A Trial Comparing Combination Treatment (Solifenacin Plus Mirabegron) With One Treatment Alone (Solifenacin)

Study Overview
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Brief Summary
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The purpose of this study was to see if adding a new type of medication recently approved to treat overactive bladder (mirabegron) to an antimuscarinic treatment (solifenacin) would be more effective in controlling incontinence than when using the antimuscarinic treatment alone.

Official Title
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A Randomized, Double-Blind, Multi-Centre Study to Evaluate the Efficacy and Safety of Adding Mirabegron to Solifenacin in Incontinent OAB Subjects Who Have Received Solifenacin for 4 Weeks and Warrant Additional Relief for Their OAB Symptoms

Conditions
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Urinary Bladder Diseases, Urinary Bladder Overactive, Urologic Diseases

Intervention / Treatment
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* Drug: mirabegron 25 mg
* Drug: mirabegron 50 mg
* Drug: solifenacin 5 mg
* Drug: solifenacin 10 mg
* Drug: mirabegron 25 mg matching placebo
* Drug: mirabegron 50 mg matching placebo
* Drug: solifenacin 5 mg matching placebo
* Drug: solifenacin 10 mg matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Main Inclusion at Screening: Subject has symptoms of OAB (urinary frequency and urgency with urgency incontinence) for >= 3 months prior to the screening visit Subject is willing and able to complete the micturition diary and questionnaires correctly, including collection and measurement of urine output for 3 days prior to each visit; Subject has symptoms of wet OAB (urinary frequency and urgency with incontinence or mixed incontinence with predominant urgency incontinence), and reports an average of at least 2 incontinence episodes per day. Main Inclusion at Run-in (Visit 2): Subject experiences on average at least 1 episode of urgency (grade 3 or 4) with or without incontinence per 24-hour period during the 3-day micturition diary period. Subject experiences on average at least 2 incontinence episodes per 24-hour period during the 3-day micturition diary period. Subject experiences on average at least 8 micturitions (excluding incontinence episodes) per 24-hour period during the 3-day micturition diary period. Main Inclusion at Randomization (Visit 3): Subject experiences at least 1 incontinence episode during the 3-day micturition diary period and wishes to increase their treatment for OAB symptoms. Exclusion Criteria: Main Exclusion at Screening: Subject in the opinion of the investigator has clinically significant Bladder Outlet Obstruction (BOO). Subject has significant Post-void residual (PVR) volume (PVR > 150 ml). Subject has significant stress incontinence or mixed stress/urgency incontinence where stress is the predominant factor as determined by the investigator Subject has an indwelling catheter or practices intermittent self catheterization. Subject has evidence of a UTI. Subject has chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy, or previous or current malignant disease of the pelvic organs Subject has moderate to severe hepatic impairment Subject has severe renal impairment or End Stage Renal disease Subject has a clinically significant abnormal Electrocardiogram (ECG) Subject has a concurrent malignancy or history of cancer (except noninvasive skin cancer) within the last 5 years prior to screening. Subject has a QTcF interval > 450 ms for males or > 470 ms for females or is at risk of QT prolongation (e.g., family history of long QT syndrome, hypokalaemia). Subject has received intravesical treatment in the past 12 months with e.g., botulinum toxin, resiniferatoxin, capsaicin. Subject has severe uncontrolled hypertension, which is defined as a sitting average systolic blood pressure ≥ 180 mmHg and/or average diastolic blood pressure ≥ 110 mmHg. Main Exclusion at Randomization (visit 3): Subject has achieved 100% continence from Visit 2 to Visit 3 (no incontinence episodes are recorded in the 3 day diary administered for 3 days prior to Visit 3). Subject does not desire an increase in study medication. Subject has an average total daily urine volume > 3000ml as recorded in the micturition diary. Subject has severe uncontrolled hypertension, which is defined as a sitting average systolic blood pressure ≥ 180 mmHg and/or average diastolic blood pressure ≥ 110 mmHg. Subject has a clinically significant abnormal ECG

