict of interest: G.J. Criner reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from Almirall, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from CSA Medical, personal fees from Eolo, personal fees from GlaxoSmithKline, personal fees from HGE Technologies, personal fees from Novartis, personal fees from Nuvaira, personal fees from Olympus, personal fees from Pulmonx, personal fees from Verona, personal fees from NGM Bio, outside the submitted work.

Copyright ©ERS 2020.

Figures

FIGURE 1
FIGURE 1
Number of combined moderate or severe COPD exacerbations per patient by prior exacerbation subgroup. The exacerbation history subgroups are defined as single moderate (1 moderate/no severe exacerbation in the prior year), frequent moderate (≥2 moderate/no severe exacerbations in the prior year) and severe (≥1 severe/any moderate exacerbation in the prior year). FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol.
FIGURE 2
FIGURE 2
Annual rate of on-treatment a) moderate or severe and b) severe exacerbations (post-hoc analysis) according to exacerbation history in the year prior to screening for each treatment comparison. The exacerbation history subgroups are defined as single moderate (1 moderate/no severe exacerbation in the prior year), frequent moderate (≥2 moderate/no severe exacerbations in the prior year) and severe (≥1 severe/any moderate exacerbation in the prior year). Data are presented as model estimated annual rate (95% CI), unless otherwise stated. FF: fluticasone furoate; RR: rate ratio; UMEC: umeclidinium; VI: vilanterol.
FIGURE 3
FIGURE 3
Time-to-first combined a) moderate or severe and b) severe COPD exacerbations (post-hoc analysis) by treatment by prior exacerbation subgroup for each treatment comparison. The exacerbation history subgroups are defined as single moderate (1 moderate/no severe exacerbation in the prior year), frequent moderate (≥2 moderate/no severe exacerbations in the prior year) and severe (≥1 severe/any moderate exacerbation in the prior year). Data are presented as patients with events n/N (%), unless otherwise stated. FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol.
FIGURE 4
FIGURE 4
Annual rate of moderate or severe exacerbations, by baseline blood eosinophil count and individual treatment group by prior exacerbation subgroup: a) single moderate, b) frequent moderate and c) severe. The exacerbation history subgroups are defined as single moderate (1 moderate/no severe exacerbation in the prior year), frequent moderate (≥2 moderate/no severe exacerbations in the prior year) and severe (≥1 severe/any moderate exacerbation in the prior year). FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol.
FIGURE 5
FIGURE 5
Between-treatment differences of a, c, e) FF/UMEC/VI versus UMEC/VI and b, d, f) FF/VI versus UMEC/VI in rates of moderate or severe exacerbations, by baseline blood eosinophil count and prior exacerbation subgroup: a, b) single moderate, c, d) frequent moderate, e, f) severe. The exacerbation history subgroups are defined as single moderate (1 moderate/no severe exacerbation in the prior year), frequent moderate (≥2 moderate/no severe exacerbations in the prior year) and severe (≥1 severe/any moderate exacerbation in the prior year). FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol.
FIGURE 6
FIGURE 6
LS mean (95% CI) change in St George's Respiratory Questionnaire (SGRQ) at week 52 by prior exacerbation subgroup. The exacerbation history subgroups are defined as single moderate (1 moderate/no severe exacerbation in the prior year), frequent moderate (≥2 moderate/no severe exacerbations in the prior year) and severe (≥1 severe/any moderate exacerbation in the prior year). Post hoc analysis. Data presented as between-treatment difference (95% CI) in LS mean change from baseline at week 52 in SGRQ total score for FF/UMEC/VI versus UMEC/VI, FF/UMEC/VI versus FF/VI and UMEC/VI versus FF/VI. FF: fluticasone furoate; LS: least squares; UMEC: umeclidinium; VI: vilanterol. *: p<0.05.

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