Sequencing and Combination of Mirabegron and TTNS in Overactive Bladder Syndrome: a Multicenter, Randomized, Open-label, Crossover Trial

Study Overview
=================
Brief Summary
-----------------
Research question: A wealth of existing research has established the independent effectiveness of mirabegron and neuromodulation in the treatment of overactive bladder syndrome. Optimizing the use of these effective and well-tolerated treatment modalities is an important clinical goal and warrants further research. The primary aim of this trial is to answer the questions: how does varying the treatment sequence involving mirabegron and transcutaneous tibial nerve stimulation (TTNS) affect efficacy and patient acceptance and what is the second-line efficacy of either treatment modality? Primary objective: To evaluate improvement in storage symptoms, as measured by changes in Overactive Bladder Symptom Score (OABSS), International Prostate Symptom Score (IPSS) and parameters of voiding diary, in overactive bladder (OAB) patients receiving mirabegron or TTNS as first-line therapy when crossed over to second-line therapy with the opposite treatment modality Secondary objectives: To evaluate improvement in symptoms, as measured by changes in OABSS, IPSS and parameters of voiding diary, on first-line therapy with mirabegron or TTNS followed by combination multi-modal therapy To evaluate the effect of multi-modal treatment approach on patient's perception of treatment satisfaction and symptom control To evaluate urodynamic profiles of patients treated with multi-modal approach

Detailed Description
-----------------
Study design: Prospective, randomized, multicenter, open-label, cross-over trial Treatment sequence: randomized with 1:1 ratio to either Sequence A or Sequence B Sequence A: mirabegron 50mg monotherapy x 8 weeks -> multi-modal combination treatment x 4 weeks -> TTNS monotherapy x 8 weeks Sequence B: TTNS monotherapy x 8 weeks -> multi-modal combination treatment x 4 weeks -> mirabegron 50mg monotherapy x 8 weeks Patient population: adults ≥ 20 years who have experienced symptoms of OAB, as defined by International Continence Society (ICS) diagnostic criteria, for at least 3 months Sample size: approximately 180 patients

Official Title
-----------------
Sequencing and Combination of Mirabegron and Transcutaneous Tibial Nerve Stimulation (TTNS) in Overactive Bladder Syndrome: a Multicenter, Randomized, Open-label, Crossover Trial

Conditions
-----------------
Overactive Bladder Syndrome

Intervention / Treatment
-----------------
* Drug: mirabegron
* Procedure: TTNS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult OAB patients ≥20 years Diagnosed with moderate to severe OAB (with or without urgency incontinence) based on OABSS >5 and clinical assessment, with UUI-predominant presentation, for at least 3 months Able to receive TTNS and accommodate treatment logistics (30 min per on-site session, twice weekly) Provided informed consent to participate in the study Exclusion Criteria: Neurologic conditions associated with OAB symptoms History of stress urinary incontinence Use of intravesical onabotulinumoxinA within recent 6 months Postvoid residual urine volume (PVR) ≥ 100mL Evidence of active urinary tract infection or urinary tract stone at screening Genitourinary tract operation during the 3-month period prior to baseline Confirmed or suspected genitourinary tract or pelvic malignancy History of uncontrolled hypertension (systolic >160 mmHg and/or diastolic >110 mmHg) History of intolerance to mirabegron Patients with pacemakers or implantable defibrillators Patients prone to excessive bleeding Patients with nerve damage that could impact percutaneous tibial nerve or pelvic floor function Patients who are pregnant or planning to become pregnant during the duration of treatment History of medical conditions or presence of patient factors that, in the judgement of the investigator, would preclude adherence to study protocol

