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. 2023 Aug 22;35:101198. doi: 10.1016/j.conctc.2023.101198

Rationale and design of an implant procedure and pivotal study to evaluate safety and effectiveness of Medtronic's tibial neuromodulation device

Una J Lee a,∗, Keith Xavier b, Kevin Benson c, Kimberly Burgess d, Janet E Harris-Hicks e,1, Robert Simon f, Jeffrey G Proctor g, Katie C Bittner h, Kira Q Stolen h, Chris P Irwin h, Sarah J Offutt h, Anne E Miller h, Elizabeth M Michaud h, Phillip C Falkner h, J Chris Coetzee i
PMCID: PMC10491630  PMID: 37691849

Abstract

Percutaneous tibial neuromodulation is a medical guideline recommended therapy for treating symptoms of overactive bladder. Stimulation is delivered to the tibial nerve via a thin needle placed percutaneously for 30 min once a week for 12-weeks, and monthly thereafter. Studies have shown that this therapy can effectively relieve symptoms of overactive bladder; however, the frequent office visits present a barrier to patients and can impact therapy effectiveness. To mitigate the burden of frequent clinic visits, small implantable devices are being developed to deliver tibial neuromodulation. These devices are implanted during a single minimally invasive procedure and deliver stimulation intermittently, similar to percutaneous tibial neuromodulation. Here, we describe the implant procedure and design of a pivotal study evaluating the safety and effectiveness for an implantable tibial neuromodulation device. The Evaluation of Implantable Tibial Neuromodulation (TITAN 2) pivotal study is a prospective, multicenter, investigational device exemption study being conducted at up to 30 sites in the United States and enrolling subjects with symptoms of overactive bladder.

Keywords: Overactive bladder, Neuromodulation, Tibial neuromodulation, Incontinence, Urinary, Lower urinary tract dysfunction

1. Introduction

Overactive bladder is a common, costly medical condition which impacts an estimated 43 million Americans, and has been shown to negatively impact quality of life [[1], [2], [3], [4]]. Implantable tibial neuromodulation therapy is designed to offer an alternative treatment option to patients with overactive bladder who are interested in and eligible for treatments beyond overactive bladder medications, fluid restriction, and behavioral modification. It is estimated that ∼70% of patients discontinue overactive bladder medication [5], yet fewer than 4% of overactive bladder patients receive FDA approved treatments beyond behavioral modifications and medications [6]. These data suggest an unmet need in overactive bladder patients. There is a large population of adult men and women of all ages who suffer from ongoing symptoms of overactive bladder – urgency, urinary frequency, urinary urge incontinence, and/or nocturia. In the overactive bladder population, there are many patients who have tried first- (fluid and behavioral modification) and second- (medication) line treatment options that have failed. Currently, third-line treatment options include sacral neuromodulation (SNM) which requires a multi-stage procedure typically under some form of anesthesia; chemo denervation of the bladder using onabotulinumtoxin A, which requires repeat injections and willingness to self-catheterize due to risk of urinary retention; and percutaneous tibial neuromodulation which requires weekly visits to the office for 3 months followed by approximately monthly visits[7]. An implantable tibial neuromodulation therapy adds an additional treatment option that is a single, minimally invasive implant procedure.

Tibial neuromodulation alleviates symptoms of overactive bladder by modulating tibial nerve activity via delivery of electrical pulses to the tibial nerve that runs posterior to the tibia and extends into the sacral plexus. Tibial neuromodulation has historically been delivered via a percutaneous approach using an acupuncture-like needle placed in the lower, inner aspect of either leg, cephalad to the medial malleolus. Percutaneous tibial neuromodulation therapy is a Food and Drug Administration (FDA) cleared in-office procedure and medical guideline indicated therapy [7] that is supported by clinical evidence [8] including two randomized controlled trials[9,10]. Efficacy of percutaneous tibial neuromodulation has been demonstrated to be superior to sham[9] and comparable to medications[10], and with a favorable safety profile. In a prospective study that had high adherence to therapy sessions, UUI responder rates have been shown to be as high as 78% after 12 sessions[11]. However, the available data suggest that outside of prospective clinical studies, real-world therapy adherence to the first 12 sessions varies and may be as low as 26%[12].

