Clinical trial design and new therapies for pulmonary arterial hypertension

Abstract

Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.

Molecular genetic framework underlying pulmonary arterial hypertension

“…To date, trials in patients based on genetically isolated targets have been focused on use of the calcineurin inhibitor tacrolimus which, among other effects, activates BMP signalling to reverse vascular occlusion in rat models, and seems to be well tolerated in patients with PAH 111 . Although preliminary in vitro findings support the potential restoration of potassium channel activity after pharmacological intervention in loss-of-function KCNK3 and ABCC8 cell models, further preclinical testing is required to evaluate the feasibility of manipulating these targets for patient benefit 36,97,112 .…”

Evidence synthesis in pulmonary arterial hypertension: a systematic review and critical appraisal

“…A related shortcoming of appraised studies is the choice of outcomes analyzed, which was found to be selective, incomprehensive, and usually not accompanied by clear justification. The most commonly assessed outcome was 6MWDdespite failure of multiple studies to consistently establish significant associations between 6MWD and clinically more relevant outcomes such PAH-related hospitalization, lung transplantation, initiation of rescue therapy or death [28,29,44,52,86,87]. Moreover, the assessed evidence synthesis studies generally neither presented a review of the outcome definitions and outcome measures of included trials, nor an assessment of imputation rules for handling missing data.…”

The Role of Noninvasive Endpoints in Predicting Long-Term Outcomes in Pulmonary Arterial Hypertension

“…For instance, morbidity and mortality event trials require a large number of subjects in order to demonstrate effects even as early as 1 year [59,60]. Looking to the future, consideration should be given to including 6MWD, FC, and BNP/NT-proBNP in the assessment of time to clinical improvement, a new endpoint proposed at the recent 6th World Symposium on Pulmonary Hypertension [61].…”