Trial designsCatheter-based alcohol-mediated renal denervation for the treatment of uncontrolled hypertension: design of two sham-controlled, randomized, blinded trials in the absence (TARGET BP OFF-MED) and presence (TARGET BP I) of antihypertensive medications
Introduction
Hypertension is the leading global cause of death and disability1, yet the prevalence of treatment and control of blood pressure among hypertensive individuals has plateaued, if not modestly declined.2,3 The persistence of uncontrolled hypertension has therefore introduced the opportunity for device-based therapies as an alternative to conventional medication therapies. Catheter-based renal denervation (RDN) has been evaluated in patients with uncontrolled hypertension, both in the presence and absence of antihypertensive medications. Specifically, recent sham-controlled trials utilizing radio-frequency and ultrasound energy have demonstrated the blood pressure lowering efficacy and safety of these methods.4,5,6,7
Alcohol has been used as an agent to chemically ablate nerves in a variety of clinical indications, secondary to its neurolytic activity. Thus, making this approach attractive for RDN in hypertension.8,9,10,11,12,13,14 As a novel RDN method, the Peregrine System Infusion Catheter is delivered into the main and large accessory renal arteries under fluoroscopic guidance to ensure correct positioning. Alcohol is infused directly into the perivascular space (adventitia and periadventitial space) via three micro-needles supported by “guide tubes.” (see Figure 1). Such a method permits deep (up to 8 mm from the intimal surface) and circumferential delivery of alcohol to the perivascular space to allow reproducible renal sympathetic nerve denervation, which has been demonstrated in a porcine model.15,16
First-in-man and open-label clinical trials have demonstrated the clinical safety and feasibility of this chemical approach to RDN using the Peregrine Catheter.17,18 The safety profile of alcohol mediated RDN in these two studies was good with low incidence of adverse effects. Notably, the absence of nephrotoxic or systemic effects17 and absence of any periprocedural major vascular complications or major bleeding, acute kidney injury or death within 1 month of the RDN procedure in 43/45 (96%) of subjects.18 The prospective, single-arm, open-label, multicenter Peregrine Post-Market trial demonstrated that the injection of 0.6 mL of alcohol per artery can induce clinically meaningful reductions in 24-hour ambulatory and office blood pressure.18 The encouraging results from these initial clinical trials established the foundation for the ongoing TARGET BP I (NCT02910414) and TARGET BP OFF-MED (NCT03503773) trials. These two prospective, randomized, assessor-blinded, sham procedure-controlled, multicenter trials are designed to assess the efficacy and safety of alcohol-mediated RDN in uncontrolled hypertensive subjects either in the absence of antihypertensive medication (TARGET BP OFF-MED trial) or prescribed 2-5 antihypertensive medications (TARGET BP I trial). Moreover, the pivotal TARGET BP I trial will explore the impact of alcohol-mediated RDN on subject self-reported health status, including quality of life (QoL) and sleep behavior. Enrollment is closed in TARGET BP OFF-MED and ongoing in TARGET BP I, with primary endpoint results of the TARGET BP OFF-MED trial expected later in 2021 and for the TARGET BP I trial in 2023.
Section snippets
The peregrine system kit
The Peregrine System Kit is an investigational combination product, consisting of a device component, the Peregrine Catheter, and dehydrated alcohol, United States Pharmacopeia (USP), as the drug component. The mode of action and the design of the Peregrine Catheter have been described previously.15,17,19 Specifically, the Peregrine Catheter is designed to accommodate the typical range of renal artery diameters (4-7 mm) when deployed and intended to deliver alcohol to the perivascular area of
Discussion
The TARGET BP trials are the first randomized, blinded, sham-controlled trials to assess the safety and efficacy of chemical RDN using alcohol as the neurolytic agent. The TARGET BP OFF-MED trial aims to confirm the biologic proof of principle of alcohol-mediated RDN and will inform treatment of uncontrolled hypertension in the absence of antihypertensive medication. The TARGET BP I trial is intended to confirm the efficacy and safety of RDN with the Peregrine Kit among patients with
Conclusion
The TARGET BP trials are underway, with the TARGET BP OFF-MED trial now nearing the completion of randomization. Trial completion is expected in 2023 for TARGET BP OFF-MED and in 2024 for TARGET BP I. Together, these randomized, international clinical trials will provide important insights relevant to the safety and efficacy of chemical RDN with alcohol using the Peregrine Kit, as a means to treat hypertension.
Funding
The TARGET BP trials are funded by Ablative Solutions, Inc. F. Mahfoud is supported by Deutsche Gesellschaft für Kardiologie (DGK), and Deutsche Forschungsgemeinschaft (SFB TRR219) and has received scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic and ReCor Medical. P. J. Blankestijn reports research support from ReCor Medical and Ablative Solutions, and advisory board fee from Medtronic. All payments were done to the institution.
A. Persu reports having
Disclosure
T. A. Fischell is an employee and shareholder in Ablative Solutions. H. Paris reports no conflict of interest. M. Weber reports investigator and consulting relationships with Ablative Solutions, Medtronic and ReCor Medical. R. E. Schmieder received consulting honoraria from Medtronic, ReCor Medical and Ablative Solutions. A. Pathak received speaker honoraria from Ablative Solutions, Medtronic and ReCor Medical, and is investigator for trials sponsored by Medtronic, ReCor Medical and Ablative
Acknowledgments
We would like to thank Nicole Haratani and Maurice Buchbinder for their contributions towards the conceptualization and methodology development of this clinical program. We thank Elke Beutels and Debbie Reynolds for her their valuable editorial support.
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