Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design

Abstract

Background: The SPYRAL HTN clinical trial program was initiated with two 80-patient pilot studies, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, which provided biological proof of principle that renal denervation has a blood pressure-lowering effect versus sham controls for subjects with uncontrolled hypertension in the absence or presence of antihypertensive medications, respectively.

Trial design: Two multicenter, prospective, randomized, sham-controlled trials have been designed to evaluate the safety and efficacy of catheter-based renal denervation for the reduction of blood pressure in subjects with hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) or presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications. The primary efficacy endpoint is baseline-adjusted change from baseline in 24-h ambulatory systolic blood pressure. The primary safety endpoint is incidence of major adverse events at 1 month after randomization (or 6 months in cases of new renal artery stenosis). Both trials utilize a Bayesian design to allow for prespecified interim analyses to take place, and thus, the final sample sizes are dependent on whether enrollment is stopped at the first or second interim analysis. SPYRAL HTN-OFF MED Pivotal will enroll up to 300 subjects and SPYRAL HTN-ON MED Expansion will enroll up to 221 subjects. A novel Bayesian power prior approach will leverage historical information from the pilot studies, with a degree of discounting determined by the level of agreement with data from the prospectively powered studies.

Conclusions: The Bayesian paradigm represents a novel and promising approach in device-based hypertension trials.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02439749 (SPYRAL HTN-OFF MED Pivotal) and NCT02439775 (SPYRAL HTN-ON MED Expansion).

Keywords: Blood pressure; Device-based statistics; Renal sympathetic nervous system; Sham; Trial design.

Conflict of interest statement

Prof. Böhm and Prof. Mahfoud are supported by the Deutsche Forschungsgemeinschaft (SFB, Aachen - Homburg, TRR 219, S01). Prof. Böhm: Consultant fees from Bayer AG, Abbott Vascular, Amgen, AstraZeneca, Boehringer Ingelheim, Servier, Medtronic, Vifor, and Novartis. Dr. Townsend: Consultant fees from Medtronic. Dr. Weber: consultant to Medtronic, ReCor, Ablative Solutions, Boston Scientific, Novartis, Bristol-Myers Squibb and Abbvie. Dr. Kandzari: Grant support from Medtronic, Boston Scientific Corporation, and Biotronik; and consultant fees from Medtronic, Biotronik, and CSI. Prof. Mahfoud: supported by Deutsche Hochdruckliga, Deutsche Gesellschaft für Kardiologie and Deutsche Forschungsgemeinschaft and has received speakers honoraria from Medtronic and ReCor. Prof Kario: Grant support from A & D, MSD K.K., Asteras Pharma, Otsuka Pharmaceutical, Otsuka holdings, Omron Healthcare, Sanwakagaku Kenkyusho, Daiichi Sankyo Co., Sumitomo, Dainippon pharma, Takeda Pharmaceutical, Teijin Pharma, Japan Boehringer Ingerheim, Pfizer, Fukuda lifetec, Dukuda Denshi, Bristol-Myers Squibb, Mocida Pharmaceutical and Roche Diagnostic; and consultant fees from Idorsia, Omron Healthcare, Daiichi Sankyo, and Terumo Medical Corporation. Prof Schmieder: Grant support from Medtronic, ReCor, and Ablative Solutions; and consultant fees from Medtronic and ReCor. Dr. Tsioufis: Grant support from St. Jude Medical and Recordatti; and consultant fees from Medtronic, Servier, Bayer AG, Menarini, Novartis, AstraZeneca, Boehringer Ingelheim, Pfizer, Chiesi, Pharmanel, Sanofi-Aventis, Amgen, and ELPEN. Dr. Hickey, Mr. Fahy, Ms. DeBruin, and Dr. Brar are full-time employees and shareholders of Medtronic. Prof. Pocock: Nothing to disclose.

Figures

Fig. 1

Subject flow through the SPYRAL HTN-OFF MED Pivotal (a) and SPYRAL HTN-ON MED Expansion (b) trials; ABPM ambulatory blood pressure monitor, DBP diastolic blood pressure, SBP systolic blood pressure

Fig. 1

Subject flow through the SPYRAL HTN-OFF MED Pivotal (a) and SPYRAL HTN-ON MED Expansion (b) trials; ABPM ambulatory blood pressure monitor, DBP diastolic blood pressure, SBP systolic blood pressure

Fig. 2

Diagrammatic illustration of the Bayesian discount prior methodology. Top panel: the prior data have similar outcomes to the current/pivotal data, meaning that nearly all information is utilized in the primary analysis. Middle panel: there is some overlap, meaning that the partial information is carried over into the primary analysis. Bottom panel: the outcomes are disparate, meaning that little-to-none data of the information from the prior are utilized for the primary analysis. Figure represents three hypothetical scenarios only