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination (solifenacin + mirabegron)<br>Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period. | Drug: mirabegron 25 mg<br>* Mirabegron was supplied as the marketed formulation in the 25 mg OCAS (Oral Controlled Absorption System) modified release tablets. Medication was taken orally with a glass of water, with or without food.<br>* Other names: Betanis;Drug: mirabegron 50 mg<br>* Mirabegron was supplied as the marketed formulation in the 50 mg OCAS (Oral Controlled Absorption System) modified release tablets. Medication was taken orally with a glass of water, with or without food.<br>* Other names: Vesicare;Drug: solifenacin 5 mg<br>* Solifenacin was provided as the marketed formulation in the 5 mg strength. Medication was taken orally with a glass of water, with or without food.<br>* Other names: Vesikur;Drug: solifenacin 10 mg matching placebo<br>* Matching placebo of solifenacin succinate 10 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.<br>|
| Active Comparator: Solifenacin 5 mg<br>Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period | Drug: solifenacin 5 mg<br>* Solifenacin was provided as the marketed formulation in the 5 mg strength. Medication was taken orally with a glass of water, with or without food.<br>* Other names: Vesikur;Drug: mirabegron 25 mg matching placebo<br>* Matching placebo of mirabegron OCAS 25 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.<br>Drug: mirabegron 50 mg matching placebo<br>* Matching placebo of mirabegron OCAS 50 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.<br>Drug: solifenacin 10 mg matching placebo<br>* Matching placebo of solifenacin succinate 10 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.<br>|
| Active Comparator: Solifenacin 10 mg<br>Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period. | Drug: solifenacin 10 mg<br>* Solifenacin was provided as the marketed formulation in the 10 mg strength. Medication was taken orally with a glass of water, with or without food.<br>* Other names: Vesikur;Drug: mirabegron 25 mg matching placebo<br>* Matching placebo of mirabegron OCAS 25 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.<br>Drug: mirabegron 50 mg matching placebo<br>* Matching placebo of mirabegron OCAS 50 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.<br>Drug: solifenacin 5 mg matching placebo<br>* Matching placebo of solifenacin succinate 5 mg tablets was supplied. Medication was taken orally with a glass of water, with or without food.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of Treatment (EoT) in Mean Number of Incontinence Episodes Per 24 Hours | The mean number of incontinence episodes (complaint of any involuntary leakage of urine) per day was derived from number of incontinence episodes recorded on valid diary days during the 3-day micturition diary period divided by the number of valid diary days during the 3-day micturition diary period. The analysis population consisted of the Full Analysis Set (FAS) which comprised of all the Randomized Analysis Set's (RAS) participants who met the following criteria: took at least 1 dose of double-blind study drug after randomization, reported at least 1 micturition in the baseline diary & at least 1 micturition postbaseline & reported at least 1 incontinence episode in the baseline diary. For participants who withdrew before EoT (week 12) and have no measurement available for that diary period, the Last Observation Carried Forward (LOCF) value during the double-blind study period was used as EoT value to derive the primary variable. | Baseline and end of treatment (up to 12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Weeks 4, 8 & 12 in Mean Number of Incontinence Episodes Per 24 Hours | The mean number of incontinence episodes (complaint of any involuntary leakage of urine) per day was derived from number of incontinence episodes recorded on valid diary days during the 3-day micturition diary period divided by the number of valid diary days during the 3-day micturition diary period. | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in Mean Number of Micturitions Per 24 Hours | The average number of micturitions (voluntary urinations (excluding incontinence only episodes)) per 24 hours was derived from number of micturitions recorded on valid diary days during the 3-day micturition diary period divided by the number of valid diary days during the 3-day micturition diary period (excluding incontinence only episodes). | Baseline and weeks 4, 8 & 12 | 
| Number of Incontinence Episodes Reported During the 3-Day Diary | The number of incontinence episodes (complaint of any involuntary leakage of urine) per day was derived from total number of incontinence episodes on valid diary days recorded during the 3-day micturition diary period. | Weeks 4, 8 and 12 | 
