Study Supports Use of Risk Scores as Early Endpoints in Clinical Trials

Results suggest using score changes as endpoints would let studies be completed faster

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Scores on standardized risk assessments showed a clear treatment effect with Orenitram (treprostinil) after three months in a pulmonary arterial hypertension (PAH) clinical trial, with patients showing risk score improvements being less likely to have clinical worsening later on.

The results of this new analysis suggest early changes in risk scores could be used as a surrogate endpoint in clinical trials, allowing studies to potentially be done faster and minimizing the time some participants take an ineffective placebo.

The study, “Contemporary Risk Scores Predict Clinical Worsening in Pulmonary Arterial Hypertension – An Analysis of FREEDOM-EV,” was published in The Journal of Heart and Lung Transplantation. The work was funded by United Therapeutics, which markets Orenitram.

The Phase 3 clinical trial FREEDOM-EV (NCT01560624) compared Orenitram against a placebo in 690 adults with PAH who had started on another treatment. Throughout that study, participants completed a battery of clinical assessments, including the six-minute walk test (a measure of exercise capacity), blood tests, and a WHO functional classification.

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Results showed Orenitram significantly reduced the risk of clinical worsening, broadly defined to include death, hospitalization, disease progression, or a need for new treatments, among other criteria.

An international team of scientists at United and several academic centers used data collected during FREEDOM-EV to calculate the standardized risk scores for study participants at various points throughout the trial. Then they compared the scores for patients on Orenitram or placebo, assessing how they correlated with clinical outcomes.

“FREEDOM-EV was the first [PAH] study to include a risk score in the prospective statistical analysis and hypothesize that a drug would improve risk scores over time,” the research team noted.

The analysis included three standardized assessments of risk for PAH, namely REVEAL 2.0, REVEAL Lite 2, and COMPERA 2.0. All of these measures assess risk based on different combinations of PAH-related factors such as WHO functional class and heart health biomarker levels.

At the study’s start, participants assigned to the Orenitram group generally had higher scores (indicating greater risk) than those in the placebo group for all three measures. The median follow-up time in both groups was slightly more than a year.

In all three scoring systems, a treatment-specific shift in risk scores was evident at 12 weeks (about three months). Those on Orenitram were more likely to see a score improvement, whereas those on a placebo tended to get worse.

“The pattern of PBO [placebo] participants being less likely to improve and more likely to worsen persisted throughout the study regardless of the scoring tool,” the researchers wrote.

The risk scores calculated at 12 weeks were significantly associated with the risk of clinical worsening later on, and those who had an early risk score improvement were unlikely to show subsequent clinical worsening, analyses showed.

These findings suggest “that contemporary risk scores change in response to effective therapy and may be useful surrogates for CW [clinical worsening],” the scientists concluded.

The researchers said these findings support the use of risk scores to measure the effectiveness of potential PAH treatments in clinical trials.

“If further validated, adoption of risk scores or net clinical benefit as an endpoint could improve trial efficiency by reducing the study size, while limiting exposure to placebo and emphasizing clinically relevant improvements in the evaluation of a novel therapy,” they wrote.