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Enrichment Benefits of Risk Algorithms for Pulmonary Arterial Hypertension Clinical Trials
Journal article   Open access   Peer reviewed

Enrichment Benefits of Risk Algorithms for Pulmonary Arterial Hypertension Clinical Trials

Jacqueline V Scott, Christine E Garnett, Manreet K Kanwar, Norman L Stockbridge and Raymond L Benza
American journal of respiratory and critical care medicine, v 203(6), pp 726-736
15 Mar 2021
DOI: https://doi.org/10.1164/rccm.202002-0357OC
PMID: 32937078
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958501View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Adult Aged Aged, 80 and over Algorithms Antihypertensive Agents - therapeutic use Clinical Trials as Topic - standards Cohort Studies Familial Primary Pulmonary Hypertension - drug therapy Female Guidelines as Topic Humans Male Middle Aged Pulmonary Arterial Hypertension - drug therapy Risk Assessment - statistics & numerical data United States
Event-driven primary endpoints are increasingly used in pulmonary arterial hypertension clinical trials, substantially increasing required sample sizes and trial lengths. The U.S. Food and Drug Administration advocates the use of prognostic enrichment of clinical trials by preselecting a patient population with increased likelihood of experiencing the trial's primary endpoint. This study compares validated clinical scales of risk (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, the French score, and Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management [REVEAL] 2.0) to identify patients who are likely to experience a clinical worsening event for trial enrichment. Baseline data from three pulmonary arterial hypertension clinical trials (AMBITION [a Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension], SERAPHIN [Study of Macitentan on Morbidity and Mortality in Patients with Symptomatic Pulmonary Arterial Hypertension], and GRIPHON [Selexipag in Pulmonary Arterial Hypertension]) were pooled and standardized. Receiver operating curves were used to measure each algorithm's performance in predicting clinical worsening within the pooled placebo cohort. Power simulations were conducted to determine sample size and treatment time reductions for multiple enrichment strategies. A cost analysis was performed to illustrate potential financial savings by applying enrichment to GRIPHON. All risk algorithms were compared using area under the receiver operating curve and substantially outperformed prediction per New York Heart Association Functional Class. The REVEAL 2.0's risk grouping provided the greatest time and sample size savings in AMBITION and GRIPHON for all enrichment strategies but lacked appropriate inputs (i.e., N-terminal-proB-type natriuretic peptide) to perform as well in SERAPHIN. Cost analysis applied to GRIPHON demonstrated the greatest financial benefit by enrolling patients with a REVEAL score ≥8. This preliminary study demonstrates the feasibility of risk algorithms for pulmonary arterial hypertension trial enrichment and a need for further investigation.

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22 citations in Web of Science
24 citations in Scopus

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Collaboration types
Domestic collaboration
Web of Science research areas
Critical Care Medicine
Respiratory System
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