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Treatment sequence: randomized with 1:1 ratio to either Sequence A or Sequence B Sequence A: mirabegron 50mg monotherapy x 8 weeks -> multi-modal combination treatment x 4 weeks -> TTNS monotherapy x 8 weeks Sequence B: TTNS monotherapy x 8 weeks -> multi-modal combination treatment x 4 weeks -> mirabegron 50mg monotherapy x 8 weeks
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A<br>mirabegron 50mg OD x 8 weeks, followed by mirabegron 50mg OD and TTNS for 4 weeks, followed by TTNS twice a week x 8 weeks | Drug: mirabegron<br>* mirabegron 50mg QD<br>Procedure: TTNS<br>* transcutaneous tibial nerve stimulation<br>|
| Experimental: Sequence B<br>TTNS twice a week x 8 weeks, followed by mirabegron 50mg OD and TTNS for 4 weeks, followed by mirabegron 50mg OD x 8 weeks | Drug: mirabegron<br>* mirabegron 50mg QD<br>Procedure: TTNS<br>* transcutaneous tibial nerve stimulation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline to end of treatment (EoT) (Week 20) in OABSS | Changes from baseline to Week 20 in OABSS (Overactive Bladder Symptom Score) (a lower OABSS score represents a better outcome). Symptom improvement is defined as OABSS total score decreased by ≥ 3 points at EoT | Baseline and Week 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline to Week 12 in OABSS | Changes from baseline to Week 12 in OABSS (Overactive Bladder Symptom Score) (a lower OABSS score represents a better outcome) | Baseline and Week 12 | 
| Changes from baseline to Week 12 and 20/end of treatment (EoT) in IPSS | Changes from baseline in IPSS (International Prostate Symptom Score) at Week 12 and 20 (a lower IPSS represents a better outcome) | Baseline, and Week 12 and 20 | 
| Change from Baseline to Week 12 and 20/end of treatment (EoT) in Mean Number of Micturitions per 24 Hours | The average number of micturitions (urinations) per 24 hours is derived from the number of times a patient urinates (excluding incontinence only episodes) per day recorded by the patient in a micturition diary for 3-days prior to clinic visits at Baseline and Week 12 and 20/end of treatment (EoT). | Baseline, and Week 12 and 20 | 
| Change from Baseline to Week 12 and 20/end of treatment (EoT) in Mean Number of Nocturia Episodes per 24 Hours | Nocturia is defined as waking at night one or more times to void. The average number of times a patient urinates (excluding incontinence only episodes) during sleeping time per day is derived from a micturition diary in which a patient records for 3 days prior to clinic visits at Baseline and Week 12 and 20/end of treatment (EoT). | Baseline, and Week 12 and 20 | 
| Change from Baseline to Week 12 and 20/end of treatment (EoT) in Mean Number of Urgency Episodes per 24 Hours | The average number of urgency episodes (the sudden, compelling desire to pass urine that is difficult to defer) is derived from episodes reocrded by the patient in a micturition diary in which a patient completes for 3 days prior to clinic visits at Baseline and Week 12 and 20/end of treatment (EoT). | Baseline, and Week 12 and 20 | 
| Change from Baseline to Week 12 and 20/end of treatment (EoT) in Mean Number of Urgency Incontinence Episodes per 24 Hours | The involuntary leakage of urine accompanied or immediately proceeded by urgency, derived from the number of incontinence episodes recorded by the patient in a micturition diary in which a patient completes for 3 days prior to clinic visits at Baseline and Week 12 and 20/end of treatment (EoT). | Baseline, and Week 12 and 20 | 
| Changes from Week 8 to Week 20 in OABSS | Changes from Week 8 to Week 20 in OABSS (Overactive Bladder Symptom Score) (a lower OABSS represents a better outcome) | Week 8 to Week 20 | 
| Changes from Week 8 to Week 20 in IPSS | Changes from Week 8 to Week 20 in IPSS (International Prostate Symptom Score) (a lower IPSS represents a better outcome) | Week 8 to Week 20 | 
| Changes from Week 8 to Week 20 in Mean Number of Micturitions per 24 Hours | The average number of micturitions (urinations) per 24 hours is derived from the number of times a patient urinates (excluding incontinence only episodes) per day recorded by the patient in a 3-day micturition diary. | Week 8 to Week 20 | 