Implantable tibial neuromodulation therapy offers a promising alternative delivery method for an established treatment. The implantable device precludes the need for regular office visits for therapy delivery, making adherence to therapy more easily attainable. At this time, there is one FDA approved implantable tibial neuromodulation device which is the eCOIN device (Valencia Technologies, Valencia CA): a device implanted subcutaneously above the fascial layer in the lower leg. Data from the pivotal study support implantable tibial neuromodulation as a safe and effective treatment of urinary urge incontinence with a clinical success rate of 68%, a device and procedure related adverse event rate of 19%, and a 3% serious adverse event rate related to the device or procedure[13]. Three additional implantable tibial neuromodulation devices are currently in clinical trial and do not have published pivotal clinical study data: Protect PNS (Uro Medical, Boca Raton FL) is being studied in a randomized, controlled, non-inferiority clinical trial versus SNM in the treatment of urinary urgency and incontinence resulting from refractory OAB (NCT02577302); RENOVA IStim ™(BlueWind, Park City, UT) is being studied in a prospective, single arm study (Oasis, NCT03596671); and Intibia (Coloplast, Minneapolis MN) is being studied in a randomized therapeutic versus non-therapeutic trial where all subjects will eventually receive therapeutic stimulation (NCT05250908). All of these devices are designed to stimulate the tibial nerve, but at this time there is limited published information about the implant procedures for the implantable tibial neuromodulation devices under pivotal study investigation. At the time of acceptance of this manuscript, Bluewind Medical's implantable tibial neuromodulation system de novo request was granted by US FDA.

The Evaluation of Implantable Tibial Neuromodulation (TITAN 2) Pivotal Study was designed to evaluate the safety and effectiveness of Medtronic's implantable system that delivers tibial neuromodulation therapy. The TITAN 2 pivotal study is a prospective, multicenter, investigational device exemption study being conducted at up to 30 sites in the United States and enrolling subjects with symptoms of overactive bladder. The objective of this paper is to describe (1) the implantable tibial neuromodulation device implant procedure, (2) feasibility study design and results of the TITAN 1 feasibility study, and (3) the methodology of the TITAN 2 clinical trial including pivotal study design, participants, objectives, endpoints, and statistical analysis.

2. Methods

2.1. Tibial neuromodulation implant procedure

Medtronic's Implantable Tibial Neurostimulator is a leadless, implantable pulse generator that delivers electrical stimulation to the tibial nerve. Using local anesthetic, the device is implanted subcutaneously through an open approach in the lower leg on top of the deep fascia overlying the tibial nerve (Fig. 1). Landmarks are used to identify the incision location. A small incision is made and blunt dissection is used to create a pocket on top of the deep fascia overlying the nerve. After the appropriately sized subcutaneous pocket is created, the neurostimulator is inserted into the pocket. Fixation of the neurostimulator using the suture loop is optional prior to wound closure. Infection control, including antibiotic use, is advised per physician discretion and the associated institution's standard of care. The skin incision is closed with sutures and sterile dressings are applied. The patient is fitted and provided with a compressive ankle support to wear in the post-procedure recovery period following implant to allow for healing and to minimize device movement.

Fig. 1.

