Evolution and optimization of clinical trial endpoints and design in pulmonary arterial hypertension.
Marco CaccamoFrank E HarrellAnna R HemnesPublished in: Pulmonary circulation (2023)
Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations of patients, clinicians, and regulators in this evolving therapy area. The most commonly used primary endpoint in PAH trials has been 6-min walk distance (6MWD), leading to the approval of several targeted therapies. However, single surrogate endpoints such as 6MWD or hemodynamic parameters may not correlate with clinical outcomes. Composite endpoints of clinical worsening have been developed to reflect patients' overall condition more accurately, although there is no standard definition of worsening. Recently there has been a shift to composite endpoints assessing clinical improvement, and risk scores developed from registry data are increasingly being used. Biomarkers are another area of interest, although brain natriuretic peptide and its N -terminal prohormone are the only markers used for risk assessment or as endpoints in PAH. A range of other genetic, metabolic, and immunologic markers is currently under investigation, along with conventional and novel imaging modalities. Patient-reported outcomes are an increasingly important part of evaluating new therapies, and several PAH-specific tools are now available. In the future, alternative statistical techniques and trial designs, such as patient enrichment strategies, will play a role in evaluating PAH-targeted therapies. In addition, modern sequencing techniques, imaging analyses, and high-dimensional statistical modeling/machine learning may reveal novel markers that can play a role in the diagnosis and monitoring of PAH.
Keyphrases
- pulmonary arterial hypertension
- clinical trial
- patient reported outcomes
- end stage renal disease
- ejection fraction
- risk assessment
- machine learning
- newly diagnosed
- prognostic factors
- peritoneal dialysis
- pulmonary artery
- high resolution
- randomized controlled trial
- phase ii
- stem cells
- gene expression
- open label
- transcription factor
- mesenchymal stem cells
- big data
- polycyclic aromatic hydrocarbons
- coronary artery
- brain injury
- photodynamic therapy