UPDATE: Sept. 6, 2019: CMS has signed off on LivaNova's proposed protocol for the 1,000-participant U.S. trial of its vagus nerve stimulation system in certain individuals with treatment-resistant depression. With the agency's go-ahead, LivaNova CEO Damien McDonald said in a statement the company is "ready to activate sites that will enroll patients."

Enrollment of up to 500 unipolar and up to 500 bipolar patients​ is likely to begin in late 2019 and will max out at 100 U.S. sites. The company noted in its announcement it has the potential to extend the randomized, placebo-controlled, double-blinded trial with at least one-year follow-up into a prospective longitudinal study.

The trial initiation follows CMS finalizing plans in February to cover the device for Medicare beneficiaries enrolled in the study through a coverage with evidence development (CED) framework. The CED model means CMS may offer coverage within the context of a clinical study only. CMS describes a CED cycle as "completed" when it removes study participation as a requirement to receive coverage.

Dive Brief:

• Details of LivaNova’s study needed to secure Medicare reimbursement for the company’s implanted vagus nerve stimulation (VNS) device for treatment-resistant depression (TRD) have been posted online at ClinicalTrials.gov.
• The trial’s control arm will be an inactive sham device, a fact that analysts at Jefferies predicted will boost the odds of the study being successful. Patients can often feel VNS when it is on, making true blinding difficult, the analysts said, and an inactive sham arm reduces the chance of a placebo effect.
• Called Recover, the trial is expected to begin enrollment July 31, with a target cohort of 1,000 participants, and will have a 12-month endpoint, according to the study description.

Dive Insight:

While FDA approved vagus nerve stimulation in 2005 to treat severe recurrent unipolar and bipolar depression, the Centers for Medicare and Medicaid Services in 2007 declined to cover the neuromodulation system. The government payer determined there was sufficient evidence to conclude that VMS is not reasonable and necessary for the treatment of resistant depression. Private insurance carriers routinely deny coverage of the treatment, despite FDA’s approval of the implant.

LivaNova has set out to change that. The London-based medtech manufacturer in late 2017 asked CMS to reconsider its decision. In February, CMS released a national coverage analysis memo that proposed expanding Medicare coverage to VNS for TRD, with the caveat that the device demonstrate improved health outcomes for patients in a double-blind, randomized study with a followup duration of at least one year.

The pacemaker-like device is implanted under the skin in the chest and programed to send electrical pulses along the vagus nerve to the brain. It was approved to control seizures in patients with drug-resistant epilepsy in 1994 in Europe and in 1997 in the United States. The system is also being studied to validate autonomic regulation therapy in heart failure patients.

LivaNova’s new clinical trial will evaluate whether VNS therapy is superior to no stimulation for reducing symptom severity based on multiple depression scale assessment tools at 12 months. After completing the 12-month endpoint, patients will transition into a five-year longitudinal portion of the study. Patients in the control arm will have their devices activated at that point.

Analysts at Jefferies project a 65% probability of success in the study, noting the trial listing indicates the company can move to a registry without enrolling all 1,000 patients if certain interim success measures are met. The analysts predict commercialization under a registry by the end of 2021, with a ramp to 34,000 implants by 2028.

LivaNova was formed in 2015 through the merger of Houston-based Cyberonics, developer of the VNS system, and Milan, Italy-based Sorin, a specialist in devices for open heart surgery, heart valve repair and replacement, and cardiac rhythm management.