What’s on the Horizon for Implantable Tibial Nerve Stimulation?
By: Ariana L. Smith, MD, FPMRS | Posted on: 01 Jun 2022
There is quite a bit of excitement in the field of implantable tibial nerve stimulation (ITNS) for the treatment of refractory overactive bladder (OAB). There are several new technologies in the pipeline and 1 device (eCoin®, Fig. 1) that recently received premarket approval from the U.S. Food and Drug Administration (FDA) on March 2, 2022.
Tibial nerve stimulation (TNS) for the treatment of OAB has been around for quite some time. Dr. Edward McGuire used Chinese acupuncture of the tibial nerve in 1983 and found that electrical stimulation of the posterior tibial nerve resulted in a decrease of bladder overactivity.1 This was met with initial skepticism, but today electrical stimulation of the tibial nerve is a scientifically proven treatment for OAB. The exact mechanism of action is unclear, but it is hypothesized that electrical impulses to the tibial nerve travel to the nerve roots at the lumbosacral plexus and modulate afferent and efferent fibers responsible for bladder function.2
So why all the recent interest in an implantable tibial nerve device? First of all, OAB affects millions of people worldwide with a large potential market for treatment,3 and neuromodulation is a widely accepted third-line therapy for OAB with sacral nerve stimulation (SNS) receiving FDA approval in 1997 and percutaneous tibial nerve stimulation (PTNS) in 2005. Second, TNS is simple and effective; a needle electrode is placed near the tibial nerve at the level of the medial malleolus and connected to a nerve stimulator that emits electrical pulses. Randomized controlled trials (RCTs) have established the evidence base and support for use of TNS for the treatment of OAB. SUmiT (Study of Urgent PC vs Sham Effectiveness in Treatment of Overactive Bladder Symptoms) enrolled 220 participants and found 54.5% in the PTNS group vs 20.9% in the sham group had moderately or markedly improved bladder symptoms at 13 weeks (p <0.01).4 An extension study found 77% of responders maintained therapeutic response at 3 years with an average of 1.1 PTNS sessions per month.5 OrBIT (Overactive Bladder Innovative Therapy Trial) compared PTNS to tolterodine; the study enrolled 100 participants and found 79.5% in the PTNS group vs 54.8% in the tolterodine group were cured or improved (p=0.01).6 However, the therapy schedule for PTNS is inconvenient, with 12, 30-minute weekly sessions, followed by monthly maintenance sessions. Desire for greater convenience has given the biotechnology companies something to work on. An implantable option would allow for home or on-the-go stimulation with the ability to personalize stimulation needs, tailoring both the frequency of therapy as well as the duration of stimulation with each session. It also opens the door to continuous TNS, much like SNS.
An implantable device to stimulate the tibial nerve (Urgent® SC) was first described by Van der Pal et al in 2006.7 Eight participants with OAB were implanted with an electromagnetic pulse receiver and 2 monopolar electrodes activated by an external generator. Initial feasibility data showed improvement in urinary parameters and quality of life. At 9 years, 7 patients remained with the device and 3 of the 4 who had successful treatment response at 1 year were still using it.8 At 18 years, 5 participants were contacted and none of them continued to use the device due to technical failure.9 None reported implantation site pain or migration of the device. Laborie has recently acquired this device, but it is unclear if they will advance the technology.
Several years went by before the next 6 devices were introduced. eCoin (electroceutical coin), made by Valencia Technologies, is a nickel-sized and -shaped, leadless, 3-year titanium battery. It is implanted in the office using local anesthetic in about 20–30 minutes. The device delivers automatic stimulation for 30 minutes twice weekly from the center cathode to the anode electrode at the outer edge. Amplitude can be adjusted with an external controller, and it does not require recharging. The 6-month feasibility data on 46 participants demonstrated 69.6% had reduction in urgency incontinence (UUI) episodes and more than 20.0% were completely dry.10 There was a 2.3% infection rate. At 12 months, 65% of participants were considered responders with 26% of participants achieving complete continence.11 The premarket approval of eCoin was based on results of a pivotal trial where 68% of participants (133, 98% female) experienced at least a 50% reduction in UUI episodes at 1 year, 81% responded that they felt “better” to “very much better” and 89% stated that they would recommend eCoin therapy to friends or family.12 Device-related adverse events occurred in 16% of participants. This device is not considered magnetic resonance imaging (MRI) safe.
