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Evolution in Clinical Trial Design: Measuring PAH Treatment Efficacy


Charles Burger, MD: Patients with pulmonary arterial hypertension are primarily affected by shortness of breath, lightheadedness, and/or chest discomfort or tightness. So, clearly, as you’re treating a patient, you want those symptoms to get better. But, their impact on their prognosis has to do with the integrity of the right heart to compensate for the pulmonary arterial hypertension. Getting improvement in the right heart size, and getting improvement in the right heart contractility and the forward flow of blood through the lungs, really determines, for the most part, harder endpoints such as their ability to stay employed, their ability to perform activities of daily living, keeping them out of the hospital, keeping them off of transplant lists or the need to have a transplant, or death. Those things, of course, are harder endpoints that will happen more long term. As you’re evaluating patients short-term though, you aren’t looking for as many of those things to have occurred, but for relative improvement in the symptom burden.

Some objective ways that are called surrogate markers, but are still objective to measure that symptom burden and their exercise capacity, are simple 6-minute walk tests or a submaximal exercise test where a patient might go up and down on a stair, and you measure their oxygenation, their heart rate, and their CO2 excretion. Those things can be very powerful predictors in populations of patients in terms of the absolute numbers. So, they’re useful in clinical studies, because they do apply to populations. But, they’re also useful as trends in an individual patient. You obviously want somebody who can’t walk very far in 6 minutes to improve that distance.

Some of the other challenges, however, are if the pulmonary arterial hypertension is from connective tissue disease or scleroderma, for example. Patients have other reasons why they may not feel well. They have arthritis, they have muscle atrophy, and/or they have inflammation. Scleroderma is a systemic disease which may affect the patient’s symptoms, and may affect the patient’s exercise capacity, even though you may be improving the pulmonary arterial hypertension. So, it’s complex when you use the surrogate markers, because other things obviously can affect those markers without it being the pulmonary arterial hypertension.

Clinical trials are now evolving in a way that is productively adding to the body of literature. Historically, as we looked back at clinical studies for pulmonary arterial hypertension—because the drug options were few and far between, the numbers of patients that had been identified were few, and the number of experts were few—short-term studies with surrogate markers seemed the most appropriate. As we learned that the first drug approved changed mortality by using mortality as an endpoint in these more historical studies, it didn’t seem to be particularly ethical, and was not used as a hard endpoint. However, as the experts who were performing clinical studies provided more and more insight into the methodology of more modern studies, it became apparent that a more complex endpoint with harder subsets within that endpoint, such as the need for transplant, the need to go to infusion intravenous therapy, or prevention of hospitalization from pulmonary arterial hypertension, were important harder endpoints to build into the prospective studies.

So, oftentimes, as represented by more modern studies, there will be an endpoint that’s multidimensional. It will really be a characterization of disease progression. If the patient is improving their symptoms, they’re walking fine, they’re staying out of the hospital, they haven’t had a need for transplant or infusion therapy, and obviously if they’re still alive, that’s a multifaceted endpoint that is really analyzed as what we call a composite outcome-based endpoint. And then, that’s the high-level primary endpoint for more modern studies to say if there are less of these events in the treatment group versus the non-treatment group.

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