Fig. 1

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Implantable Tibial Neuromodulation Device Implant Location. Schematic drawing of a right ankle demonstrating implant location for the neurostimulator. Red lines indicate anterior edge of the Achilles and posterior edge of the Tibia. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

2.2. Feasibility study Design and results

Prior to designing the TITAN 2 study, Medtronic conducted feasibility work via the Evaluation of Implantable Tibial Neuromodulation (TITAN 1) feasibility study. TITAN 1 was a prospective, multicenter study that enrolled 24 subjects from 7 sites, 20 of whom were implanted with an investigational implantable tibial neuromodulation device. The primary objective of the TITAN 1 study was to characterize procedural learnings through 14-days post-implant using a series of questions about the implant procedure. Subject responses to stimulation, including the lowest stimulation at which a motor response could be observed (motor threshold), the lowest stimulation amplitude at which the subject reported sensation of stimulation (sensory threshold), type of sensation (e.g., tapping), and type of motor response (e.g., great toe flexion) were collected at implant and follow-ups. Stimulation was delivered for 60 min every other day at 20 Hz, 200 μs with a stimulation amplitude set to a comfortable level above the motor and/or sensory threshold.

All 20 subjects completed the 14-day visit and all 8 implanting physicians from 7 sites completed the procedural learnings questionnaire. All respondents reported the training conducted prior to the first implant was adequate. For each procedural step (identifying landmarks, dissecting to the level of the fascia, creating the subcutaneous pocket, inserting the implantable neurostimulator, and pocket closure), 90–95% of respondents rated these “easy” or “somewhat easy.” Only one implanter chose to use the suture loop for fixation. All twenty implant procedures used a sterile scrub and sterile preparation of the implant site. Eight subjects were given pre-operative intravenous antibiotics, and 11 subjects were given post-operative oral antibiotics. Five of the twenty subjects reported no antibiotic use.

Safety data in this early phase of the study (time between study start and last subject's 14-day follow-up visit) are as follows: 5 device-, procedure-, and/or therapy-related adverse events (AEs) were reported in three subjects including 1 serious adverse event (wound infection) which resulted in device explant 6 weeks after implant. During this timeframe, no AEs were reported for suspected device migration.

Motor and sensory threshold testing data were collected in the TITAN 1 study to understand responses to nerve stimulation. All twenty study subjects demonstrated motor and/or sensory response to stimulation at two implant timepoints (intra-operative and post-operative) and at the 7-day follow-up visit (Fig. 2). Eighteen of nineteen subjects demonstrated motor and/or sensory response at the 14-day follow-up visit; for one subject, the threshold assessment was not performed. The types of motor and sensory responses varied across study visits (Fig. 2), and there was little change in the average motor and sensory threshold through the 14-day follow up visit (Fig. 3). Review of x-rays from a subset of 5 subjects at implant and 1-month follow up indicated that there was no device movement in the anterior/posterior direction (average change: 1.0 ± 1.0 mm) and only very minimal movement in the cephalad direction (average change: 2.5 ± 2.8 mm) within the created pocket.

Fig. 2.

Fig. 2

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Types of Motor and Sensory Response from the TITAN 1 Feasibility Study. Top. Counts of subjects with motor and/or sensory responses at each testing timepoint (intraoperative, postoperative, 7-day follow up, and 14-day follow up). Middle. Number of subjects reporting each type of motor response: foot extension, toe fanning, great toe flexion, and/or other, in increasingly dark shades of blue at each timepoint. Far right bar indicates number of subjects reporting any motor response (black) or none (grey). Bottom. Number of subjects reporting each type of sensory response type: numbness, heat/temperature, tapping, tingling, and other, in increasingly dark shades of blue at each timepoint. Far right bar indicates number of subjects reporting any sensory response (black), or none (grey). Subjects could report multiple motor or sensory response types so total counts may add up to more than the number of subjects. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3.

Fig. 3

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Threshold Data from the TITAN 1 Feasibility Study. Average motor (blue) and sensory (red) thresholds during intraoperative (N = 16 motor, N = 18 sensory), postoperative (N = 17 motor, N = 16 sensory), 7-day follow up (N = 14 motor, N = 20 sensory), and 14-day follow up (N = 13 motor, N = 18 sensory) testing. Data are show as mean ± standard error of the mean. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

The motor and sensory testing data demonstrated that the tibial nerve was consistently stimulated. Together with the survey responses, these data provided assurance that the implant procedure as described in the implant instructions was adequate, and minor changes were made to the instructions prior to the TITAN 2 pivotal study. These changes included additional landmark guidance for neurostimulator placement and clarification of eligibility criteria related to poor wound healing.

