ArticleTherapeutic innovation & regulatory science2022
Design and Analysis of Studies Based on Hierarchical Composite Endpoints: Insights from the DARE-19 Trial.
Article in Therapeutic innovation & regulatory science, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04350593 (An International, Multicenter, Randomized, Double-blind, Placebo-controlled, Phase III Study Evaluating the Efficacy and Safety of Dapagliflozin in Respiratory Failure in Patients With COVID-19), which is not on this map. Cited by 11 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
An International, Multicenter, Randomized, Double-blind, Placebo-controlled, Phase III Study Evaluating the Efficacy and Safety of Dapagliflozin in Respiratory Failure in Patients With COVID-19
Who cites it
11 citing papers in PubMed, 25 citations in OpenAlex.
- On Hierarchical Composite Endpoints in Pediatric Cancer Supportive Care: Illustrative Examples From Two Multi-Center Phase-III Randomized Clinical Trials.Pediatric blood & cancer · 2026Trial
- Efficacy and safety of dapagliflozin in patients hospitalized with COVID-19 with and without type 2 diabetes: a prespecified analysis of the DARE-19 randomized trial.Cardiovascular diabetology · 2025Trial
- Definition, analysis, reporting, and interpretation of perioperative bleeding in randomized controlled trials: a methodological systematic review.Perioperative medicine (London, England) · 2026Review
- Linezolid in addition to standard antibiotic treatment forBMJ open · 2026Article
- Article
- Making Sense of Hierarchical Composite End Points in Randomized Clinical Trials-A Primer for Infectious Diseases Clinicians and Researchers.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2025Review
- Opening the DOOR to More Informative Hospital Trials by Ranking Treatment Experiences.Annals of the American Thoracic Society · 2025Article
- Severe maternal morbidity in the high income setting: a systematic review of composite definitions.EClinicalMedicine · 2025Article
- Outcome improvement for anaemia and iron deficiency in ERAS hip and knee arthroplasty: a descriptive analysis.Perioperative medicine (London, England) · 2024Review
- Anakinra authorized to treat severe coronavirus disease 2019; Sepsis breakthrough or time to reflect?Frontiers in microbiology · 2023Article
- Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches.Frontiers in medicine · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND/
aimDARE-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.
methodsHierarchical 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.
resultsWe 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.
conclusionsHCEs 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.