| Changes from Week 8 to Week 20 in Mean Number of Nocturia Episodes per 24 Hours | Nocturia is defined as waking at night one or more times to void. The average number of times a patient urinates (excluding incontinence only episodes) during sleeping time per day is derived from the 3-day patient micturition diary. | Week 8 to Week 20 | 
| Changes from Week 8 to Week 20 in Mean Number of Urgency Episodes per 24 Hours | The average number of urgency episodes (the sudden, compelling desire to pass urine that is difficult to defer) derived from episodes recorded by the patient in a 3-day micturition diary | Week 8 to Week 20 | 
| Changes from Week 8 to Week 20 in Mean Number of Urgency Incontinence Episodes per 24 Hours | The involuntary leakage of urine accompanied or immediately proceeded by urgency, derived from the number of incontinence episodes recorded by the patient in a 3-day micturition diary | Week 8 to Week 20 | 
| Changes from Week 12 to Week 20 in OABSS | Changes from Week 12 to Week 20 in OABSS (Overactive Bladder Symptom Score) (a lower OABSS represents a better outcome) | Week 12 to Week 20 | 
| Changes from Week 12 to Week 20 in IPSS | Changes from Week 12 to Week 20 in IPSS (International Prostate Symptom Score) (a lower IPSS represents a better outcome) | Week 12 to Week 20 | 
| Changes from Week 12 to Week 20 in Mean Number of Micturitions per 24 Hours | The average number of micturitions (urinations) per 24 hours is derived from the number of times a patient urinates (excluding incontinence only episodes) per day recorded by the patient in a 3-day micturition diary. | Week 12 to Week 20 | 
| Changes from Week 12 to Week 20 in Mean Number of Nocturia Episodes per 24 Hours | Nocturia is defined as waking at night one or more times to void. The average number of times a patient urinates (excluding incontinence only episodes) during sleeping time per day is derived from the 3-day patient micturition diary. | Week 12 to Week 20 | 
| Changes from Week 12 to Week 20 in Mean Number of Urgency Episodes per 24 Hours | The average number of urgency episodes (the sudden, compelling desire to pass urine that is difficult to defer) derived from episodes recorded by the patient in a 3-day micturition diary | Week 12 to Week 20 | 
| Changes from Week 12 to Week 20 in Mean Number of Urgency Incontinence Episodes per 24 Hours | The involuntary leakage of urine accompanied or immediately proceeded by urgency, derived from the number of incontinence episodes recorded by the patient in a 3-day micturition diary | Week 12 to Week 20 | 
| Changes from baseline to Week 12 and 20/end of treatment (EoT) in Overactive Bladder Questionnaire-Short Form (OAB-Q-SF) score | Overactive Bladder Questionnaire-Short Form (OAB-Q-SF) is a participant-reported instrument consisting of 19 items that assess the degree to which a participant is bothered by OAB symptoms, and the degree of impact of OAB symptoms on daily life. Participants rate each item using a 6-point Likert Scale ranging from Not at all to A very great deal for the symptom bother items and none of the time to All of the time for the Health Related Quality of Life (HRQL) items. | Baseline, and Week 12 and 20 | 
| Changes from baseline to Week 12 and 20/end of treatment (EoT) in Bladder Assessment Tool (BAT) score | Bladder Assessment Tool (BAT) is a participant-reported instrument consisting of 17 questions regarding the symptoms, bothering, impacts and treatment satisfaction in the past 7 days. Scores range from 0 to 88, a reduction in BAT score indicates an improvement. | Baseline, and Week 12 and 20 | 
| Changes from baseline to Week 12 and 20/end of treatment (EoT) in Treatment Satisfaction-Visual Analog Scale (TS-VAS) score | Treatment Satisfaction-Visual Analog Scale (TS-VAS) is a quantitative instrument assessing participant improvement in participants with OAB. A score of 10 on the TS-VAS indicates complete satisfaction, whereas a positive change from baseline indicates improvement. | Baseline, and Week 12 and 20 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
overactive bladder, mirabegron, transcutaneous tibial nerve stimulation