3. Results

3.1. Pivotal study Design and participants

The TITAN 2 pivotal study is a prospective, multicenter, investigational device exemption study designed to demonstrate safety and effectiveness of Medtronic's implantable tibial neurostimulator in subjects with overactive bladder. The TITAN 2 study has been approved by the Food and Drug Administration and institutional review boards. The study is expected to be conducted at up to 30 study sites located in the United States. Up to 200 subjects will be enrolled to obtain at least 121 subjects who have the study device implanted. To ensure a widespread distribution of data and to minimize study site bias in study results, a single study site will be limited to 24 subjects implanted. All subjects will sign a study specific consent form and will be considered enrolled at that time.

Subjects with symptoms of overactive bladder, specifically urinary urge incontinence, that meet all eligibility criteria (Table 1) will be implanted with Medtronic's implantable tibial neurostimulator. Following implant, subjects will attend follow up visits through 2-years post-implant (Fig. 3).

Table 1.

Key TITAN 2 eligibility criteria.

Inclusion Criteria
1. Subjects 18 years of age or older
2. Qualifying voiding diary demonstrating a minimum of 3 episodes of urinary urge incontinence in 72 h
3. Have a diagnosis of urinary urge incontinence for at least 6 months
4. Failed and/or are not a candidate for conservative therapies
5. Failed and/or are intolerant to at least 2 overactive bladder medications or contraindicated for overactive bladder pharmacological therapies
6. Willing and able to accurately complete study diaries, questionnaires, attend visits, operate the system, and comply with the study protocol
7. Willing and able to provide signed and dated informed consent
Exclusion Criteria
1. Have neurological conditions such as multiple sclerosis, clinically significant peripheral neuropathy or spinal cord injury
2. Have primary stress incontinence-based MESA questionnaire or physician evaluation
3. History of a prior implantable tibial neuromodulation system
4. Anatomical defects, clinically significant edema or previous surgeries which precludes use of the device
5. Previous pelvic floor surgery in the last 6 months
6. Women who are pregnant or planning to become pregnant during the course of the study
7. Characteristics indicating a poor understanding of the study or characteristics that indicate the subject may have poor compliance with the study protocol requirements.
8. Concurrent participation in another clinical study that may add additional safety risks and/or confound study results.
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Inclusion and exclusion criteria (Table 1) were designed to ensure that subjects in this study have refractory idiopathic overactive bladder, are not currently receiving any treatment for their symptoms, and are not at risk for poor healing after the implant procedure. Screening activities include completion of a voiding diary to evaluate urinary symptoms and the MESA questionnaire to evaluate the extent of stress incontinence and urge incontinence in potential subjects.

The tibial neurostimulator implant will follow the implant methodology described above, and subjects will have their therapy turned on within 24 h of implant procedure. The recommended stimulation paradigm is 30 min of stimulation every other day with a stimulation frequency of 20 Hz and pulse width of 200 μs. The stimulation amplitude will be set to a comfortable level above sensory and/or motor threshold for each subject at each study visit. At each study visit, motor threshold, sensory threshold, and programmed amplitude will be collected (Fig. 4).

Fig. 4.

Fig. 4

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TITAN 2 Visit Schedule and Data Collection. Diagram of study visits and associated data collection (blue shaded blocks) for each visit. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Subjects will complete a voiding diary and quality of life questionnaires at the 3-, 6-, 12-, and 24-month follow up visits to track symptom change from baseline (Fig. 4). Reportable adverse events will be collected at each study visit and safety will be monitored continuously throughout the study. To ensure the safety of this novel implant procedure and that the device is adequately tracked and reported, all device related adverse events and serious adverse events will be reviewed by the study Clinical Events Committee (CEC) comprised of 3 voting members (independent urologists) and 1 nonvoting member (orthopedic surgeon consultant). Furthermore, the study has pre-defined safety related signals for pausing the study: after 7 study subjects experience device migration or device erosion that results in a device explant. This criterion corresponds to a rate of 6% (7/121) of the total planned implanted subjects and ensures that the final 90% confidence interval lower bound (2.7%) for the observed rate exceeds the previously reported rate of adverse events related to migration that led to device explant (2.2%)[14].

