Medtronic PLC is hoping to use lessons learned from the SYMPLICITY HTN-3 trial, which failed to meet its primary endpoint, in a planned study of its second-generation Symplicity Spyral renal denervation system that it will submit for FDA review soon.

“We remain confident in our leadership in this field. Since the results of [SYMPLICITY] HTN-3, we have analyzed confounding factors of that trial, performed groundbreaking pre-clinical research, and engaged numerous expert clinicians and stakeholders,” Medtronic CEO Omar Ishrak said during the company’s fiscal third-quarter 2015 earnings call on Feb. 17.

The company plans to formally submit an investigational device exemption to FDA for a new global renal denervation clinical trial, Ishrak said. He noted that Medtronic will offer more detail on the trial over the next few weeks.

Medtronic’s announcement comes about two weeks after Boston Scientific Corp. disclosed plans to evaluate its Vessix renal denervation system in the new REDUCE-HTN REINFORCE trial, which is “designed to isolate the effects of our Vessix renal denervation system while minimizing the impact of multiple medications and patient compliance that occurred in other trials,” Boston Scientific CEO Michael F. Mahoney said during the company’s fourth-quarter 2014 earnings call on Feb. 4.

FDA recently granted an IDE for REDUCE-HTN REINFORCE and the company expects it to begin enrolling patients in the first half of 2015

Controlling Confounders

Using a catheter to ablate the renal nerves showed promise as a treatment for severe hypertension in several single-arm trials. But SYMPLICITY HTN-3, the first major sham-controlled trial of renal denervation in patients with uncontrolled hypertension, found that treatment with the first-generation Symplicity did not significantly improve systolic blood pressure compared to the sham. Patients enrolled in the trial had a systolic blood pressure of more than 160 mmHg despite taking at least three anti-hypertensive medications including a diuretic. (See [A#01140407009].)

Since the results were announced last Spring, Medtronic, Boston Scientific and other companies developing renal denervation systems, including St. Jude Medical Inc. (EnligTHN) and Johnson & Johnson/Cordis Corp. (Renlane) have been working with FDA and hypertension experts to understand why the technique failed to show benefit in SYMPLICITY HTN-3 and if new trial designs could help. (See [A#01140728009].)

As a result of those discussions, “we know what we want to do with the next IDE study, and we will see if we can come to agreement with the agency on moving forward on it,” Medtronic Cardiac and Vascular Group President Michael Coyle said during the earnings call.

This new trial will be “a lot different,” from SYMPLICITY HTN-3, Coyle said. The trial will use the Symplicity Spyral device, which earned a CE mark in Europe in 2013. Unlike the single-electrode Symplicity system tested in SYMPLICITY HTN-3, Symplicity Spyral has four electrodes set in a spiral formation that can fire either simultaneously or sequentially, according to the company. (See Also see "Medtronic Marches Ahead In Renal Denervation; Announces Symplicity’s Inclusion In US Parallel Review Program" - Medtech Insight, 27 March, 2013..)

He added, “We will be actually ablating in a different location and with a different protocol [compared to previous trials]. A lot of work went into the study design itself, obviously to see if we could increase the treatment effect in the treatment arm [and] lower the effect in the control arm.”

The experts who have analyzed SYMPLICITY HTN-3 largely agree that future trials of renal denervation must do a better job controlling the anti-hypertensive medication regimens of the patients in the trial, in both the sham and treatment arms.

The variation in medication regimens among patients was “a very big problem in the SYMPLICITY HTN-3 study," William White, from the University of Connecticut Health Center in Farmington and former American Society for Hypertension president, told “The Gray Sheet” last July. "There were lots of people going on and off medications back and forth and a lot of contamination [of the data].

“We will be actually ablating in a different location and with a different protocol [compared to previous trials]," Medtronic's Michael Coyle said.

Medtronic has “been working with numerous experts in the field to identify what drug regimens and comparators should be used, and they will be meaningfully different in this proposed study than what we used before," Coyle emphasized.

"Obviously, we’re going to be trying to really tighten the variability that we saw in both the treatment and control arms, and we have a number of ideas in protocol to be able to deal with that.”

Boston Scientific is not revealing details of REDUCE-HTN REINFORCE yet, the firm gave similar signals during its recent earnings call that would it be designed to account for multiple factors that may not have been well addressed in SYMPLICITY HTN-3.

“There were lots of confounders as you know in the SIMPLICITY [HTN-3] trial and we feel we should pull out some of the obvious ones in relation to patient compliance, manipulation of medication, the length of the primary endpoint, and stability of the patient, as well as highlighting the performance of what we think is a differentiated product," said Keith Dawkins, the firm's Chief Medical Officer.

“We think this will be a very important scientific study not just for Boston Scientific and Vessix but actually for the field to justify the role of renal denervation in the treatment of difficult hypertension,” Dawkins said.

Renal Denervation Round 2: Medtronic, Boston Sci Move Ahead With Studies

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