Design and Analysis of Studies Based on Hierarchical Composite Endpoints: Insights from the DARE-19 Trial

Samvel B Gasparyan, Joan Buenconsejo, Elaine K Kowalewski, Jan Oscarsson, Olof F Bengtsson, Russell Esterline, Gary G Koch, Otavio Berwanger, Mikhail N Kosiborod, Samvel B Gasparyan, Joan Buenconsejo, Elaine K Kowalewski, Jan Oscarsson, Olof F Bengtsson, Russell Esterline, Gary G Koch, Otavio Berwanger, Mikhail N Kosiborod

Abstract

Background/aim: DARE-19 (NCT04350593) was a randomized trial studying the effects of dapagliflozin, an SGLT2 inhibitor, in hospitalized patients with COVID-19 pneumonia and cardiometabolic risk factors. The conduct of DARE-19 offered the opportunity to define an innovative and clinically meaningful endpoint in a new disease that would best reflect the known profile of dapagliflozin, accompanied by the statistical challenges of analysis and interpretation of such a novel endpoint.

Methods: Hierarchical composite endpoints (HCEs) are based on clinical outcomes which, unlike traditional composite endpoints incorporate ranking of components according to clinical importance. Design of an HCE requires the clinical considerations specific to the therapeutic area under study and the mechanism of action of the investigational treatment. Statistical aspects for the clinical endpoints include the proper definition of the estimand as suggested by ICH E9(R1) for the precise specification of the treatment effect measured by an HCE.

Results: We describe the estimand of the DARE-19 trial, where an HCE was constructed to capture the treatment effect of dapagliflozin in hospitalized patients with COVID-19, and was analyzed using a win odds. Practical aspects of designing new studies based on an HCE are described. These include sample size, power, and minimal detectable effect calculations for an HCE based on the win odds analysis, as well as handling of missing data and the clinical interpretability of the win odds in relation to the estimand.

Conclusions: HCEs are flexible endpoints that can be adapted for use in different therapeutic areas, with win odds as the analysis method. DARE-19 is an example of a COVID-19 trial with an HCE as one of the primary endpoints for estimating a clinically interpretable treatment effect in the COVID-19 setting.

Keywords: COVID-19; Dapagliflozin; Hierarchical composite endpoints; SGLT2 inhibitors; Win odds.

Conflict of interest statement

SBG, JO, OFB and RE are employees and stockholders of AstraZeneca. JB was an employee of AstraZeneca at the time the manuscript was being prepared and now is employed at Bristol-Myers-Squibb. EKK has nothing to declare. GGK is the Principal Investigator of a biostatistics grant from AstraZeneca. He is also the Principal Investigator for biostatistics grants from other biopharmaceutical sponsors that have no relationship to the submitted work. OB has received research Grants from AstraZeneca, Pfizer, Servier, Novartis, Amgen, Bayer, and Boheringer-Ingelheim. MNK has received a research grant for the conduct of this study from AstraZeneca. He has also received Grant and research support from AstraZeneca. He has received a Grant and honoraria from Boehringer-Ingelheim, and honoraria from AstraZeneca, Alnylam, Amgen, Bayer, Eli Lilly, Esperion, Merck (Diabetes and Cardiovascular), Janssen, Novo Nordisk, Pharmacosmos and Vifor Pharma.

© 2022. The Drug Information Association, Inc.

Figures

Fig. 1
Fig. 1
WHO Ordinal Scale for clinical improvement in COVID-19
Fig. 2
Fig. 2
Bar chart of categories of the HCE in DARE-19 by treatment groups (FAS)

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