Impact of pre-enrolment medication use on clinical outcomes in SUMMIT

Abstract

The impact of prior treatment on results of clinical trials in chronic obstructive pulmonary disease (COPD) has been debated. We used data from the Study to Understand Mortality and Morbidity in COPD Trial to examine the impact of prior treatment on the effects of randomised study drugs on mortality and exacerbations. We used data on 16 417 patients with moderate COPD and heightened cardiovascular risk and information on prior medications to examine the effects of fluticasone furoate (FF), vilanterol (VI) and combined FF/VI compared to placebo on moderate and severe exacerbation as well as mortality. The study was event-driven with a median study exposure of 1.8 years. This study was registered with ClinicalTrials.gov, number NCT01313676. There were no consistent associations between treatment prior to study entry and the effects of FF, VI or FF/VI on exacerbations during the study. However, patients taking inhaled corticosteroids and one or more bronchodilators prior to study entry seemed to have a better effect of active treatments than of placebo on mortality (hazard ratio for FF/VI 0.65, 95% CI 0.48-0.89). Survival in those randomised to placebo was independent of treatment prior to study enrolment. Prior treatment appears to affect treatment effects on mortality but not exacerbations in a randomised controlled trial of patients with COPD and heightened cardiovascular risk.

Conflict of interest statement

Conflict of interest: J. Vestbo reports that he was reimbursed for his work as chair of the SUMMIT Steering Committee by GlaxoSmithKline during the conduct of the study; and that he has received consultancy fees for the COPD Phase 2 and 3 programme and payment for lectures including service in a speaker bureau from GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer Ingelheim, Novartis and AstraZeneca, outside the submitted work. Conflict of interest: M. Dransfield reports consulting fees from GlaxoSmithKline during the conduct of the study; and grants from the Department of Defense and the NIH, personal fees for consulting and contract clinical trials from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, PneumRx/BTG and Boston Scientific, support for contract clinical trials from Novartis, Yungjin and Pulmonx, and consulting fees from Genentech and Quark Pharmaceuticals, outside the submitted work. Conflict of interest: J.A. Anderson is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: R.D. Brook reports work on the SUMMIT Steering Committee for GSK during the conduct of the study. Conflict of interest: P.M.A. Calverley reports personal fees from Astra Zeneca Pharmaceuticals, GSK, Boehringer Ingelheim and Recipharm, outside the submitted work. Conflict of interest: B.R. Celli reports support for a research site from AstraZeneca, and consulting fees from GlaxoSmithKline, Boehringer Ingelheim, Novartis, Chiesi and Menarini, all outside the submitted work. Conflict of interest: N.J. Cowans is an employee of Veramed Limited, a company that GSK paid to carry out the statistical analysis for this article. Conflict of interest: C. Crim reports is an employee of and holds restricted shares in GlaxoSmithKline. Conflict of interest: F. Martinez reports that GSK was the supporter of the parent study to the current study; and honoraria and nonfinancial travel support from the American College of Chest Physicians for COPD CME programmes in India, personal fees and nonfinancial travel support from AstraZeneca for COPD advisory boards, the study steering committee and an ALAT presentation, personal fees and nonfinancial support from Boehringer Ingelheim for a COPD advisory board, an ATS presentation, an IPF study steering committee, an IPF disease state presentation at ALAT and a progressive pulmonary fibrosis DSMB, nonfinancial support from ProterrixBio for a COPD scientific advisory board, honoraria from Columbia University for a COPD CME programme, honoraria and nonpersonal travel support from ConCert for a COPD advisory board, personal fees and nonpersonal travel support from Genentech for a COPD advisory board, personal fees and nonfinancial support from GlaxoSmithKline for COPD advisory boards, a study steering committee, a DSMB and an ERS presentation, honoraria from Haymarket Communications for a COPD CME presentation, honoraria and nonpersonal travel support from the Inova Fairfax Health System for a COPD CME presentation, honoraria from Integritas for a COPD CME presentation, honoraria and nonpersonal travel support from MD Magazine for a COPD CME programme, honoraria from Methodist Hospital Brooklyn for a COPD CME programme, honoraria and nonpersonal travel support from Miller Communications for COPD and IPF CME programmes, honoraria and nonpersonal travel support from the National Association for Continuing Education for COPD and IPF CME programmes, honoraria and nonpersonal travel support from Novartis for a COPD advisory board and international meeting COPD presentations, honoraria from New York University for a COPD CME programme, personal fees and nonfinancial support from Pearl Pharmaceuticals for COPD advisory boards and a COPD steering committee, honoraria and nonpersonal travel support from PeerView Communications for COPD and IPF CME programmes, honoraria and nonpersonal travel support from Prime Communications for COPD CME programmes, honoraria and nonpersonal travel support from the Puerto Rican Respiratory Society for a COPD and IPF CME programme, honoraria and nonpersonal travel support from Chiesi for a COPD CME presentation and an advisory board, honoraria and nonpersonal travel support from Sunovion for COPD advisory boards, honoraria and nonpersonal travel support from Theravance for a COPD advisory board, honoraria from Unity for COPD teleconferences, honoraria from UpToDate for COPD CME, honoraria from WebMD/MedScape for COPD CME presentations, honoraria from the Western Connecticut Health Network for COPD CME presentations, coauthorship from Afferent/Merck for an IPF study steering committee, honoraria from Academic CME for IPF CME programmes, coauthorship from Gilead for an IPF study steering committee, nonfinancial support from Nitto for an IPF study teleconference and steering committee, honoraria from Patara for venture capital expert advice for an IPF study, honoraria from PeerView for an IPF CME presentation, honoraria from PlatformIQ for an IPF CME programme, honoraria and nonpersonal travel support from Potomac for IPF CME presentations, nonfinancial support from Stromedix/Biogen for an IPF study DSMB and IPF study steering committee, honoraria and nonpersonal travel support from the University of Alabama Birmingham for and IPF CME presentation, coauthorship from Veracyte for an IPF study steering committee, nonpersonal travel support to attend an IPF study meeting and an honorarium for an advisory board from Zambon, an honorarium for acting as AJRCCM DE from the American Thoracic Society, grants from the NIH, an honorarium and travel support from the Physicians Education Resource for a COPD CME programme, an honorarium from Rockpointe for a COPD CME programme, nonfinancial support from Prometic for an IPF steering committee, grants from Rare Disease Health are Communications, and an honorarium and travel support from Teva for a COPD advisory board, outside the submitted work. Conflict of interest: D.E. Newby reports consultancy fees from GSK for serving on the trial steering committee during the conduct of the study, and grants and personal fees for other research and consultancy activities from GSK, outside the submitted work. Conflict of interest: J. Yates is an employee of and holds shares in GSK. Conflict of interest: P. Lange reports personal fees for membership of the data monitoring board from GSK during the conduct of the study; and consultancy and teaching fees from AstraZeneca, Boehringer Ingelheim, Chiesi and GSK, outside the submitted work.

Figures

FIGURE 1

Overall mortality in the four treatment groups (placebo, fluticasone furoate (FF), vilanterol (VI) and FF/VI) according to previous treatment use. a) Those receiving no inhaled pre-treatment maintenance medication; b) those on inhaled corticosteroids and long-acting bronchodilators as previous treatment use.

FIGURE 2

Risk of moderate/severe exacerbations in the four treatment groups (placebo, fluticasone furoate (FF), vilanterol (VI) and FF/VI) according to previous treatment use. a) Those receiving no inhaled pre-treatment maintenance medication; b) those on inhaled corticosteroids and long-acting bronchodilators as previous treatment use. COPD: chronic obstructive pulmonary disease.