A Study to Evaluate Tolerability and Participants Preference Between Mirabegron and Tolterodine Extended Release (ER) in Participants With Overactive Bladder (OAB)

Study Overview
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Brief Summary
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The purpose of this study was to assess tolerability of mirabegron compared to tolterodine ER in the treatment of participants with symptoms of Overactive Bladder (OAB) as well as the impact of treatment on micturition frequency and incontinence episodes.

Detailed Description
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The study consisted of two double-blind treatment periods with a wash-out period in between.

Official Title
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A Prospective, Double-Blind, Randomized, Two-Period Crossover, Multi-Center Study to Evaluate the Tolerability and Patient Preference Between Myrbetriq® and Detrol® LA in Subjects With Overactive Bladder (OAB)

Conditions
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Overactive Bladder (OAB)

Intervention / Treatment
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* Drug: Mirabegron
* Drug: Tolterodine ER


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is willing and able to complete the micturition diary and questionnaires correctly. Participant has symptoms of OAB (urinary frequency and urgency with or without incontinence) for greater than or equal to 3 months prior to Screening. Participant must be treatment-naïve to pharmaceutical agents for OAB. Female participant must not donate ova starting at Screening and throughout the study period, and for 30 days after the final study drug administration. Male participant must not donate sperm starting at Screening and throughout the study period and for at least 30 days after final study drug administration. Participant agrees not to participate in another interventional study from the time of screening until the final study visit. Inclusion Criteria assessed at Visit 2 (Week 0) based on the 3-day micturition diary: Participant continues to meet all inclusion criteria of Visit 1. Participant must experience at least 3 episodes of urgency (grade 3 or 4) during the 3 day micturition diary. Participant must experience an average of greater than or equal to 8 micturitions/day on the 3 day micturition diary Exclusion Criteria: Female participant who is lactating or is intending to breastfeed during the study period and for 30 days after the final study visit. The participant has clinically significant bladder outlet obstruction (BOO) posing a risk of urinary retention. Participant has significant stress incontinence or mixed stress/urgency incontinence where stress is the predominant factor. Participant has evidence of Urinary Tract Infection (UTI) (urine culture greater than 100,000 cfu/mL) as assessed at Screening (Visit 1). The participant can be rescreened after successful treatment of the UTI (confirmed by a laboratory result of negative urine culture). Participant has a neurological cause for detrusor overactivity (e.g., neurogenic bladder, diabetic neuropathy or systemic or central neurological disease such as multiple sclerosis and Parkinson's disease). Participant has an indwelling catheter or practices intermittent self-catheterization. Participant has a chronic inflammatory condition such as interstitial cystitis, bladder stones, previous pelvic radiation therapy, or previous or current malignant disease of the pelvic organs (i.e., within the confines of the pelvis including the bladder and rectum in both sexes and the uterus, ovaries, and fallopian tubes in females); or of the lower gastrointestinal tract. Participant has uncontrolled narrow angle glaucoma, urinary or gastric retention, severe colitis ulcerosa, toxic megacolon, myasthenia gravis, polio or any other medical condition which makes the use of anticholinergics contraindicated. Participant has received intravesical injection in the past 12 months with botulinum toxin, resiniferatoxin, or capsaicin. Participant has received invasive treatment including electro-stimulation therapy. Participant is receiving a bladder training program or pelvic floor exercises which started or has changed less than 30 days prior to Screening. Participant has hepatic impairment defined as Child-Pugh Class A, B or C. Participant has severe renal impairment defined as creatinine clearance less than 30 mL/min. A participant with End Stage Renal Disease or undergoing dialysis is also not a candidate for the study. Participant has severe uncontrolled hypertension, which is defined as a sitting systolic blood pressure greater than or equal 180 mmHg and/or diastolic blood pressure greater than or equal 110 mmHg. Participant has evidence of QT prolongation on electrocardiogram (ECG) defined as QTcF greater than 450 msec for males, QTcF greater than 470 msec for females or a known history of QT prolongation. Participant has a serum creatinine greater than 150 µmol/L, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2x upper limit of normal (ULN), or γ-GT greater than 3x ULN and considered clinically significant. Participant has a hypersensitivity to any components of Myrbetriq (mirabegron), other β-AR agonists, tolterodine or other antimuscarinic agents, or any of the inactive ingredients. Participant has been treated with an experimental device within 30 days or received an investigational agent within 30 days prior to Screening. Participant has a concurrent malignancy or history of any malignancy (within the past 5 years), except non-metastatic basal or squamous cell carcinoma of the skin that has been treated successfully. Participant with current history of alcohol and/or drug abuse. Participant is involved in the conduct of the study as an employee of the Astellas group, third party associated with the study, or the study site team. Exclusion Criteria assessed at Visit 2 (Week 0): Participant fulfills any exclusion criteria at Visit 1.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AB: Mirabegron/Tolterodine ER<br>In the treatment sequence AB participants received 25 mg of mirabegron (Myrbetriq) oral controlled absorption system (OCAS) modified-release tablets and 4 mg of placebo-to-match (PTM) tolterodine ER (Detrol LA) orally once a day during period 1. In the period 2, participants received 4 mg of tolterodine ER and 25 mg of PTM mirabegron orally once a day. Four weeks after the start of each 8-week treatment period, 25 mg of mirabegron or mirabegron PTM was increased to 50 mg for the remainder of the treatment period. | Drug: Mirabegron<br>* Oral<br>* Other names: YM178;Drug: Tolterodine ER<br>* Oral<br>* Other names: Detrol LA;|