| Change From Baseline in Mean Volume Voided (MVV) Per Micturition | MVV per micturition was defined as MVV (mL) per micturition during last 3 days of the 3-day micturition diary period. MVV per micturition was calculated as the sum of each volume voided for each record with volume voided > 0 on valid diary days divided by the total number of records with a volume voided > 0 on valid diary days during the 3-day micturition diary period. | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline to EoT in Corrected Micturition Frequency (CMF) | CMF was defined as the mean number of micturitions per 24 hours that participants would have at EoT if their fluid intake had remained unchanged since baseline. This was calculated by the MVV per Micturition at baseline multiplied by the mean number of micturitions per 24 hours at baseline divided by the MVV per micturition at EoT. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline in Mean Number of Urgency Incontinence (UI) Episodes Per 24 Hours | UI was defined as the complaint of involuntary urine leakage accompanied by or immediately preceded by urgency. UI was measured using the Patient Perception of Intensity of Urgency Scale (PPIUS), a patient reported outcome validated 5-point categorical scale rating the degree of associated urinary urgency severity (0=No urgency, I felt no need to empty my bladder, but did so for other reasons. 1=Mild, I could postpone voiding as long as necessary, without fear of wetting myself. 2= Moderate, I could postpone voiding for a short while, without fear of wetting myself. 3=Severe, I could not postpone voiding, but had to rush to the toilet in order not to wet myself. 4=Urgency incontinence, I leaked before arriving to the toilet). One urgency incontinence episode was counted for each record of the diary in which the following occurred: incontinence episode or 'both' was recorded & severity of urinary urgency recorded was 3 or 4. | Baseline and weeks 4, 8 & 12 | 
| Number of UI Episodes Reported During the 3-Day Diary | Number of UI episodes was calculated using the number of UI episodes recorded on valid diary days during the 3-day micturition diary period. NOTE: Only urgency incontinence episodes recorded on a valid diary day were counted. | Weeks 4, 8 and 12 | 
| Change From Baseline in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours | An urgency episode was defined as the complaint of a sudden, compelling desire to pass urine, which is difficult to defer. The mean number of urgency episodes (severity of 3 or 4) per 24 hours was defined as the average number of times a participant recorded an urgency episode (severity of 3 or 4) with or without incontinence per day during the 3-day micturition diary period. Measured using the PPIUS scale. This was calculated using the sum of each record with an urgency episode (severity of 3 or 4) recorded on a valid diary day divided by the number of valid diary days during the 3-day micturition diary period. | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in Mean Number of Pads Per 24 Hours | The mean number of pads per 24 hours was defined as the average number of times a participant recorded a new pad used per day during the 3-day micturition diary period. This was calculated using the number of new pads used during valid diary days during the 3-day micturition diary period divided by the number of valid diary days during the 3-day micturition diary period. | Baseline and weeks 4, 8 & 12 | 
| Number of Pads Used During the 3-Day Diary | The number of pads used was defined as the number of times a participant recorded a new pad used during the 3-day micturition diary period. This was calculated using the sum of each record with new pad checked. Only records with new pad checked on a valid diary day were counted. | Weeks 4, 8 and 12 | 
| Change From Baseline in Mean Number of Nocturia Episodes | Mean number of nocturia episodes was defined as the number of times a participant urinated (excluding incontinence only episodes) while sleeping during the 3-day diary period, divided by the number of valid diary days during the diary period. Night time episode of incontinence only was not considered a nocturia episode. Nocturia episodes were counted for each micturition record which occurred between the date/time of going to bed with intention to sleep and the date/time of getting up with intention to stay awake on a valid diary day & which was accompanied by a sleep interruption. Nocturia only determined for those who were not night-shift workers. | Baseline and weeks 4, 8 & 12 | 
| Number of Nocturia Episodes Reported Over 3-Day Diary | The number of nocturia episodes was defined as the number of times a participant urinated (excluding incontinence only episodes) during sleeping time during the 3-day micturition diary period. This was calculated using the sum of each nocturia episode recorded on valid diary days during the 3-day micturition diary period. | Weeks 4, 8 and 12 | 
