Discussion
CF, vision, pulmonary exacerbations, ICH, PEx, CF PEx
SECONDARY
The BEAT CF PEx core protocol sets out a prospective cohort designed to perpetually enroll people with CF to evaluate the comparative effectiveness of interventions used for managing PEx. It is intended that sub-studies will be nested within this cohort in order to generate high-quality evidence to optimize the management of PEx.The primary endpoint is the absolute change in ppFEVThe decision was made for the primary outcome to be absolute rather than relative change in the ppFEVImportantly, additional endpoints will be captured which include safety, effects on microbiology, and more patient-centered outcomes such as the CRISS (symptom score) which provides information that is complementary to lung function measurements and which captures different aspects of clinical response [There is no consensus regarding the optimal endpoints for children with CF who are too young to perform spirometry [No clear consensus exists around the definition of PEx of CF and definitions that might fit adult patients do not necessarily fit children [We have followed the latest ICH statistical guidance (E9 (R1)) to specify analyses in the estimand framework [As well as establishing a prospective observational cohort, the PEx core protocol will serve as the highest tier of a “master protocol” for the nesting of clinical trials and other sub-studies within the cohort. The concept of the master protocol has evolved over the past decade, alongside growing interest in complex study designs like basket, umbrella, and platform trials [We have employed a modular and hierarchical approach to the protocol documentation, borrowing from the approach and nomenclature of REMAP-CAP, which is primarily an adaptive platform trial with a core protocol, with a series of appendices for each treatment domain [As well as creating a pool for identifying study participants, the value of nesting studies within an existing large cohort or registry is that it reduces the incremental cost and burden of data capture and allows investigators to assess how representative study participants are of the patient population and therefore how generalizable any findings are likely to be. It is intended that most PEx cohort participants will become eligible to participate in a PEx Treatment Platform in which selected aspects of PERIT management will be randomly assigned, as well as other cohort-nested sub-studies to address secondary research aims. The details for the PEx Treatment Platform and any nested sub-studies will be defined separately in subprotocols.We have presented the PEx core protocol here using the SPIRIT checklist for clinical trials [The PEx core protocol (and any nested sub-studies) is designed to support embedding of study procedures in routine clinical care. Embedding not only reduces the costs and burdens of research, but it is also intended to capture the real-world use of therapy, arguably making any findings more relevant for decision-making. Our vision is a ‘learning health system’ approach to CF management, collecting data from pulmonary exacerbations to generate and rapidly translate insights from analysis into patient care. To this end, the project is overseen by a central steering committee which comprises representatives from the project investigators, the community reference groups, and stakeholders from the clinical craft groups.