Symplicity Bombshell as U.S. Pivotal Trial Fails to Meet Primary Efficacy Endpoint

Medtronic, Inc. has announced that its U.S. pivotal trial in renal denervation for treatment-resistant hypertension, SYMPLICITY HTN-3, has failed to meet its primary efficacy endpoint. The trial did however meet its primary safety endpoint, and the trial’s Data Safety Monitoring Board (DSMB) concluded that there were no safety concerns in the study.

Background

SYMPLICITY HTN-3 is the first blinded, randomized, controlled trial designed to evaluate the safety and effectiveness of renal denervation with the investigational Symplicity renal denervation system in patients with treatment-resistant hypertension and systolic blood pressure higher than 160 mmHg in the United States. That the study failed to meet its efficacy endpoints is little short of devastating for a therapy that has been touted as the biggest thing to happen in treatment of drug-resistant hypertension for years.

What’s fascinating is that this is the first sham-controlled trial, in which patients were assigned either treatment or no treatment, but were blinded to the therapy delivered, by all undergoing an interventional procedure. Previous studies have shown a ~30mmHg reduction in systolic blood pressure following treatment, and while the clinical data from HTN3 hasn’t been divulged at this time, it seems likely that either that headline figure has not been replicated or it has not proven significantly different to that delivered in the non treatment group.

Either way, it’s serious enough for Medtronic to announce that it will now set up a panel of independent advisors made up of physicians and researchers who will be asked to make recommendations about the future of the global hypertension clinical trial program, as well as provide advice on continued physician and patient access to the Symplicity technology in countries with regulatory approvals.

In the meantime the company says it will suspend enrollment in the three countries where renal denervation hypertension trials are being conducted for regulatory approvals (SYMPLICITY HTN-4 in the U.S., HTN-Japan and HTN-India). It will also inform clinical trial sites and investigators, global regulatory bodies, and customers of the study findings and its decisions, while continuing to ensure patient access to the Symplicity technology at the discretion of their physicians in markets where it is approved.

Medtronic says it will continue the global SYMPLICITY post-market surveillance registry and renal denervation studies evaluating other non-hypertension indications, and it will follow-up for all patients randomized in the trial will continue as planned out to five years.

Reassuringly the study met its safety endpoints, so patients already treated using the therapy are not at risk of adverse consequences.

One consequence that does now rear its ugly head is the financial one for Medtronic. The company says it will be evaluating the carrying value of the renal denervation assets and based on the above trial results, and may well incur a one-time impairment charge in the future will be likely.

Investigator comments

“SYMPLICITY HTN-3 met its primary safety endpoint related to the incidence of major adverse events one month following randomization and renal artery stenosis to six months,” said Deepak L. Bhatt, M.D., M.P.H., executive director, Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart and Vascular Center, professor of medicine, Harvard Medical School, and co-principal investigator of SYMPLICITY HTN-3. “Importantly, however, the trial did not meet its primary efficacy endpoint.”

George Bakris, M.D., professor of medicine and director of the ASH Comprehensive Hypertension Center at the University of Chicago Medicine, past-president of the American Society of Hypertension, and co-principal investigator of SYMPLICITY HTN-3 stated, “While it’s disappointing the trial did not meet its primary efficacy endpoint, this is the most rigorous renal denervation clinical trial conducted to date, and the first of its kind to include a sham-control group. We look forward to advancing these data into the peer-review process and will submit these findings for presentation and scientific discussion at an upcoming scientific congress.”

Company comments

“We are disappointed that the clinical trial failed to meet its primary efficacy endpoint,” said Dr. Rick Kuntz, chief medical officer, Medtronic. “We believe this course of action is the most prudent and will help us thoroughly evaluate these findings and determine the appropriate next steps for renal denervation therapy. We would like to thank the patients and investigators for their participation in the trial and their important contribution to the field of hypertension research.”

Source: Medtronic, Inc.

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