End points and clinical trial designs in pulmonary arterial hypertension: Clinical and regulatory perspectives

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Abstract

To date, randomized controlled clinical trials performed in pulmonary arterial hypertension (PAH) have been relatively short-term studies involving mainly patients with advanced disease. The primary end points in these trials have addressed exercise capacity, usually by using the 6-min walk test. Although this approach is still warranted in future trials assessing new treatments, it is likely that the focus will shift toward trials of longer duration, involving patients with less advanced disease, and that different drugs and drug-combination regimens will be compared. In such trials, it is possible that a composite of markers indicating clinical deterioration (e.g., hospitalization for right heart failure, the requirement for the introduction of an alternative treatment, and predefined indicators of worsening exercise tolerance) may be more useful as primary end points. Quality of life will become a very important issue; however, appropriate quality-of-life questionnaires for PAH have yet to be developed. In addition, hemodynamics will likely remain valuable as secondary end points, but future clinical trials should include hemodynamics obtained both during exercise and at rest. Finally, cardiopulmonary exercise testing, echocardiographic studies, and biochemical parameters, such as brain natriuretic peptide or troponin T, may also prove useful as secondary end points in the future.

Abbreviations

BNP
brain natriuretic peptide
CO
cardiac output
CPET
cardiopulmonary exercise testing
EMEA
European Agency for the Evaluation of Medicinal Products
FDA
Food and Drug Administration
LV
left ventricle/ventricular
NYHA
New York Heart Association
PAH
pulmonary arterial hypertension
PAP
pulmonary artery pressure
PAPm
mean pulmonary artery pressure
PCWP
pulmonary capillary wedge pressure
PVR
pulmonary vascular resistance
QoL
quality of life
RV
right ventricle/ventricular
Vo2
oxygen consumption
WHO
World Health Organization

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