BlueWind RENOVATM iStim is a cylindrical, batteryless, rechargeable system with an external control unit that delivers 30 minutes of stimulation 3–6 days per week (Fig. 2).13 There is a clinician programmer with the ability to remotely access the patient control unit. The OPTIMIST (Overactive Bladder Posterior Tibial Implantable MIcro STimulator) trial enrolled 36 participants (5 men, 31 women; mean age 54.1 years) and noted an operating time of 35 minutes to implant the device.14 At 6 months, 71% reached clinical success and 27.8% (34) were dry. Nearly half of the participants (47%) experienced site pain, suspected infection or wound complication, most of which resolved in 1–2 weeks, with 1 device removal and 1 participant withdrawal. At 3 years, of the 16 participants contacted, 75% has sustained symptom and quality of life improvement.15 There was no migration reported and only 1 participant underwent removal. A newer version of the iStim has been developed which uses an ultrasound-guided injection technique. This is anticipated to decrease site pain and wound-related complications. The OASIS (OverActive Bladder StImulation System Study) pivotal study is underway and anticipated to complete accrual of 200 participants by June 2022. This device is categorized as MRI conditional.
The Protect PNS™ system by Uro Medical Corporation is a percutaneous, implantable pulse generator that delivers stimulation for 6+ hours daily (Fig. 3). It is performed in the office using an injectable retrograde insertion technique. It is then secured to the dermis with a permanent suture distally to prevent proximal migration. A rechargeable external power source is worn around the ankle. The feasibility study included 7 participants and found a reduction in UUI episodes; 3 of the 7 participants reported sustained reduction in UUI episodes at 12 months. There were 5 adverse events including lead tenting, suture erosion and loss of stimulation. The PROTECT multicenter noninferiority RCT vs SNS completed accrual in October 2021 (200 patients).16 The primary endpoint is UUI episodes at 3 months, which means data should be available soon. The Guardian multicenter RCT vs medical management (600 patients) is underway. This device is currently under regulatory review for market approval by the FDA.
Figure 2. a, cylindrical Blue Wind RENOVA 3 cm stimulator implant and x-ray. b, patient wearable stimulator.
Figure 3. Protect PNS percutaneous implantable pulse generator. Image used by permission of Uro Medical.
Figure 4. Bioness StimRouter with lead, external pulse transmitter and patient programmer. Image used by permission of Bioventus.
Bioness StimRouter™ is an office-based, ultrasound-guided, implanted lead with an integrated receiver, anchor and 3 electrodes (Fig. 4). The 3 electrodes are to be placed in contact with the posterior tibial nerve.17 The external pulse transmitter and electrode patch is worn 30 minutes 3–7 days per week. The patient programmer tracks usage and controls the pulse transmitter. The multicenter pivotal RCT vs sham (180 patients) over 24 months is underway. This device is MRI conditional.
Nine Continents (acquired by Coloplast in 2020) also has a device for ITNS under development. It is a self-powered unit placed in the lower leg under local anesthesia that can provide diagnostic data via telemetry. No patient activation or recharging is necessary. The feasibility study enrolled 10 participants and followed them for 26 weeks; data are forthcoming. Coloplast aims to initiate the pivotal studies of the ITNS this year and obtain premarket approval in the U.S. and European Union market in the 2024–2025 time frame.
Medtronic also has an ITNS device under development. The TITAN 1 multicenter feasibility study completed accrual of 24 participants in August 2021, and results are expected to be available to the public in June 2022.18 I suspect they are promising because the TITAN 2 pivotal trial got the green light from the FDA and is currently underway with planned recruitment of 170 participants.19
With so much on the horizon, where will ITNS fit in the treatment algorithm for OAB? The Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction/AUA OAB Treatment Guideline (updated in 2019) includes PTNS as part of third-line therapy alongside SNS and botulinum toxin.20 It is unclear, however, if this guideline would be applicable to new technology utilizing the tibial nerve in an implantable fashion. Since the mechanism of action is the same as PTNS, inclusion in the guideline will likely depend on interpretation of the data from the pivotal trials.
ITNS is promising, with variable number of days and duration of stimulation possible and creating less burden on the patient. Long-term safety, efficacy and tolerability are unknown at this time but expected to be acceptable. With all the interest conveyed by the biotech companies, there is sure to be more to come on these technologies.