3.2. Objectives and endpoints

Overactive bladder is a syndrome that is diagnosed based on symptoms alone, and subjects may have multiple symptoms including urinary urge incontinence, urinary frequency, and urgency. The primary and secondary objectives of this study were designed to evaluate each of the symptoms of overactive bladder and the health-related quality of life using commonly reported and validated measures. All eligible subjects will be considered to have urinary urge incontinence by meeting the inclusion criteria of a minimum of 3 episodes of urinary urge incontinence in 72 h. Subjects will be considered to have urinary frequency by having 10 or more voids per day.

The primary and secondary endpoints of this study are as follows.

3.2.1. Primary endpoint

  • •

    Proportion of implanted subjects experiencing a reduction of 50% or more in daily urinary urge incontinence episodes (urinary urge incontinence responder rate) at 6 months after device implant

3.2.2. Secondary endpoints

  • •

    Change in urinary urge incontinence episodes at 6 months compared to baseline in subjects with urinary urge incontinence at baseline

  • •

    Change in daily urinary frequency episodes (voids/day) at 6 months compared to baseline in subjects with urinary frequency at baseline

  • •

    Change in urinary urgency assessed through the urgency perception scale (UPS) at 6 months compared to baseline

  • •

    Change in overactive bladder quality of life questionnaire health related quality of life (OAB-q-HRQL) Total Score at 6 months compared to baseline

3.3. Study design methodology and rationale

Data from blinded, randomized controlled trials of percutaneous tibial neuromodulation devices provide evidence to support the effectiveness of tibial neuromodulation to relieve symptoms of overactive bladder as compared to sham[9,15]. Percutaneous tibial neuromodulation is performed exclusively in the clinic with stimulation delivered via a needle placed near the tibial nerve and a transcutaneous ground electrode, whereas implanted tibial neuromodulation is delivered to the subject every few days at home with a single electrode built into the device. One previously published sham method for percutaneous tibial neuromodulation involved placement of a Streitberger placebo needle at the tibial nerve to simulate the sensation of needle puncture and delivery of stimulation to the foot without direct activation of the tibial nerve via a set of transcutaneous electrodes[16]. A similar sham design is not possible for an implanted device because stimulation can only be delivered at the location of the device. Implantation of a tibial device in a non-effective location raises ethical questions about unnecessary risk to the control subjects, who would later need an explant and reimplantation to receive tibial stimulation.

An alternative design could include subthreshold (motor or sensory) stimulation; however, subthreshold stimulation for sacral neuromodulation (another neuromodulation therapy for overactive bladder) has been demonstrated to provide therapeutic effect[17]. In the tibial neuromodulation space, there is no defined minimum duration or amplitude of stimulation necessary to elicit therapeutic effects, making it difficult to design a sham arm that is well blinded. Within-subject variability could cause additional issues with the treatment blinding sought by use of subthreshold stimulation; during early follow-up in the TITAN 1 study, 60% (12/20) of subjects experienced a 7-day, 14-day, or 1-month reduction in stimulation threshold compared to post-operative levels, indicating that many subjects could be at risk for being unblinded due to receiving a stimulation level that could become sensory before the next visit.

An unblinded or poorly blinded randomized controlled trial may introduce bias in the control arm that could lead to an overestimate of effect size. Neuromodulation studies from the pain field can be used to demonstrate this phenomenon: one randomized controlled trial evaluating peripheral nerve stimulation for pain found an unrealistically low responder rate of 10% in the control arm, suggesting that these subjects may not have been properly blinded[18]. Similarly, the Reactiv8B study by MainStay Medical found that responder rates were lower for patients who correctly identified their sham assignment (25% responder rate) compared to those that incorrectly identified their group (83% responder rate) or said they “did not know” (50% responder rate)[19].

