Elsevier

American Heart Journal

Volume 195, January 2018, Pages 115-129
American Heart Journal

Trial Design
A multinational clinical approach to assessing the effectiveness of catheter-based ultrasound renal denervation: The RADIANCE-HTN and REQUIRE clinical study designs

https://doi.org/10.1016/j.ahj.2017.09.006Get rights and content

Catheter-based renal denervation is a new approach to treat hypertension via modulation of the renal sympathetic nerves. Although nonrandomized and small, open-label randomized studies resulted in significant reductions in office blood pressure 6 months after renal denervation with monopolar radiofrequency catheters, the first prospective, randomized, sham-controlled study (Symplicity HTN-3) failed to meet its blood pressure efficacy end point. New clinical trials with new catheters have since been designed to address the limitations of earlier studies. Accordingly, the RADIANCE-HTN and REQUIRE studies are multicenter, blinded, randomized, sham-controlled trials designed to assess the blood pressure–lowering efficacy of the ultrasound-based renal denervation system (Paradise) in patients with established hypertension either on or off antihypertensive medications, is designed to evaluate patients in 2 cohorts—SOLO and TRIO, in the United States and Europe. The SOLO cohort includes patients with essential hypertension, at low cardiovascular risk, and either controlled on 1 to 2 antihypertensive medications or uncontrolled on 0 to 2 antihypertensive medications. Patients undergo a 4-week medication washout period before randomization to renal denervation (treatment) or renal angiogram (sham). The TRIO cohort includes patients with hypertension resistant to at least 3 antihypertensive drugs including a diuretic. Patients will be stabilized on a single-pill, triple-antihypertensive-drug combination for 4 weeks before randomization to treatment or sham. Reduction in daytime ambulatory systolic blood pressure (primary end point) will be assessed at 2 months in both cohorts. A predefined medication escalation protocol, as needed for blood pressure control, is implemented between 2 and 6 months in both cohorts by a study staff member blinded to the randomization process. At 6 months, daytime ambulatory blood pressure and antihypertensive treatment score will be assessed. REQUIRE is designed to evaluate patients with resistant hypertension on standard of care medication in Japan and Korea. Reduction in 24-hour ambulatory systolic blood pressure will be assessed at 3 months (primary end point). Both studies are enrolling patients, and their results are expected in 2018.

Section snippets

The Paradise Renal Denervation System

The Paradise Renal Denervation System is a catheter-based system that delivers ultrasound energy circumferentially to thermally ablate the renal sympathetic nerves. It includes a single-use 6F catheter and an automated, portable, customized generator. The catheter consists of a through-lumen shaft with a cylindrical piezoelectric ceramic transducer located at the distal end of the catheter. The catheter has a distal balloon, which is pressurized by the generator to a range of 1.5 to 2.0 atm

Nonclinical evaluation of the Paradise system

The Paradise System dose settings were selected based on computer simulations and an ex vivo thermal gel model, and subsequently confirmed in a normotensive porcine model to achieve a target circumferential ablation of the renal sympathetic nerves, which run in a plexus at varying depths of 1 to 6 mm in the periadventitia region. Circumferential lesions with marked renal nerve injury of nerve bundles of varying sizes are induced at each ablation site. These lesions are associated with marked

Clinical evaluation of the Paradise System

The preliminary safety and BP-lowering efficacy of the Paradise System have been evaluated in a total of 131 patients with RHTN in single-arm observational studies (first in human feasibility REDUCE study, n = 15 patients35; REALISE, n = 20 patients, ClinicalTrials.gov identifier NCT01529372; ACHIEVE, n = 96 patients, ClinicalTrials.gov identifier NCT01789918). A clinically significant reduction in both office and 24-hour ASBP was observed 6 months after RDN in all 3 clinical studies (data on file).

RADIANCE-HTN and REQUIRE clinical study designs

The RADIANCE-HTN (ClinicalTrials.gov identifier NCT02649426) and REQUIRE (ClinicalTrials.gov identifier NCT02918305) clinical studies are designed to assess the BP-lowering efficacy of the Paradise Renal Denervation System in adult patients with hypertension in the United States, Europe, Japan, and Korea. These studies are funded by Otsuka Holdings Co, Ltd, and ReCor Medical, Inc. Leslie Coleman, DVM, MS, DACLAM, an employee of ReCor Medical, helped with the writing, editing, and formatting of

RADIANCE-HTN

RADIANCE-HTN is a multicenter, randomized, double-blind, sham-controlled, 2-cohort (off-medication SOLO cohort and on-medication TRIO cohort, see below) superiority trial conducted in the United States (22 centers) and in Europe (17 centers in France, Germany, the Netherlands, and United Kingdom) (Figure 1).

The primary objective of the study is to evaluate whether renal denervation with the Paradise System can significantly and safely reduce daytime ASBP at 2 months compared with a sham

REQUIRE

REQUIRE is a multicenter, randomized, double-blind, sham-controlled, superiority trial designed to demonstrate the safety and BP-lowering effectiveness of the Paradise Renal Denervation System in patients with RHTN in Japan and Korea (Figure 2). The primary end point of the study will be the reduction in 24-hour ASBP from baseline to 3 months. Hypothesizing a 6-mm Hg treatment effect (lowering) of renal denervation with an SD of 12 mm Hg, the number of patients required to detect a difference

Renal denervation procedure

A consistent renal denervation procedure will be used for all subjects enrolled in the RADIANCE-HTN and REQUIRE studies. Two to 4 circumferential ultrasound emissions of 7-second duration will be delivered within the main renal artery bilaterally. At least one emission will be delivered proximal to radiographically visible side branches. At least one emission will be delivered within accessory arteries ≥4 mm diameter (Figure 3).

Discussion

The RADIANCE-HTN and REQUIRE clinical studies are designed to evaluate the potential effectiveness of ultrasound-based renal denervation with the Paradise System in patients with essential hypertension, either resistant or not, and either treated or not treated with concomitant antihypertensive drugs. The RADIANCE-HTN and REQUIRE studies were designed to be parallel, although with differences in subject populations, ambulatory BP inclusion criteria, primary end point, and use of a predefined

Funding

The RADIANCE-HTN study is funded by ReCor Medical, Inc. The REQUIRE study is funded by JIMRO Co, Ltd.

Author contributions

Study concept and design: Drs Mauri, Kario, and Azizi

Drafting of the manuscript: Drs Mauri, Kario, and Azizi

Critical revision of the manuscript for important intellectual content: Drs Mauri, Kario, Basile, Daemen, Davies, Francis, Kirtane, Mahfoud, Schemieder, Weber, Nanto, and Azizi

Disclosure

Dr Mauri reports grants to institution from Amgen, Abbott, Boston Scientific, Boehringer Ingelheim, Biotronik, and Corvia, and consulting fees from Amgen, Eli Lilly, St. Jude Medical, ReCor, and Corvia. Dr Kario reports grants from Teijin Pharma Limited, Omron Helthcare Co, Ltd, FUKUDA DENSHI, Bayer Yakuhin Ltd, A&D Co, Ltd, Daiichi Sankyo Company, Ltd, Mochida Pharmaceutical Co, Ltd, EA pharma, Otsuka Pharmaceutical Co, Ltd, Boehringer Ingelheim Japan Inc, Mitsubishi Tanabe Pharma Corporation,

Acknowledgments

Leslie Coleman, DVM, MS, DACLAM, an employee of ReCor Medical, helped with the writing, editing, and formatting of this article. She was compensated by ReCor Medical for her work.

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