INTREPID: New DBS System for Parkinson's Meets Endpoints

NEW ORLEANS — A new multiple-source system for deep-brain stimulation (DBS) in patients with Parkinson's disease proved effective in the randomized, double-blind INTREPID trial, meeting its primary and many secondary endpoints.

The Vercise DBS System (Boston Scientific) was approved by the US Food and Drug Administration in December 2017. It has been used in Europe since 2012.

"Although DBS efficacy has been substantiated by several randomized controlled trials, the degree of improvement has varied significantly in these studies," Robert E. Gross, MD, PhD, from Emory University School of Medicine, Atlanta, Georgia, reported at the American Association of Neurological Surgeons (AANS) 2018 Annual Meeting.

"The results of the INTREPID trial demonstrate that the use of a multiple-source, constant-current DBS system is safe and effective in the treatment of Parkinson's disease symptoms," he said.

According to Boston Scientific, the Vercise implantable pulse generator (IPG) is the smallest rechargeable DBS device available in the United States and, depending on individual use, can have a battery life of more than 15 years. The multiple-source device has a proprietary capability that independently controls the amount of current delivered by each electrode on the implanted leads, which have eight contacts. The goal is more selective activation and a better-defined distribution of the current.

The INTREPID study assessed improvements in motor function and quality of life in persons with Parkinson's disease following bilateral subthalamic nucleus DBS using the new system.

The new DBS system has some "unique features," Gross said, including the following:

Multiple independent current-controlled sources designed to provide selective activation of specific contacts;
Electrode contacts that can be individually activated and increased in their intensity, as compared to the other contacts;
A lead design that includes the usual tight spacing but also a long span with eight contacts to increase flexibility;
Rechargeable battery, with a "small IPG footprint" and gentle contours; and
Wireless patient-user interface, which facilitates ease of use.

INTREPID was a multicenter, prospective, double-blind randomized controlled trial in which 160 patients, mean age 60 years and mean duration of disease 10 years, were implanted bilaterally in the subthalamic nucleus with the Vercise system.

Blinded participants were randomly assigned, 2 to 4 weeks later, to receive active (n = 121) or control (n = 39) settings for a 12-week period.

Patients were primarily male and had a mean Unified Parkinson's Disease Rating Scale (UPDRS) score of 43.4. That score improved to 18.5 with medication during the screening phase. Their mean "off" time was about 7 hours per day and mean "on" time with troublesome dyskinesia was 4.35 hours.

Blinded assessors measured improvements in motor function and quality of life by using a Parkinson's disease diary, UPDRS, Parkinson's Disease Questionnaire 39, and a battery of neuropsychological tests.

The primary outcome was difference in mean change from baseline to 12 weeks after randomization between the groups in mean number of waking hours per day with good symptom control and no troublesome dyskinesia with no increase in antiparkinsonian medications. This was determined by the patient diaries.

INTREPID differed from previous studies of other devices, Gross said, in that it was double-blind with a sham control (sham stimulation); patients' scores were assessed after implantation (the baseline), which controls for implantation effects; and increases in medications were not allowed — patients needing an increase had their change in "on" time marked as zero for the primary endpoint analysis.

Three More Hours of Quality "On" Time

The mean difference in "on" time was 3.03 ± 4.5 hours for active treatment vs sham (P < .001) when patients did not increase their antiparkinsonian medications as prespecified for the primary endpoint.

This was based on an average "on" time without troublesome dyskinesias of 12.37 hours for stimulation vs 8.96 for sham treatment at 12 weeks.

When the analysis was done allowing for this increase in medications, the difference between the groups was even greater at 3.71 ± 4.5 hours.

Table 1. Difference in Change From Baseline in "On" Time Without Troublesome Dyskinesias at 12 Weeks

Time Point	Active (n = 121) (h)	Control (n = 39) (h)
Baseline (after surgery)	7.78	8.08
Week 12	12.37	8.96
Change from baseline to week 12^a	3.74	0.72
Change from baseline to week 12 without medication rule	4.60	0.88
^aStudy's primary endpoint.

This study also met several secondary endpoints:

Change in UPDRS-III (motor) subscore in the stimulation-on/medication-off condition (P < .0001);
Change in Schwab & England scale (P < .0001);
Higher Mean Clinical Global Impression scores as assessed by patient (P < .0001) and physician (P = .0025); and
Better treatment satisfaction score at 12 weeks (P < .0001).

Additionally, at 52 weeks, in the open-label optimization phase, UPDRS motor scores improved by 49.2% from baseline (P < .001), and mean "on" time without troublesome dyskinesia increased by 6 hours (P < .001).

"As compared to four other clinical trials, we saw a greater amount of 'on' time improvement in this study," Gross said. "Notably, this is a double-blind evaluation, which none of the other four studies had."

There were 103 serious adverse events; no unanticipated adverse events; and 3 deaths unrelated to the device, the procedure, or the stimulation. Infections were the most common serious adverse event (4.7%), and intracranial hemorrhage occurred in 3 patients (1.6%).

"The overall safety profile of the Vercise System is comparable to other published reports," he said.

Welcome Addition, but Not "Earth-Shaking"

Aviva Abosch, MD, PhD, professor of neurosurgery at the University of Colorado Health Sciences, Denver, who was the study's formal discussant, called INTREPID a "carefully designed and well-executed" trial with the aim of evaluating a DBS system that is new to the US market in the setting of bilateral subthalamic DBS for Parkinson's disease.

She said is worth noting that the new system features a traditional concentric ring electrode design and not steerable current technology, and the study "did not allow patients the freedom to choose a nonrechargeable battery," all of which are device features currently available outside of the United States and to which US neurosurgeons would like to have access.

"Nonetheless, the study did meet its primary and secondary endpoints, and there were no unexpected adverse events. The rate of device and procedural serious adverse events was comparable to publications that have appeared in the literature for other manufacturers," she said.

"So there is nothing earth-shaking about these results," Abosch concluded, "but after two decades with only one DBS manufacturer available in the US, it's good for our patients and it's crucial moving forward in the field to have access to other devices."

The INTREPID trial was funded by Boston Scientific. Gross has consulted for Medtronic Abbott/SJMC, Neuropace, MRI interventions, Monteris, Zimmer Biomet, and Boston Scientific. Abosch has consulted for Medtronic and Alpha Omega.

American Association of Neurological Surgeons (AANS) 2018 Annual Meeting. Late-breaking abstract. Presented May 1, 2018.

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