Enrichment Benefits of Risk Algorithms for Pulmonary Arterial Hypertension Clinical Trials.

Scott, Jacqueline V; Garnett, Christine E; Kanwar, Manreet K; Stockbridge, Norman L; Benza, Raymond L

RATIONALE 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. OBJECTIVE This study compares validated clinical scales of risk (COMPERA, the French score, and REVEAL 2.0) to identify patients that are likely to experience a clinical worsening event for trial enrichment. METHODS Baseline data from three pulmonary arterial hypertension clinical trials (AMBITION, SERAPHIN, and GRIPHON) 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. MEASUREMENTS AND RESULTS All risk algorithms were compared using area under the receiver-operating curve and substantially outperformed prediction per New York Heart Association Functional Class. 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. CONCLUSION This preliminary study demonstrates the feasibility of risk algorithms for pulmonary arterial hypertension trial enrichment and a need for further investigation.