Instead, the TITAN 2 study was designed as a prospective non-randomized study where success is based on a performance goal informed by literature available on other OAB therapies. OAB is a well-known disease state with well-established performance criteria. The use of a performance goal for the primary objective addresses potential placebo and Hawthorne effects. These effects exist in all clinical trials, and use of a performance goal based on previous clinical trial data from multiple alternative FDA-approved OAB therapies inherently accounts for these effects and in some situations may account for placebo effects better than a concurrent sham control.

3.4. Measurement tools

To capture the impact of TNM therapy on both the full symptom complexity of overactive bladder and the quality of life of subjects with overactive bladder, several measurement tools are being employed including validated patient reported outcomes. The timepoints of data collection for each measurement tool are shown in Fig. 4, and each tool is described below.

3.4.1. Voiding diaries

Voiding diaries are considered the current standard for assessing symptom improvement in overactive bladder and are commonly used as primary endpoints in clinical trials [[20], [21], [22], [23], [24], [25]], including other pivotal trials for implantable tibial neuromodulation[13]. Subjects in the TITAN 2 study will record their symptoms on paper voiding diaries completed for 3-days prior to each study visit. The diaries will ask the subjects to report whether they experienced a leak or a void, the date and time of the event, the level of urgency prior to the episode on a 4-point scale (Indevus Urgency Severity Scale, IUSS), estimated volume of leaks, and whether the episode woke the subject.

While voiding diaries are commonly used to quantify individual urinary events, they do not necessarily provide a complete picture of the extent to which these symptoms affect the quality of life of subjects, or which symptoms are the most bothersome for the subject. Some subjects may be most bothered by leaking, while others may find urgency to be more problematic for their lifestyle. In the TITAN 2 study, several patient-reported outcome measures provide a comprehensive assessment of improvement in subject quality of life after tibial neuromodulation therapy. These instruments are described in the following sections.

3.4.2. OAB

Overactive Bladder Quality of Life Questionnaire (OAB-q) is a 33-item validated questionnaire that was developed to assess the overall impact of overactive bladder (OAB) on patient reported health-related quality of life (HRQL) and to assess the extent to which the symptoms are bothersome[26]. The questionnaire is available in both a 1-week and 4-week recall for symptom assessment. The 4-week recall is used here because data are collected at 3-months post-implant and later follow up visits. The questionnaire includes four domains – coping, concern, sleep, and social – to evaluate the impact of overactive bladder symptoms on several aspects of a subject's quality of life. The health-related quality of life score is a composite of the 4 domains and commonly reported in clinical studies. The OAB-q is similar to another commonly used validated quality of life questionnaire, the International Consultation on Incontinence Questionnaire Overactive Bladder Module (ICIQ-OABq). The questions that comprise a total health related quality of life score are similar between these two questionnaires. They differ in that the OAB-q contains additional questions that comprise a symptom bother score, while the ICIQ-OABq has a question related to symptom interference.

3.4.3. Nocturia

Nocturia is a bothersome symptom that can lead to significant sleep disruptions for subjects with OAB. The International Continence Society defines nocturia as waking to pass urine during the main sleep period[27]. Nocturia is distinct from night-time frequency, however these two can be difficult to distinguish using voiding diaries. The TITAN 2 study will supplement the voiding diaries with the Nocturia Quality of Life (N-QoL) Questionnaire to evaluate the change in quality of life specific to nocturia symptoms. The N-QOL is a 13-item validated questionnaire which provides a detailed and robust measure to assess the impact of nocturia on quality of life[28].

