As PAH Science Advances, Trial Design Comes Under Microscope


Investigators are considering how best to interpret the results of potential new therapies.

The science of pulmonary arterial hypertension (PAH) has advanced significantly in recent years. However, as the push for new and better therapies gains momentum, clinical trial investigators are thinking long and hard about how best to demonstrate and interpret patient improvement.

One issue has to do with the question of which end points are best to meaningfully track patient responses to therapies.

Marius Hoeper, MD, of Germany’s Hannover Medical School, said in clinical practice, physicians tend to use a variety of measures to track patient improvement.

“PH physicians usually take a holistic view,” he said, “i.e., they consider the broad picture.”

That broad picture includes everything from patient’s exercise capacity, assessed by 6-minute walking distance (6MWD); to serum levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP); to right heart function; and simply how the patient feels.

In clinical trials, though, figuring out the best way to track patient improvement across a broad study population is more complicated—and even more critical.

Michael Lewis, MD, who directs respiratory care services at the Cedars Sinai Medical Center, in Los Angeles, said there are currently two primary end points the Food and Drug Administration (FDA) will accept. One is 6MWD, the other is time to clinical worsening, which measures the time between therapy administration and clear signs of worsening like death, hospitalization, or the need to escalate therapy.

However, he said time to clinical worsening is used less often in clinical trials, because you generally need a larger patient population and a longer time frame in order to accurately capture it.

“In some of the earlier studies, they only went about 12 to 16 weeks,” he explained. “ that's not a lot of time to show that.”

The phase III trial of sotatercept (Winrevair), for which Hoeper was the corresponding author, used 6MWD as its primary end point, and time to clinical worsening as a secondary end point. However, they also used a newer end point—multicomponent improvement—as one of their secondary end points.

In the trial, multicomponent improvement was measured by the percentage of patients who met criteria for improvement in 6MWD, maintenance or achievement of an NT-proBNP level under 300 pg per milliliter, and improvement in World Health Organization (WHO) functional class. Hoeper said these variables reflect functional capacity and right ventricular strain.

“At the same time, these variables are powerful predictors of outcomes,” he said.

However, Hoeper added that the multicomponent improvement end point remains an “arbitrary” measure, in the sense that it has not been fully validated and is not accepted by the FDA as a primary end point.

Lewis is currently investigating a potential cell-based therapy for PAH. He said a different issue of trial design is generating interest.

“What’s being emphasized a lot now is the issue of responders and non-responders,” he said.

While a trial might have positive data in terms of the overall number of people who respond to a particular therapy, Lewis said the picture might actually be more complicated.

“If you look at it in tremendous detail, there are going to be groups of patients that are great responders, groups that are modest responders, and groups that don't respond or actually do worse,” he said. “The pendulum is swinging towards trying to identify who are—quote—‘significant’ responders.”

Gaining a better understanding of which patients respond most strongly to which types of therapies could pave the way for more personalized approaches to PAH care, he said. That will be an increasingly important topic and more studies are published and more therapies are approved.

In the meantime, decisions about which therapies work best for which patients will depend on doctor-patient conversations and ultimately how the patient feels about particular therapies. Lewis said for most patients, exercise capacity remains one of the biggest signs of improvement, or deterioration.

As for the multicomponent improvement end point, Hoeper said there has not been much in the way of studies designed to validate the end point. He said it has been used occasionally, but does not seem to be gaining traction.

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