First in man study of cavernous nerve neurostimulator for erectile function preservation

As background, since August 2023 we have implanted 10 men with an erectile nerve neurostimulator at the time of robot-assisted radical prostatectomy (RARP). The neurostimulator delivers immediate direct electrical stimulation to the cavernous nerves through electrode arrays placed bilaterally in the pelvis. This CaverSTIM™ device was designed by Comphya SA, Lausanne, Switzerland. The study aim was to evaluate the safety, tolerability, and effectiveness of this implanted neurostimulator at RP (ClinicalTrials.gov identifier: NCT05650866). In this first in man pilot study, 20 men (10 implanted and 10 controls) have been recruited. We have implanted 10 men, and we are gathering data on 10 matched controls. The 10 implanted men were all potent preoperatively, with a 15-item version of the International Index of Erectile Function (IIEF-15) score of ≥26 and diagnosed with clinically significant prostate cancer deemed suitable for RARP. We used a conventional retropubic RP surgery with nerve sparing where it was oncologically appropriate. Pre- and postoperatively we used multiple objective measures of erectile function, including IIEF-15 scoring and nocturnal RigiScan® (GoTop Medical, Minneapolis, MN, USA) monitoring, associated with regular timed clinic visits for assessment. Safety and tolerability was assessed by pain, intraoperative blood loss, infection or device removal. The IIEF-15 questionnaires were given to patients to complete when they attended study visits. Patients completed these without supervision. The implantable neurostimulator device (Fig. 1) involves 2 cm, bean-shaped, flexible flat patches containing 12 electrodes to ensure uniform distribution and optimal coverage of the cavernous nerves within the pelvic floor. The design was informed by previous intraoperative studies [1] demonstrating optimal intraoperative handling and coverage of the cavernous nerves. In these studies, at open RP the device was removed after trialling the electrostimulation effect. After ensuring meticulous haemostasis following prostatic removal (see Video S1), the arrays are positioned intraoperatively by suturing them to the levator ani muscle with 3-0 polyglactin 910 (Vicryl®; Ethicon Inc., Somerville, NJ, USA) suture. The prostate is removed, then the implant is placed, before vesico-urethral anastomosis. This technique is to ensure stable placement of the electrodes while accommodating the complex anatomy and maximising contact with the target nerves (Fig. 2). The implantable pulse generator (IPG) is implanted subcutaneously in the lower abdomen between the iliac crest and the umbilicus. The rationale for placement in this anatomical position of the cavernous nerves for erection is based on the work done by Costello et al. (2004) [2] on the course of the cavernous nerves at the apex of the prostate, which then swing from their position in the groove between the rectum and prostate to the mid-point of the urethra. Electrostimulation therapy began on postoperative Day 7 with daily 1-h sessions of low-intensity stimulation for nerve rehabilitation. This timing coincided with transurethral catheter removal, supporting an early start of low-intensity stimulation to optimise nerve regeneration and functional outcomes. Early stimulation is particularly effective because the milieu in the distal nerve stump is fluid and its capacity to support nerve regrowth is highly time dependent [3, 4]. On postoperative Day 21, standard-intensity stimulation for nerve activation was introduced and applied for 15 min daily. Patients adhered to this daily stimulation regimen throughout the 1-year study period. In this study, we evaluated safety and tolerability of chronic cavernous nerve stimulation after RARP, obtained the appropriate operative implantation steps during RARP, obtained preliminary data on effectiveness of cavernous nerve stimulation to evoke an erection satisfactory for sexual intercourse in the treatment of post-RP erectile dysfunction, and obtained preliminary data on the effectiveness of low-intensity stimulation to enhance recovery of natural erections. Baseline demographics and surgical data are described in Table 1. Full bilateral nerve sparing was performed in seven cases, with unilateral full and contralateral partial nerve sparing performed in three cases due to suspicion of extracapsular extension. Three patients had a positive margin, two patients had extracapsular extension, and one patient had seminal vesicle invasion. Length of stay was 1 day, and there were no clinically significant complications. The safety profile was favourable and well-tolerated. No patients reported pain at the IPG site. Two experienced mild, transient discomfort, one during running or due to belt pressure, and the other with torso movement or rotation. No device-related infections were observed. One patient developed a UTI related to prior prostatectomy, not associated with the device or its implantation. There were no device explantations, and all 10 patients retained their implants at the latest follow-up. Importantly, no other adverse events, including pain during stimulation or other device-related side effects, were reported. The implantation protocol did add 45 min to the procedure. One of the patients with a positive margin had a problematic PSA rise with an imaged local recurrence. He was sent for radiation and hormone therapy 3 months following surgery. Surprisingly he retained potency satisfactory for intercourse 4 months following radiation and hormone therapy. Nine patients are pad free and one patient is using one pad per day at Day 44. Most patients achieved an IIEF-15 score >22 points (Fig. S1). Two patients with an IIEF-15 score <15 at 90 days had it increase to >25 at 180 and 270 days, respectively. In general, the lowest IIEF-15 scores were observed at 90 days postoperatively (mean [sem] 20.1 [3.5] in eight patients), with subsequent improvement at 180 days (mean [sem] 21.6 [3.9] in seven), 270 days (mean [sem] 22.6 [4.5] in five), and 365 days (mean [sem] 28.5 [1.5] in two). The RigiScan measurements revealed remarkable maintenance of the nocturnal erection after surgery. A slight decline