Following the results of SYMPLICITY HTN-3, which failed to show benefit of renal denervation in resistant hypertension patients, Medtronic announced in April the initiation of the SPYRAL HTN clinical trial programme, studying renal denervation in uncontrolled hypertension. Also in April, Boston Scientific announced the initiation of the REDUCE-HTN: REINFORCE, a randomised, sham-controlled study designed to demonstrate the effects of the Vessix renal denervation system by minimising variability and factors that may have affected results in SYMPLICITY HTN-3.
Like Boston Scientific, Medtronic stated that the two global studies of the SPYRAL HTN programme have been designed to address the confounding factors encountered in SYMPLICITY HTN-3, including medication, patient population and procedural variability, to ensure the clinical potential of the therapy is evaluated.
Physicians in both studies announced by Medtronic will perform renal denervation with Medtronic’s next-generation renal denervation technology, composed of the 6F-compatible, multielectrode Symplicity Spyral catheter and Symplicity G3 radiofrequency generator. The Symplicity Spyral catheter and G3 generator are investigational in the USA and Japan.
The principal investigators for the two global studies are Michael Böhm, University of Saarland in Homburg/Saar, Germany; David Kandzari, Piedmont Heart Institute in Atlanta, USA; Kazuomi Kario, Jichi Medical University School of Medicine in Tochigi, Japan; and Raymond Townsend, University of Pennsylvania, USA.
The SPYRAL HTN programme includes two global, prospective, randomised, sham-controlled trials conducted simultaneously to investigate the impact of renal denervation both in the absence of and in the presence of antihypertensive medications. The SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED studies will each include approximately 100 patients with moderate- to high-risk hypertension, as opposed to the severe, treatment resistant population studied in SYMPLCITY HTN-3. These studies will be conducted at approximately 20 centres in the USA and other countries.
The SPYRAL HTN-OFF MED study is designed to isolate the effect of renal denervation on blood pressure reduction. Similar to the traditional design of antihypertensive pharmaceutical clinical trials, this approach was recommended by both the FDA and the global clinical community. Separately, the SPYRAL HTN-ON MED study will evaluate the effect of renal denervation on blood pressure in the presence of antihypertensive medication. Unlike the SYMPLICITY HTN-3 trial, which enrolled patients with very high blood pressure that was not controlled despite an average of five antihypertensive medications at maximum tolerated dosages, the SPYRAL HTN-ON MED study requires patients who, despite use of drugs from three of the most common classes of medications prescribed for hypertension, do not achieve adequate blood pressure control. These drugs are not required to be prescribed at maximum tolerated medication dosages, a factor which may have contributed to variability in patient adherence and the large number of medication changes during SYMPLICITY HTN-3. Additionally, adherence will be closely monitored and there will be a focus on ambulatory blood pressure monitoring to ensure consistency between both arms of the on- and off-medication studies.
Based on the outcomes of these two initial studies of the SPYRAL HTN programme, Medtronic will evaluate next steps for a pivotal study to support a pre-market application submission to the FDA and Shonin submission in Japan.
Vessix sham-controlled study
The first patient in the REDUCE-HTN: REINFORCE study was enrolled at Cardiology P.C. at Princeton Baptist Medical Center in Birmingham, USA, by Farrell Mendelsohn (site principal investigator) and referred by Michael Wilensky. Boston Scientific has received an investigational device exemption (IDE) for the study from the FDA.
The REDUCE-HTN: REINFORCE study will enrol 100 patients. The primary efficacy assessment is the mean reduction in average 24-hour ambulatory systolic blood pressure at eight weeks post randomisation. First results may be obtained in the first half of 2016.
According to Boston Scientific, the Vessix system is a differentiated and advanced renal denervation system using a multielectrode bipolar catheter designed to reduce procedural variability. It features a 30-second treatment time and an over-the-wire, balloon-based approach familiar to most cardiac and vascular specialists.
“Previous results of renal denervation studies have been affected by a focus on patients with the difficult-to-define condition of treatment-resistant hypertension, made even more complex by uncertainties regarding their use of hypertension medications,” says Michael Weber, co-principal investigator, SUNY Downstate College of Medicine, New York, USA. “We need to find clarity, and we believe this innovative study design will enable us to do so.”