Non-invasive Saphenous Nerve Stimulation Therapy for Overactive Bladder

Non-invasive Saphenous Nerve Stimulation Therapy for Overactive Bladder: A Randomized Controlled Trial (NOVASTIM)

The goal of this clinical trial is to study the NiNA System and how it works to treat overactive bladder. Up to 290 participants will be enrolled in the study in the USA and Australia.

The investigational NiNA System includes a wearable neurostimulator device ("NiNA" or "Device"), a flexible wrap to secure the Device to the calf during treatment of the saphenous nerve (SAFN), with smartphone-based control application with patient support features that allow users to control the stimulation therapy and receive reminder on days they are supposed to provide therapy ("NiNA App") or an enhanced smartphone-based control application which also has patient support features and educational multi-media content ("NiNA Care App").

The main questions the study aims to answer are: 1) How does the NiNA system compare to a common overactive bladder (OAB) medication; 2) How well does the NiNA system improve overactive bladder symptoms; and, 3) Does the NiNA system produce any unwanted side-effects.

In the study half the participants randomly receive the NiNA system and the other half first receive the OAB medication and later are treated with the NiNA System.

The Participants in the investigative Device arm (NiNA) will:

Provide NiNA system treatments very day for 30 minutes during a 28 day induction/restore period. This is followed by maintenance treatments (30 minutes, 3-times a week) until 12 weeks, when the primary endpoint data are measured. Participants continue maintenance (30 minutes, 3-times a week) for the remaining 52 weeks of the study.

Participants in the OAB medication arm will:

Take a capsule every day (tolterodine tartrate extended release (ER) 4 mg) for twelve weeks.

At 12 weeks, OAB medication arm Participants will stop taking the OAB medication and cross-over to treatment with the NiNA system. One-third of the cross-over Participants will be use a phone-based software application that allows them to control the neurostimulator and receive reminders on days the are scheduled to provide their therapy (NiNA App) and the other two-thirds of the cross-over Participants will use a phone based software application that also contains educational videos that reinforce the therapy (NiNA Care App). Assignment to each arm is random.

The study will measure primary and secondary endpoints completely remotely using digital questionnaires that are presented to Participants on a specialized software application installed on their phones ("Study App"):

Changes in OAB symptoms at a defined set of time points using the following instruments:

1. Bladder diary (3-day, consecutive);
2. Self-administered and validated Quality-of-Life questionnaires (see Effectiveness Assessments);
3. Additional assessments of participant satisfaction and preferences will be obtained using participant study surveys and questionnaires at defined study time points.

Inclusion Criteria:

1. 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
2. Self-reported symptoms of OAB for at least 6 months
3. Self-reported to be able to read and understand English sufficiently to provide informed consent
4. Have the required language, cognitive and physical capabilities to comply with study requirements per study investigator or delegate
5. Urinary frequency (eight or more micturitions per 24 hours)
6. 3 - 27 episodes of UUI demonstrated on a consecutive 3-day bladder diary
7. No pharmacological treatment of OAB for 2 weeks prior to screening
8. Demonstrates a positive nerve recruitment test in at least one leg
9. 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:

1. Unable to ambulate independently.
2. Has indwelling urinary catheter or requires intermittent catheterization.
3. Any current or prior use of tolterodine (any formulation)
4. Currently treated with any azole antifungals (e.g., ketoconazole, itraconazole, miconazole), macrolide antibiotics (erythromycin, clarithromycin), cyclosporine or vinblastine.
5. Previously treated with advanced therapy treatment options for OAB including botulinum toxin injections, sacral neuromodulation, percutaneous tibial nerve stimulation or surgery.
6. Has an active implantable device such as a pacemaker, implantable cardioverter-defibrillator (ICD), implanted neurostimulator.
7. Has bilateral knee or tibial plateau implants.
8. Treatment with advanced therapy options for stress urinary incontinence (SUI) including incontinence slings, surgery and urethral bulking within the previous 12 months
9. Has an artificial urinary sphincter implant.
10. Has previously participated in any OAB clinical research.
11. Past or current history of clinically significant bladder outlet obstruction or urinary retention.
12. Past or current history of gastric retention, narrow-angle glaucoma, or significant reduction in renal or liver function.
13. 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.
14. Has more than 3 occurrences of nocturia per night, on average, based on the 3-day bladder diary at baseline.
15. Neurogenic lower urinary tract dysfunction as determined by medical history.
16. Unable to comply with the study protocol including inability to utilize smart phone technology ("app" use).
17. Unable to place and use the investigational device and use supporting software per study personnel.
18. Exhibits neurologic deficit secondary to neurologic disease or injury that could impact either saphenous nerve or pelvic floor function, per study investigator.
19. Has inadequate skin integrity or any evidence of an infection or inflammation in both legs within the target treatment area per study investigator.
20. Has significant scarring on both legs around the treatment sites from prior surgery or injury, per study investigator.
21. Has significant skin condition, peripheral neuropathy or clinically significant edema that, in the opinion of the investigator, would interfere with transcutaneous saphenous nerve stimulation.
22. History of recurrent urinary tract infections (two or more within 6 months or 3 in one year).
23. Untreated urinary tract infection at the time of screening assessment.
24. Has clinically significant abnormalities on the urine dipstick test or per the discretion of the study investigator.
25. Is or could be pregnant or breastfeeding based on self-report or a urine pregnancy test.
26. Self-reports clinically significant and untreated pelvic organ prolapse that protrudes beyond the vaginal introitus.
27. Displays polyuria with a daily urine output > 3000 ml/day per participant's baseline frequency-volume chart at screening.
28. Self-reports significant lower urinary tract pain or diagnosis of interstitial cystitis/bladder pain syndrome.
29. Has a self-reported history of lower urinary tract cancers of any etiology, active pelvic cancer diagnosis or radiation therapy of the pelvic area.
30. Experiences uncontrolled diabetes that would impact study enrollment or completion, in the opinion of the investigator.
31. Cannot tolerate 30 minutes of stimulation above saphenous nerve recruitment thresholds.
32. 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