in nocturnal erectile activity was observed at 90 days, in accordance with the IIEF-15 results, and a continuous recovery was observed at 180 days, with measurements approaching baseline levels at the 1-year mark (percentage compared to the preoperative baseline: 90 days (mean [sem] 70.2% [15.2%] for the penile base, 55.7% [18.1%] for the penile tip in eight patients), 270 days (mean [sem] 67.6% [16.1%] for the base, 108.3% [3.8%] for the tip in four) and 1-year (mean [sem] 113.3% [31.2%] for the base, 96.1% [21.1%] for the tip in two). Seven of the 10 men, with a minimum follow-up of 6 weeks (6 weeks to 18 months for the group), implanted with the device have retained postoperative potency. Two experienced deteriorations then recovery, at 6 and 9 months respectively, and one has not yet had a satisfactory return of potency at last follow-up (9 months). It appears that potency is retained rather than lost as seven men were able to resume unaided sexual intercourse in the first few weeks following catheter removal. These outcomes were supported by the IIEF-15 scores and nocturnal RigiScan measurements. These patients have had no need to use erectile function aids such as phosphodiesterase type 5 inhibitors (PDE5i) or intracavernosal injections, although these were offered but declined in our postoperative erectile function rehabilitation clinic. Perineal RP was performed on 75 patients first described by Young [5] in 1905. The operation further improved after Walsh and Donker [6] described the course of the cavernous nerves. Further improvements have come with the advent of minimally invasive RARP. Since improvements in RARP techniques, the incontinence rates after RP requiring intervention are 5%. In high volume centres, 95% of men are now pad free after 3–6 months. Urologists can reasonably reassure their patients that they will likely not be troubled by incontinence in the longer term. There are multiple references in the literature to this metric. In practice now, we inform patients that we can keep them continent, and the 5% who require intervention usually require a sub-urethral sling, rather than previous with much worse incontinence, where artificial sphincters have been implanted. The major postoperative quality-of-life problem now for men undergoing RP is the high risk of postoperative erectile dysfunction. In major centres where the procedure is performed regularly and in technically excellent fashion, best outcomes for potency preservation following RP are ~30% [7]. Reports from single centres of potency outcomes following RP have been reported higher [8]. These higher potency outcome rates have not been able to be replicated in large multicentre multi-surgeon series [9]. Generally following RP, in men potent prior to surgery, there is an initial period (3–9 months) of loss of potency, most probably due to neuropraxia of the cavernous nerves. About a third of men will recover good functional potency, some needing enhancement with PDE5i or intracavernosal injections. Despite our surgical knowledge of the location of the neurovascular bundle, these parasympathetic nerves are invisible to the human eye. It appears injury to the parasympathetic neural pathways sometimes causes irreversible loss of erectile function. Nerve injury can occur by traction, diathermy, or simple cutting. Despite numerous suggested changes in technique to improve potency, erection recovery rates after RP remain stubbornly low. The initial proof of concept work performing intraoperative electrostimulation with a single electrode was reported by Lue and Burnett [10]. These studies demonstrated that with nerve electrostimulation with a single electrode it was possible to cause an erection. In 2018, Skoufias et al. [1], for proof of principle, placed the CaverSTIM device over the neurovascular bundle at the time of open RP in 20 men. Visual tumescence was observed in these patients during the operation. The device was removed, and the operation completed. In this report we have used multiple electrode arrays bilaterally, rather than single arrays, to cover most of the area of the cavernous nerves. Costello et al. [2] and Clarebrough et al. [11], using anatomical neural staining, reported there were between four and 16 of these erectile parasympathetic nerves bilaterally. Most surprising in our cohort of 10 men, in seven there was no, or otherwise minor, decline in erectile function, with preservation and maintenance of erectile function immediately following catheter removal after surgery. These patients were able to achieve sexual intercourse without additional aids such as PDE5i, vacuum devices, or intracavernosal injections. We remain uncertain of the exact mechanism whereby after neurostimulator insertion there is no decline in erectile function postoperatively and were surprised by the lack of decline in erectile function. If these results are maintained, the ability to avoid the serious quality of life side-effect of erectile dysfunction may positively affect decision-making for men offered surgery for prostate cancer. We realise that these results will need to be replicated in our planned controlled study of 250 men, commencing in 2026. This study was funded by Comphya Australia Pty Ltd, Melbourne, Australia. Anthony James Costello, Arthur L. Burnett, and Philip Ellard Dundee are members of the Clinical Advisory Board of Comphya SA, a medical device startup based in Lausanne, Switzerland. They serve in this capacity without remuneration and each hold minor share options in the company. Helen Rosemary Crowe and Michael Donald Cromer also hold minor share options in the company. Rodrigo Fraga-Silva, Nikos Stergiopulos, and Mikael Sturny are founders and shareholders of Comphya SA. Fiona Joseph is an employee of Comphya SA. Fig. S1. The IIEF-15 Erectile Function (EF) domain. Data show the IIEF-15 EF domain for each study participant, measured at baseline (preoperative) and at 44, 90, 180, 270, and 365 days after surgery. Day 0 represents the date of surgery. The dashed line indicates the threshold score of 22, marking the grey area that represents erectile function recovery data. Video S1. Insertion of CaverSTIM electrodes during RARP. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.