Non-invasive Saphenous Nerve Stimulation Therapy for Overactive Bladder

The objective of this study is to assess that Saphenous nerve (SAFN) stimulation with the NiNA System is at least non-inferior to the use of tolterodine tartrate 4 mg extended release (ER), taken daily in reducing the number of daily urgency urinary incontinence (UUI) episodes.

The investigational device is the NiNA System which includes a wearable neurostimulator device with a stimulation matrix having 6 conductive gel pads that allow patients to provide targeted neurostimulation by adjusting stimulation field geometry ("NiNA" or "Device"), a flexible wrap to secure the neurostimulator and stimulation matrix to the upper calf during treatment, and a smartphone-based control application with patient support features ("NiNA App") or an alternate smartphone-based control application with patient support features and educational content ("NiNA Care App").

The active control in the study is Tolterodine tartrate 4 mg capsules, extended-release (ER) capsules, taken daily, which are indicated for the treatment of individuals having OAB with symptoms of urinary incontinence, urgency, and frequency.

The study design is a Prospective, dual center, randomized, adaptive, decentralized trial of the NiNA System vs an active control.

The study will enroll up to 290 participants, based on an adaptive design with prospectively planned sample size re-estimation (SSR) when 50% of the minimal estimated total study cohort (i.e., 108 of 216 participants combined across the Investigational Device Group & Active Control Group) has achieved the primary endpoint of 12 weeks.

Participants will be randomized 1:1 to receive therapy using the investigational device (NiNA with NiNA App) or the active control. In the investigational device arm, participants will stimulate the SAFN for 30 minutes daily during a 28-day NiNA therapy induction phase and then for 30 minutes, 3-times a week during therapy maintenance which is provided beyond the induction phase, to maintain potential therapeutic benefit. Once the primary endpoint at 12 weeks is reached, investigational device arm Participants will continue with the maintenance phase therapy until the end of the study at 52 weeks.

In the active control arm, participants take tolterodine tartrate ER (4 mg), daily for 12 weeks. After 12 weeks, participants in this arm cross-over and are treated with the investigational device therapy. The cross-over group will be randomized 1:2 at the time of crossover to either:

• the investigational device (NiNA) and the NiNA App, that provides therapy reminders and allows user to control the Device; or,
• the investigational device (NiNA) and an app that additionally has multimedia educational content (NiNA Care App).

Upon crossover at 12 weeks, participants will immediately begin an induction stimulation schedule (30 minutes daily for 28 days) with no washout of the active control drug.

Following the 28-days induction phase, the post-crossover cohorts will transition to a maintenance schedule (30 minutes of stimulation for 3-days per-week) until the end of the study at 48 weeks.

Participant compliance and adherence with the NiNA therapy will be assessed at various study time points using the compliance and recordkeeping features associated with the investigational Device software app and a Study App.

Active control (tolterodine) compliance and adherence through the primary endpoint (12 weeks) will be assessed using standard digital clinical study measures such as a medication diary in the Study App.

Inclusion criteria

• Male and female nonhospitalized individuals, 18 years of age or older, who are ambulatory and able to use the NiNA device, cell-phone Apps, and toilet independently
• Self-reported symptoms of OAB for at least 6 months
• Self-reported to be able to read and understand English sufficiently to provide informed consent
• Have the required language, cognitive and physical capabilities to comply with study requirements per study investigator or delegate
• Urinary frequency (eight or more micturitions per 24 hours)
• 3 - 27 episodes of UUI demonstrated on a consecutive 3-day bladder diary
• No pharmacological treatment of OAB for 2 weeks prior to screening
• Demonstrates a positive nerve recruitment test in at least one leg
• Willing to utilize effective contraception for period of study if female of childbearing potential (e.g., complete abstinence, oral contraceptives, patch, barrier (diaphragm or condom), intrauterine contraceptive injection, intrauterine device or hormonal vaginal contraceptive ring)

Exclusion criteria

• Unable to ambulate independently.
• Has indwelling urinary catheter or requires intermittent catheterization.
• Any current or prior use of tolterodine (any formulation)
• Currently treated with any azole antifungals (e.g., ketoconazole, itraconazole, miconazole), macrolide antibiotics (erythromycin, clarithromycin), cyclosporine or vinblastine.
• Previously treated with advanced therapy treatment options for OAB including botulinum toxin injections, sacral neuromodulation, percutaneous tibial nerve stimulation or surgery.
• Has an active implantable device such as a pacemaker, implantable cardioverter-defibrillator (ICD), implanted neurostimulator.
• Has bilateral knee or tibial plateau implants.
• Treatment with advanced therapy options for stress urinary incontinence (SUI) including incontinence slings, surgery and urethral bulking within the previous 12 months
• Has an artificial urinary sphincter implant.
• Has previously participated in any OAB clinical research.
• Past or current history of clinically significant bladder outlet obstruction or urinary retention.
• Past or current history of gastric retention, narrow-angle glaucoma, or significant reduction in renal or liver function.
• Has primary stress urinary incontinence or mixed incontinence where the stress component is greater than one-third of the urgency urinary incontinence component based on the 3-day bladder diary at baseline.
• Has more than 3 occurrences of nocturia per night, on average, based on the 3-day bladder diary at baseline.
• Neurogenic lower urinary tract dysfunction as determined by medical history.
• Unable to comply with the study protocol including inability to utilize smart phone technology ("app" use).
• Unable to place and use the investigational device and use supporting software per study personnel.
• Exhibits neurologic deficit secondary to neurologic disease or injury that could impact either saphenous nerve or pelvic floor function, per study investigator.
• Has inadequate skin integrity or any evidence of an infection or inflammation in both legs within the target treatment area per study investigator.
• Has significant scarring on both legs around the treatment sites from prior surgery or injury, per study investigator.
• Has significant skin condition, peripheral neuropathy or clinically significant edema that, in the opinion of the investigator, would interfere with transcutaneous saphenous nerve stimulation.
• History of recurrent urinary tract infections (two or more within 6 months or 3 in one year).
• Untreated urinary tract infection at the time of screening assessment.
• Has clinically significant abnormalities on the urine dipstick test or per the discretion of the study investigator.
• Is or could be pregnant or breastfeeding based on self-report or a urine pregnancy test.
• Self-reports clinically significant and untreated pelvic organ prolapse that protrudes beyond the vaginal introitus.
• Displays polyuria with a daily urine output > 3000 ml/day per participant's baseline frequency-volume chart at screening.
• Self-reports significant lower urinary tract pain or diagnosis of interstitial cystitis/bladder pain syndrome.
• Has a self-reported history of lower urinary tract cancers of any etiology, active pelvic cancer diagnosis or radiation therapy of the pelvic area.
• Experiences uncontrolled diabetes that would impact study enrollment or completion, in the opinion of the investigator.
• Cannot tolerate 30 minutes of stimulation above saphenous nerve recruitment thresholds.
• Any conditions or issues that, in the opinion of the PI, may make the participant not be a good fit for trial and/or place them at high risk of not completing the study