| Number of Participants With Change From Baseline to EoT in Euroqol European Quality of Life-5 Dimensions (EQ-5D) Subscale Score: Mobility | The EQ-5D is an international, standardized, nondisease specific instrument for describing and valuing health status. It has 5 dimensions: Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response levels: level 1=no problem or none; level 2=slight problems; level 3=moderate problems; level 4=severe problems; level 5=unable to perform activity. | Baseline and EoT (up to 12 weeks) | 
| Number of Participants With Change From Baseline to EoT in EQ-5D Subscale Score: Self-care | The EQ-5D is an international, standardized, nondisease specific instrument for describing and valuing health status. It has 5 dimensions: Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response levels: level 1=no problem or none; level 2=slight problems; level 3=moderate problems; level 4=severe problems; level 5=unable to perform activity. | Baseline and EoT (up to 12 weeks) | 
| Number of Participants With Change From Baseline to EoT in EQ-5D Subscale Score: Usual Activities | The EQ-5D is an international, standardized, nondisease specific instrument for describing and valuing health status. It has 5 dimensions: Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response levels: level 1=no problem or none; level 2=slight problems; level 3=moderate problems; level 4=severe problems; level 5=unable to perform activity. | Baseline and EoT (up to 12 weeks) | 
| Number of Participants With Change From Baseline to EoT in EQ-5D Subscale Score: Pain/Discomfort | The EQ-5D is an international, standardized, nondisease specific instrument for describing and valuing health status. It has 5 dimensions: Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response levels: level 1=no problem or none; level 2=slight problems; level 3=moderate problems; level 4=severe problems; level 5=unable to perform activity. | Baseline and EoT (up to 12 weeks) | 
| Number of Participants With Change From Baseline to EoT in EQ-5D Subscale Score: Anxiety/Depression | The EQ-5D is an international, standardized, nondisease specific instrument for describing and valuing health status. It has 5 dimensions: Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response levels: level 1=no problem or none; level 2=slight problems; level 3=moderate problems; level 4=severe problems; level 5=unable to perform activity. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline in Overactive Bladder Symptom (OAB-q) Symptom Bother Score | The OAB-q was a self-reported questionnaire comprising 33-items each rated on a 6-point Likert scale. The questionnaire consisted of an 8-item symptom bother scale and 25 health-related QoL (HRQL) items comprising 4 HRQL subscales (Coping, Concern, Sleep, and Social Interaction). Symptom Bother score ranges from 0 (least severity) to 100 (worst severity). | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in OAB-q Health-Related Quality of Life (HRQL) Total Score | The OAB-q was a self-reported questionnaire comprising 33-items each rated on a 6-point Likert scale. The questionnaire consisted of an 8-item symptom bother scale and 25 health-related QoL (HRQL) items comprising 4 HRQL subscales (Coping, Concern, Sleep, and Social Interaction). HRQL subscales (coping, concern, sleep and social) and total score range from 0 (worst quality of life) to 100 (best quality of life). | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in OAB-q HRQL Subscale Score: Coping | The OAB-q was a self-reported questionnaire comprising 33-items each rated on a 6-point Likert scale. The questionnaire consisted of an 8-item symptom bother scale and 25 health-related QoL (HRQL) items comprising 4 HRQL subscales (Coping, Concern, Sleep, and Social Interaction). HRQL subscales (coping, concern, sleep and social) and total score range from 0 (worst quality of life) to 100 (best quality of life). | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in OAB-q HRQL Subscale Score: Concern | The OAB-q was a self-reported questionnaire comprising 33-items each rated on a 6-point Likert scale. The questionnaire consisted of an 8-item symptom bother scale and 25 health-related QoL (HRQL) items comprising 4 HRQL subscales (Coping, Concern, Sleep, and Social Interaction). HRQL subscales (coping, concern, sleep and social) and total score range from 0 (worst quality of life) to 100 (best quality of life). | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in OAB-q HRQL Subscale Score: Sleep | The OAB-q was a self-reported questionnaire comprising 33-items each rated on a 6-point Likert scale. The questionnaire consisted of an 8-item symptom bother scale and 25 health-related QoL (HRQL) items comprising 4 HRQL subscales (Coping, Concern, Sleep, and Social Interaction). HRQL subscales (coping, concern, sleep and social) and