Third line therapies for refractory overactive bladder (OAB) undertreat patients with only 5% progressing to these invasive and/or burdensome options. A novel leadless, fully-implantable tibial nerve stimulator has unique attributes compared to current OAB treatments including a brief reproducible implant procedure using only local anesthetic and automated compliance not dependent on patient management of a remote or interval recharge. This pivotal study evaluated the safety and efficacy of the device (eCoin®) for the treatment of OAB with urgency urinary incontinence (UUI). This report focuses on the primary endpoint results after 48 weeks of therapy.

This was a prospective, multi-center, single-arm trial carried out at 15 US medical centers to evaluate treatment of refractory UUI. All subjects were intolerant of, or showed an inadequate response to, at least one 2nd or 3rd line therapy prior to enrollment. Key exclusion criteria included predominant stress urinary incontinence, neurogenic lower urinary tract dysfunction, bladder pain syndrome, chronic venous insufficiency with skin changes or pitting edema of 2+ near the ankle, clinically significant peripheral neuropathy, and varicosities in the lower leg.
 
The coin-sized, leadless device, composed of radially symmetric electrode material lining the rim and bottom center, emits a dome-shaped electrical field with a wide radius. It is implanted subcutaneously in the medial lower leg above the fascia under local anesthetic, not needing imaging nor interrogation of the device.  After a short healing period, it is activated by a trained field clinical engineer and delivers automated 30-minute therapy sessions every 3-4 days. 
Follow up visits occurred 4, 8, 12, 24, and 48 weeks post-activation and included the collection of a 3-day voiding diary, Overactive Bladder Questionnaire (OABq), Patient Global Impression of Improvement in Incontinence (PGI-I), satisfaction questionnaires, and assessment of any adverse events. The primary efficacy measure was the proportion of subjects who achieved a 50% or greater reduction from baseline in UUI episodes after 48 weeks of therapy. The primary safety endpoint was device-related adverse events from implantation to 52 weeks after implantation.

The study enrolled 137 subjects from August 2018 to April 2019. Of these, 133 (97%) were implanted with the device and 4 discontinued prior to implantation. No exclusions were based on a screening test or trial procedure. Of the implanted subjects, 132 were included in the ITT analysis population; one subject with a UUI baseline value of 0 was excluded. In the ITT population, 98% were female, mean (SD) age was 63.9 (10.9), and mean (SD) baseline UUI daily episodes was 4.3 (3.1). The treatment history demonstrates subjects reported a mean 11-year history of OAB and failing at least one alternative treatment. The mean implantation time from incision to final suture was 19.8 (SD 14.3) minutes. 

The primary efficacy analysis showed 68% (95% CI: 60%, 76%) of subjects experienced at least a 50% reduction in UUI episodes at 48-weeks post-activation. At the same time point, 43% (95% CI:34%, 52%) reduced their UUI episodes by at least 75% and 21% (95% CI:14%, 28%) experienced complete continence. Figure 1 shows the average UUI episodes per day over the course of the study.

In patient-reported outcomes, results from the OABq indicate the symptom bother scale was reduced by an average of 34.2 (SD 27.5) points, and the HRQoL scale was improved by an average of 34.5 (SD 25.9) points at 48 weeks. The average score on the PGI-I at 48 weeks was 2.3 (SD 1.4), which falls between “much better” and “better” as compared to urinary leakage before treatment. See Figure 2 for PGI-I response distribution.

In an end of study questionnaire, 97% of patients said the procedure was explained adequately to them, 89% of patients said they would recommend eCoin to friends and family and 93% of patients would go through the procedure again in five years.

On average, subjects had a permanent implant for 50.7 weeks. Sixteen percent (16%) of implanted subjects experienced device-related events through 52 weeks after implantation, mostly consisting of mild to moderate wound healing or device stimulation events managed non acutely. One subject had a related serious adverse event resolved by uneventful explant at a hospital.

In this study, 68% of patients achieved at least a 50% reduction from baseline in the number of UUI episodes and the study exceeded it’s primary efficacy endpoint by nearly 20 points, showing strong evidence of benefit. Burden on quality of life was alleviated, with all patient-reported outcomes demonstrating considerable improvement. The benign safety profile is in line with typical neuromodulation devices where infection and stimulation discomfort are the expected adverse events—all occurring in this study at anticipated rates.

The study proved subcutaneous implantation of the eCoin device is performed well with minimal resources, aftercare compliance in the lower leg is achievable, and management of the device post-implant is relatively seamless with no direct patient involvement such as operating a remote or recharge requirement. The intimate brief procedure is modest and requires minimal preparation allowing for an efficient workflow once commercially available. The 15 investigators previously naïve to the procedure delivered safe and highly effective UUI therapy without reliance on a trial or screening test. The durable results may stem from minimal patient compliance requirements and a form factor that allows for consistent automatic intermittent stimulation of the tibial nerve. This novel OAB therapy is well tolerated, reproducible amongst even inexperienced surgeons with no patient management required. Most importantly, the therapy is highly appealing to patients who report an excellent experience with this novel option. Potentially, the eCoin device will greatly treat more OAB patients by eliminating many of the barriers which reduce progression to current third-line therapies often compromised by poor adherence.