3.4.4. Urgency

Similar to nocturia, urgency will be assessed in this study using both voiding diaries and a quality-of-life questionnaire, the urgency perception scale (UPS). The voiding diaries allow for quantification of urgency on an episode level using the IUSS (4-point scale) while the UPS is a single item questionnaire that more globally assesses perceived urgency, including at times without voiding episodes[29,30]. Using both measures will allow for a comprehensive assessment of the impact of tibial neuromodulation therapy on urgency, a key symptom of overactive bladder[31].

3.4.5. PGI-I and patient satisfaction

To evaluate the overall impression of improvement, TITAN 2 subjects will complete the Patient Global Impression of Improvement (PGI-I) questionnaire: a validated single question that asks the subject to rate their urinary symptoms now as compared with prior to beginning treatment on a 7 point scale including responses of very much better, much better, a little better, no change, a little worse, much worse, and very much worse[32,33]. Subjects will also complete a set of questions related to patient satisfaction of the therapy.

3.4.6. Goal attainment

Subjects in the TITAN 2 study will be asked at baseline to report on a goal they would like to accomplish by reducing their symptoms. Examples include reduce my sudden need to rush to the bathroom, reduce my urine loss when I have a sudden need to rush to the bathroom, or reduce the number of times I get up at night to go to the bathroom. At follow up visits, subjects will be asked if they met their stated goal. This instrument was chosen because it is not specific to a common symptom across all subjects like many of the other tools, but rather allows subjects to select a single symptom or complaint that matters most to them. This may be particularly useful for syndromes like overactive bladder where patients may not have all symptoms, and these goals place the patient's individualized overactive bladder symptoms in the context of real-world experiences. Additionally, assessing goal attainment provides personally meaningful patient reported outcomes to the medical community.

3.5. Statistical analysis

The sample size for the primary objective was estimated using a binomial distribution for a one-sided alpha = 0.025 test. Assuming the alternative hypothesis of a true urinary urge incontinence responder proportion being 15% greater than an FDA-approved performance goal, a minimum of 121 implant attempted subjects achieves at least 90% power. Secondary objectives are also expected to be adequately powered based on this sample size.

The main analysis of the study objectives will follow intention-to-treat principles including all subjects who have an attempted device implant. Imputation and statistical test plans follow a prespecified distribution dependent decision algorithm; the final methods will be documented in a future manuscript. If the primary objective is passed, the secondary objectives will each be tested following the Hochberg multiple testing strategy, thereby maintaining an overall two-sided type I error rate at 0.05 for these objectives.

All adverse events will be collected throughout the study once the informed consent form is signed. adverse events will be coded and summarized using the most recent version of Medical Dictionary for Regulatory Affairs. Relatedness of the events will be classified by the Investigator, with the clinical events committee completing final adjudication for related event types.

4. Conclusion

The TITAN 2 study results will add to the growing body of clinical evidence demonstrating safety and effectiveness for tibial neuromodulation therapy delivered via an implantable neurostimulator. The multiple tools used in the TITAN 2 study, including evidence of voiding symptom improvement along with patient reported outcomes, will provide a comprehensive evaluation of the extent to which tibial neuromodulation improves symptoms and quality of life for patients with overactive bladder. Patients and physicians stand to benefit from having multiple therapy choices to treat overactive bladder.

Funding

This work was funded by Medtronic.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Una Lee: Consultant, Medtronic, Axonics, Laborie; Primary Investigator, Patient-Centered Outcomes Research Institute, Site Investigator, Cook Myosite

Keith Xavier: Consultant for Medtronic

Kevin Benson: Consultant for Medtronic

Kimberly Burgess: Site investigator for Medtronic Sponsored study

Janet Harris-Hicks: Site investigator for Medtronic Sponsored study

Robert Simon: Consultant Medtronic and Axoncis

Jeffrey Proctor: Site investigator for Medtronic Sponsored study

J. Chris Coetzee: Consultant for Medtronic

Chris Irwin, Kira Stolen, Katie Bittner, Sarah Offutt, Beth Michaud, Anne Miller and Phillip Falkner are all Employees of Medtronic

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