Trial DesignA multinational clinical approach to assessing the effectiveness of catheter-based ultrasound renal denervation: The RADIANCE-HTN and REQUIRE clinical study designs
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.
References (41)
- et al.
Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension Interactive Forum held in Bethesda, MD, USA, October 10th 2013
J Am Soc Hypertens
(2014) - et al.
Effect of thoracolumbar sympathectomy on the clinical course of primary (essential) hypertension. A ten-year study of 100 sympthectomized patients compared with individually matched symptomatically treated control subjects
Am J Med
(1960) - et al.
Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study
Lancet
(2009) Illusions of truths in the Symplicity HTN-3 Trial: generic design strengths but neuroscience failings
J Am Soc Hypertens
(2014)- et al.
Is the failure of Symplicity HTN-3 trial to meet its efficacy endpoint the “end of the road” for renal denervation?
J Am Soc Hypertens
(2015) - et al.
Renal denervation therapy for hypertension: pathways for moving development forward
J Am Soc Hypertens
(2015) - et al.
Assessment of blinding in clinical trials
Control Clin Trials
(2004) - et al.
Blood pressure in adulthood and life expectancy with cardiovascular disease in men and women. Life course analysis
Hypertension
(2005) - et al.
Blood pressure reduction and cardiovascular prevention; an update including the 2003-2004 secondary prevention trials
Hypertens Res
(2005) - et al.
Management of hypertension with fixed dose triple combination treatments
Ther Adv Cardiovasc Dis
(2013)
The epidemiology of blood pressure and its worldwide management
Circ Res
Epidemiology of hypertension in Japan. Where are we now?
Circ J
Medication adherence in cardiovascular disease
Circulation
Measuring, analyzing and managing drug adherence in resistant hypertension
Hypertension
2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)
Eur Heart J
Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research
Circulation
Updated ESH position paper on interventional therapy of resistant hypertension
EuroIntervention
Sympathetic activation in the pathogenesis of hypertension and progression of organ damage
Hypertension
Interactions between the sympathetic nervous system and the kidneys in arterial hypertension
Cardiovasc Res
Sympathetic augmentation in hypertension. Role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation
Hypertension
Cited by (56)
Device's design and clinical perspectives for resistant hypertension therapy
2024, International Journal of Cardiology: Cardiovascular Risk and PreventionRenal Sympathetic Denervation for Hypertension
2022, Kidney International ReportsRenal Denervation: A Review
2022, American Journal of Kidney DiseasesCitation Excerpt :In addition, assumptions about the nerves in the kidney perivascular space were also revisited, and the technique for the RFA approach now includes the main renal artery and branches with lumen sizes of ≥3 mm, as well as suitable accessory arteries.21 The ultrasound and injection techniques remain focused on the main renal artery.22,23 We will cover efficacy in several domains.
Renal Artery Variations in Patients With Mild-to-Moderate Hypertension From the RADIANCE-HTN SOLO Trial
2022, Cardiovascular Revascularization MedicineUltrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial
2021, The LancetCitation Excerpt :Indeed, the SYMPLICITY HTN-3 trial reported 84 (16%) major cardiovascular and cerebrovascular events among 535 randomly assigned patients with resistant hypertension, including three deaths, during a short follow-up of 6 months.3 This is the main reason why an escape antihypertensive treatment could be prescribed in our study if blood pressure exceeded a specified threshold within the 2-month study period, and a standardised drug titration protocol was to be started in both groups while maintaining masking if blood pressure remained uncontrolled from the second month onwards.10 The RADIANCE-HTN TRIO trial is continuing with a 3-year follow-up to assess longer-term safety and efficacy.
The current status of renal denervation for the treatment of arterial hypertension
2021, Progress in Cardiovascular Diseases
RCT Nos. NCT02649426 and NCT02918305