Hypertension represents a significant global public health concern, contributing 
to vascular and renal morbidity, cardiovascular mortality, and economic burden. 
The opportunity to influence clinical outcomes through hypertension management 
is therefore paramount. Despite adherence to multiple available medical 
therapies, a significant proportion of patients have persistent blood pressure 
elevation, a condition termed resistant hypertension. Recent recognition of the 
importance of the renal sympathetic and somatic nerves in modulating blood 
pressure and the development of a novel procedure that selectively removes these 
contributors to resistant hypertension represents an opportunity to provide 
clinically meaningful benefit across wide and varied patient populations. Early 
clinical evaluation with catheter-based, selective renal sympathetic denervation 
in patients with resistant hypertension has mechanistically correlated 
sympathetic efferent denervation with decreased renal norepinephrine spillover 
and renin activity, increased renal plasma flow, and has demonstrated clinically 
significant, sustained reductions in blood pressure. The SYMPLICITY HTN-3 Trial 
is a pivotal study designed as a prospective, randomized, masked procedure, 
single-blind trial evaluating the safety and effectiveness of catheter-based 
bilateral renal denervation for the treatment of uncontrolled hypertension 
despite compliance with at least 3 antihypertensive medications of different 
classes (at least one of which is a diuretic) at maximal tolerable doses. The 
primary effectiveness endpoint is measured as the change in office-based 
systolic blood pressure from baseline to 6 months. This manuscript describes the 
design and methodology of a regulatory trial of selective renal denervation for 
the treatment of hypertension among patients who have failed pharmacologic 
therapy.