PAH Clinical Trial Designs Are Evolving, Paving the Way Toward Improved Therapies

The recent announcement of positive results for the AMBITION trial testing combinatorial ambrisentan and tadalafil in patients with pulmonary arterial hypertension (PAH) is bringing more attention to the need to actively recruit participants for clinical trials. Without patients and clinicians interested in trying new treatments for a currently incurable condition, promising new therapies cannot be brought to market for the general PAH population.

During the AMBITION trial, the University of Rochester was one of the most well-enrolled facilities with 15 patients recruited. “We are very grateful to our community partners in upstate New York and Pennsylvania for entrusting their patients to or care and encouraging their participation in clinical trials,” said Patricia J. Sime, MD, chief of the Division of Pulmonary and Critical Care Medicine at University of Rochester Medicine’s Strong Memorial Hospital, in a news release. “Above all, we are grateful to the patients who participate in clinical trials to advance the care of others.”

To provide some perspective into what is motivating PH patients to participate in the development of novel therapies, a sample of 26 patients enrolled in a study at University of Pennsylvania who were recruited from the Pulmonary Vascular Disease Program provided some insight into why they enrolled in the trial. As reported in “Motivations of Patients with Pulmonary Arterial Hypertension to Participate in Randomized Clinical Trials,” which was published in the journal Clinical Trials, the patients’ reasons for enrollment fell into four main categories. Personal benefits such as altruistic motives, personal medical risks such as side effects, non-medical benefits such as financial compensation, and nonmedical burdens such as timing of the trial could influence the patients’ decision to enroll or decline. A majority of patients had hope that their participation in a clinical trial could improve their own health, with one patient stating, “If it is something that they think is going to help, I am willing to try… I am only 61 and I don’t want to die anytime soon so I will try anything to help me.”

In terms of the types of patients sought for clinical trials, the majority of recent clinical trials for PAH therapies have enrolled fewer ill patients with New York Heart Association functional class II disease rather than those with class III or IV, as reported in the study “Patients with Pulmonary Arterial Hypertension in Clinical Trials: Who Are They?” in Proceedings of the American Thoracic Society. Barely any trials enrolled World Health Organization group 1 forms of PAH. This makes it difficult to apply trial results to all individuals with PAH seen in the clinic.

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As a result, there is a call from clinicians, scientists, and the medical community to improve the way randomized controlled trials are designed. “Advancing Clinical Trial Design in Pulmonary Hypertension,” which was published in Pulmonary Circulation, reported on a workshop put together by twelve researchers and clinicians at different medical centers, universities, and pharmaceutical companies in the United States and United Kingdom. The goal of the workshop was to discuss novel approaches to trial design and evaluate the limitations, challenges, and merits of each.

“The traditional clinical trial has been with us for over 60 years and has served us well,” wrote the authors of the report. “Nevertheless, there are reasons for believing that there is a need to consider other ways of developing new drugs.” One way of improving trials is by incorporating an adaptive design. Adaptive designs collect data throughout the trial and use the results to change certain aspects of the trial. Appropriate statistical analyses, sample sizes, and dosing ranges can be flexible during an adaptive trial.

Another report, “From Short-term Benefits to Long-term Outcomes: The Evolution of Clinical Trials in Pulmonary Arterial Hypertension,” identified that clinical trial designs have begun to shift away from traditional short-term trials that rely only on six-minute walk distance as a primary outcome. Instead, trials are being designed to evaluate long-term outcomes such as morbidity and mortality and are more comprehensively assessing combination therapies such as those tested during AMBITION.

“We are delighted that this new combination therapy may soon be an option for patients with PAH who suffer in so many ways and we look forward to continuing to make advances in patient care and discovery in the years ahead,” said Dr. Sime. Along with cutting-edge therapies, updated trial designs will continue to bring progress in treating the estimated 500,000 patients with PAH.