| Experimental: BA: Tolterodine ER /Mirabegron<br>In the treatment sequence BA participants received 4 mg of tolterodine ER and 25 mg of PTM mirabegron (OCAS) modified-release tablets orally once a day during period 1. In the period 2, participants received 25 mg of mirabegron and 4 mg of PTM tolterodine ER orally once a day. Four weeks after the start of each 8-week treatment period, 25 mg of mirabegron or mirabegron PTM was increased to 50 mg for the remainder of the treatment period. | Drug: Mirabegron<br>* Oral<br>* Other names: YM178;Drug: Tolterodine ER<br>* Oral<br>* Other names: Detrol LA;|
| Experimental: AA: Mirabegron/Mirabegron<br>In treatment sequence AA participants received 25 mg of mirabegron and PTM tolterodine ER 4 mg capsules during period 1 and 2 orally once a day. Four weeks after the start of each 8-week treatment period, 25 mg of mirabegron was increased to 50 mg for the remainder of the treatment period. | Drug: Mirabegron<br>* Oral<br>* Other names: YM178;|
| Experimental: BB: Tolterodine ER /Tolterodine ER<br>Participants received 4 mg of tolterodine ER and PTM mirabegron 25 mg OCAS modified-release tablets orally once a day during period 1 and period 2. | Drug: Tolterodine ER<br>* Oral<br>* Other names: Detrol LA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Tolerability Assessed by the Medication Tolerability Scale of the Overactive Bladder-Satisfaction (OAB-S) Questionnaire at the End of Treatment (EOT) | The medication tolerability scale measured the level of bothersomeness related to the occurrence of a side effect that was known to be related to the approved OAB medication (i.e., constipation, dry mouth, drowsiness, headache, nausea and blurred vision). The OAB medication tolerability score was calculated as a sum of the responses and converted to a scale from 0 to 100, where higher score indicates better perceived OAB medication tolerability (less bother from side-effects). | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Preference Based on a 5-Point Scale at the End of Period 2 in Participants Who Completed at Least 14 Days of Study Drug in Both Study Treatment Periods. | Participants were asked to choose which treatment period they preferred and the degree of preference. Preference was assessed on a 5-point scale assessed at the end of period 2 (strong preference for period 1, mild preference for period 1, no preference, mild preference for period 2, strong preference for period 2). Participants who selected either a mild preference or strong preference were considered as having a preference for a specific study drug and participants who selected no preference were considered as having no preference for one study drug over the other study drug. | Week 18 (End of Period 2) | 
| Scale of the OAB-S Questionnaire at the End of Treatment Period: Impact on Daily Living With OAB. | Impact on daily living with the OAB was scored from 0 to 100, with higher scores indicating greater satisfaction with ability to perform daily activities. | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 
| Scale of the OAB-S Questionnaire at the End of Treatment Period: OAB Control | OAB control was scored from 0 to 100, with higher scores indicating better OAB control. | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 
| Scale of the OAB-S Questionnaire at the End of Treatment Period: Satisfaction With OAB Control | Satisfaction with OAB control was scored from 0 to 100 with higher scores indicating greater satisfaction with OAB control. | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 
| Scale of the OAB-S Questionnaire at the End of Treatment Period: Overall Assessment of Participant's Fulfillment of OAB Medication Expectations | The final item score for overall assessment of patient's fulfillment of OAB medication expectations ranged from 1 to 5, with higher scores indicating better fulfillment of OAB medication expectations. | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 
| Scale of the OAB-S Questionnaire at the End of Treatment Period: Overall Assessment of Interruption of Day-to-Day Life Due to OAB | Overall assessment of interruption of day-to-day life due to OAB was assessed on a scale from 1 to 5, with higher scores indicating less interruption of day-to-day life due to OAB symptoms. | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 
| Scale of the OAB-S Questionnaire at the End of Treatment Period: Overall Satisfaction With OAB Medication | Overall satisfaction with OAB medication was assessed on a scale of 1 to 5, with higher scores indicating greater satisfaction with current OAB medication. | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 
| Scale of the OAB-S Questionnaire at the End of Treatment Period: Overall Assessment of Willingness to Continue OAB Medication | Overall assessment of willingness to continue OAB medication, was assessed on a scale from 1 to 5, with higher scores indicating greater desire to continue with current OAB medication. | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 
| Scale of the OAB-S Questionnaire at the End of Treatment Period: Overall Assessment of Improvement in Day-to-Day Life Due to OAB Medication | Overall assessment of improvement in day-to-day life due to OAB medication was assessed on a scale from 1 to 5, with higher scores indicating greater improvement in day-to-day life due to current OAB medication. | Week 8 (End of Period 1) and Week 18 (End of Period 2) | 
| Change From Baseline to End of Treatment (EOT) in Mean Number of Incontinence Episodes Per 24 Hours |  | Baseline and EOT (Period 1-Week 8 and Period 2- Week 18) | 
| Change From Baseline to End of Treatment (EOT) in Number of Micturitions Per 24 Hours |  | Baseline and EOT (Period 1-Week 8 and Period 2- Week 18) | 
| Number of Participants With Adverse Events | Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs; frequency, severity, seriousness and relationship to study drug), AEs of special interest, vital signs (SBP, DBP, body temperature and pulse rate) and laboratory tests (liver function tests [LFTs]). Treatment-Emergent Adverse Event (TEAEs) were defined as any adverse event starting or worsening in the period from first dose of double-blind study drug until 15 days after last dose of double-blind study drug. | Baseline to EOT (Week 18) and follow up (Week 20) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Overactive bladder (OAB), tolterodine ER, mirabegron