Clinical effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol in usual practice: the COPD INTREPID study design.

Effectiveness studies complement conventional randomised controlled trials by providing a holistic view of treatments in the setting of usual clinical practice. We present the protocol for the ongoing INTREPID (INvestigation of TRelegy Effectiveness: usual PractIce Design; ClinicalTrials.gov identifier: NCT03467425) study, a randomised, open-label, 24-week effectiveness study of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; Trelegy) delivered by the ELLIPTA inhaler versus non-ELLIPTA multiple-inhaler triple therapy in patients with chronic obstructive pulmonary disease (COPD) in usual practice settings. INTREPID was designed to provide evidence of FF/UMEC/VI effectiveness in patients with COPD managed in routine healthcare systems across multiple European countries. Between study initiation and end-of-study visits, patients will receive their medication and care as they would ordinarily receive it, from their usual healthcare provider at their usual healthcare centre. Study-specific intervention will be minimal. The primary end-point will be the proportion of COPD assessment test (CAT) responders, defined as a clinically meaningful improvement from baseline of ≥2 units, at week 24. The CAT was chosen as it provides health status information relevant to patients, physicians, health technology agencies and payers. Lung function (forced expiratory volume in 1 s) and critical inhaler errors will also be assessed in a subgroup of patients. The strengths and weaknesses of the protocol and some of the challenges associated with conducting this multicountry study, such as differences in healthcare systems and treatment practices across sites, will also be discussed.

Randomized controlled trials and real-world observational studies in evaluating cardiovascular safety of inhaled bronchodilator therapy in COPD.

Long-acting muscarinic antagonist (LAMA) or long-acting ß2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety. Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this. Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities. However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability. Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs. We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type. We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design.