total score range from 0 (worst quality of life) to 100 (best quality of life). | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in OAB-q HRQL Subscale Score: Social Interaction | The OAB-q was a self-reported questionnaire comprising 33-items each rated on a 6-point Likert scale. The questionnaire consisted of an 8-item symptom bother scale and 25 health-related QoL (HRQL) items comprising 4 HRQL subscales (Coping, Concern, Sleep, and Social Interaction). HRQL subscales (coping, concern, sleep and social) and total score range from 0 (worst quality of life) to 100 (best quality of life). | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in Treatment Satisfaction - Visual Analogue Scale (TS-VAS) Score | The TS-VAS rated participant satisfaction with treatment on a scale from 0 (No, not at all) to 10 (Yes, completely). | Baseline and weeks 4, 8 & 12 | 
| Change From Baseline in Patient Perception Bladder Control (PPBC) Score | The PPBC was a validated, global assessment tool using a 6-point Likert scale on which participants rated their subjective impression of their current bladder condition. PPBC score: 1-no problem, 2- some very minor problems, 3-some minor problems, 4-moderate problems, 5-severe problems, 6-many severe problems. | Baseline and weeks 4, 8 & 12 | 
| Number of Participants in Each Category of Patient and Clinician Global Impression of Change Scales (PGIC and CGIC) | The PGIC was a 2-part questionnaire, assessing both the change in the participant's overall condition (Patient Impression in General Health (PIBS)) and change in bladder condition since the start of the study (Patient Impression in General Health (PIGH)) (from very much worse to very much improved). The CGIC was a single questionnaire assessing the participant's change in bladder condition since the beginning of the study (Clinician Impression in Bladder Symptoms (CIBS)). | End of treatment (up to 12 weeks) | 
| Percentage of Participants With at Least a 50% Decrease From Baseline in Mean Number of Incontinence Episodes Per 24 Hours | Incontinence was defined as any involuntary leakage of urine. | Weeks 4, 8 and 12 | 
| Percentage of Participants With Zero Incontinence Episodes Postbaseline | Incontinence was defined as any involuntary leakage of urine. | Weeks 4, 8 and 12 | 
| Percentage of Participants With a Mean of at Least 8 Micturitions Per 24 Hours at Baseline and Less Than 8 Micturitions Per 24 Hours Postbaseline | Micturitions were defined as voluntary urinations (excluding incontinence only episodes). | Weeks 4, 8 and 12 | 
| Percentage of Participants With at Least a 10-Point Improvement From Baseline in OAB-q Symptom Bother Score | The OAB-q was a self-reported questionnaire comprising 33-items each rated on a 6-point Likert scale. The questionnaire consisted of an 8-item symptom bother scale and 25 health-related QoL (HRQL) items comprising 4 HRQL subscales (Coping, Concern, Sleep, and Social Interaction). Symptom Bother score ranges from 0 (least severity) to 100 (worst severity). | Weeks 4, 8 and 12 | 
| Percentage of Participants With at Least a 10-Point Improvement From Baseline in HRQL Total Score | HRQL subscales (coping, concern, sleep and social) and total score range from 0 (worst quality of life) to 100 (best quality of life). | Weeks 4, 8 and 12 | 
| Percentage of Participants With at Least a 1-Point Improvement From Baseline in PPBC | The PPBC was a validated, global assessment tool using a 6-point Likert scale on which participants rated their subjective impression of their current bladder condition. | Weeks 4, 8 and 12 | 
| Percentage of Participants With Major (at Least 2-Point) Improvement From Baseline in PPBC | The PPBC was a validated, global assessment tool using a 6-point Likert scale on which participants rated their subjective impression of their current bladder condition. | Weeks 4, 8 and 12 | 
| Number of Participants With Adverse Events (AEs) | AE was defined as any untoward medical occurrence in a participant administered a study drug or has undergone study procedures & which does not necessarily have a causal relationship with this treatment. Treatment-Emergent Adverse Event (TEAE) referred to an adverse event which started or worsened in the period from first double-blind medication intake until 30 days after the last double-blind medication intake. | From first dose of double blind treatment until 30 days after last dose (up to 16 weeks) | 
| Change From Baseline in Post Void Residual (PVR) Volume | PVR Volume was assessed by bladder scan. | Baseline and weeks 4, 8 & 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vesitrim, Betanis, Urgency, Frequency, Mirabegron, YM178, Betmiga, Vesicare, Micturition, YM905, Solifenacin, Urinary incontinence, Overactive Bladder (OAB), Myrbetriq, Vesikur, Urgency incontinence