Enrichment Benefits of Risk Algorithms for Pulmonary Arterial Hypertension Clinical Trials

Novel composite clinical endpoints and risk scores used in clinical trials in pulmonary arterial hypertension

“…Use of risk-prediction models that determine low-, intermediate-, high-risk populations can help streamline patients with the greatest potential benefit and, on the opposite side, those who are less advanced and may need a different primary endpoint to demonstrate efficacy. 56 Those who are intermediate risk have potential for improvement and worsening and may be the target of choice, especially as these are usually the most prevalent group. In addition, a change in risk could be an endpoint onto itself.…”

“…PAH patients already on dual or triple therapy randomised to the control group (or placebo group) may also have a good response rate and might require a sample size similar to that in a TTCW study unless there were some enrichment strategies employed. 56,57 The detection of treatment effects in a shorter period is also desirable and these approaches may fulfil this need.…”

Risk, Results, and Costs: Optimizing Clinical Trial Efficiency through Prognostic Enrichment

“…Finally, prognostic enrichment, the strategy proposed and examined in this issue of the Journal by Scott and colleagues (pp. 726–736 ), aims to reduce sample size for event-driven trials by including patients at a high risk for events of interest ( 3 ).…”

“…Choose too low a standard and the “high-risk” group may not be sufficiently high risk. Scott and colleagues ( 3 ) therefore compared three previously published risk scores to identify patients with pulmonary arterial hypertension (PAH) who are most likely to experience a clinical worsening event, and they then simulated sample size and treatment time reductions that would result from using these scores to enrich the study population during a PAH treatment trial. Specifically, the authors used data collected during three recent PAH trials—all of which used time to clinical worsening as the primary endpoint—to arrive at their suggested PAH study population through three steps: They compared the predictive value of three published risk scores (COMPERA [Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension], French [French pulmonary hypertension registry score], and REVEAL 2.0 [the U.S.…”

“…The current COVID-19 pandemic, during which new, rapidly developed, and high-quality evidence is desperately needed to inform medical decision making, has highlighted for the broader public what clinical trialists have known for decades: a multitude of difficult decisions must be made when designing and conducting a clinical trial, with numerous important tradeoffs being considered. Investigators who design PAH trials, and likely those studying many other conditions, are now better informed about the potential benefits of prognostic enrichment thanks to the work presented by Scott and colleagues ( 3 ). We hope and expect their study to not only inform the design of PAH trials but to also prompt additional research that will inform and advance clinical trial design in the future.…”