A Study to Evaluate the Efficacy, Safety and Tolerability of Mirabegron and Solifenacin Succinate Alone and in Combination for the Treatment of Overactive Bladder (Symphony)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Europe B.V. )
ClinicalTrials.gov Identifier:
NCT01340027
First received: April 20, 2011
Last updated: July 27, 2015
Last verified: July 2015
Results First Received: June 23, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator);   Primary Purpose: Treatment
Conditions: Urinary Bladder, Overactive
Urinary Bladder Diseases
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Interventions: Drug: Mirabegron
Drug: Solifenacin succinate
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Male and female patients with symptoms of overactive bladder (OAB; urgency, urinary frequency and/or urgency incontinence) for at least 3 months. The study was conducted at 141 sites in 20 countries in Europe.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
After screening, 1658 participants entered a 2-week, single-blind, placebo run-in period. After completion of the run-in period, 1307 participants were randomly assigned to 1 of the 12 treatment arms in a 1:1:1:1:2:1:2:2:2:2:1:1 ratio.

Reporting Groups
  Description
Placebo Participants received matching placebo tablets orally once a day for 12 weeks.
Mirabegron 25 mg Participants received mirabegron 25 mg tablets orally once a day for 12 weeks.
Mirabegron 50 mg Participants received mirabegron 50 mg tablets orally once a day for 12 weeks.
Solifenacin 2.5 mg Participants received solifenacin 2.5 mg tablets orally once a day for 12 weeks.
Solifenacin 5 mg Participants received solifenacin 5 mg tablets orally once a day for 12 weeks.
Solifenacin 10 mg Participants received solifenacin 10 mg tablets orally once a day for 12 weeks.
Solifenacin 2.5 mg + Mirabegron 25 mg Participants received solifenacin 2.5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks.
Solifenacin 2.5 mg + Mirabegron 50 mg Participants received solifenacin 2.5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks.
Solifenacin 5 mg + Mirabegron 25 mg Participants received solifenacin 5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks.
Solifenacin 5 mg + Mirabegron 50 mg Participants received solifenacin 5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks.
Solifenacin 10 mg + Mirabegron 25 mg Participants received solifenacin 10 mg and mirabegron 25 mg tablets orally once a day for 12 weeks.
Solifenacin 10 mg + Mirabegron 50 mg Participants received solifenacin 10 mg and mirabegron 50 mg tablets orally once a day for 12 weeks.

Participant Flow:   Overall Study
    Placebo     Mirabegron 25 mg     Mirabegron 50 mg     Solifenacin 2.5 mg     Solifenacin 5 mg     Solifenacin 10 mg     Solifenacin 2.5 mg + Mirabegron 25 mg     Solifenacin 2.5 mg + Mirabegron 50 mg     Solifenacin 5 mg + Mirabegron 25 mg     Solifenacin 5 mg + Mirabegron 50 mg     Solifenacin 10 mg + Mirabegron 25 mg     Solifenacin 10 mg + Mirabegron 50 mg  
STARTED     81     78     79     79     156     78     149     149     144     152     81     81  
Received Treatment     81     78     78     79     156     78     149     149     144     152     81     81  
COMPLETED     76     71     75     75     146     74     142     142     136     146     79     77  
NOT COMPLETED     5     7     4     4     10     4     7     7     8     6     2     4  
Randomized but Never Received Study Drug                 0                 0                 1                 0                 0                 0                 0                 0                 0                 0                 0                 0  
Adverse Event                 0                 1                 2                 0                 1                 2                 2                 1                 4                 1                 1                 3  
Lack of Efficacy                 0                 0                 0                 0                 0                 0                 1                 1                 1                 0                 0                 0  
Lost to Follow-up                 0                 1                 0                 0                 0                 0                 1                 0                 0                 1                 0                 0  
Protocol Violation                 1                 2                 0                 0                 6                 0                 0                 1                 2                 2                 0                 0  
Withdrawal by Subject                 4                 3                 1                 3                 3                 2                 3                 4                 1                 2                 0                 1  
Miscellaneous                 0                 0                 0                 1                 0                 0                 0                 0                 0                 0                 1                 0  



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Baseline Measure data are provided for all randomized patients who took at least 1 dose of double-blind study drug (Safety Analysis Set). One participant randomized to the Mirabegron 25 mg arm received treatment with Solifenacin 5 mg + Mirabegron 50 mg in error and is counted in that arm for safety analysis set analyses.

Reporting Groups
  Description
Placebo Participants received matching placebo tablets orally once a day for 12 weeks.
Mirabegron 25 mg Participants received mirabegron 25 mg tablets orally once a day for 12 weeks.
Mirabegron 50 mg Participants received mirabegron 50 mg tablets orally once a day for 12 weeks.
Solifenacin 2.5 mg Participants received solifenacin 2.5 mg tablets orally once a day for 12 weeks.
Solifenacin 5 mg Participants received solifenacin 5 mg tablets orally once a day for 12 weeks.
Solifenacin 10 mg Participants received solifenacin 10 mg tablets orally once a day for 12 weeks.
Solifenacin 2.5 mg +Mirabegron 25 mg Participants received solifenacin 2.5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks.
Solifenacin 2.5 mg + Mirabegron 50 mg Participants received solifenacin 2.5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks.
Solifenacin 5 mg + Mirabegron 25 mg Participants received solifenacin 5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks.
Solifenacin 5 mg + Mirabegron 50 mg Participants received solifenacin 5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks.
Solifenacin 10 mg + Mirabegron 25 mg Participants received solifenacin 10 mg and mirabegron 25 mg tablets orally once a day for 12 weeks.
Solifenacin 10 mg + Mirabegron 50 mg Participants received solifenacin 10 mg and mirabegron 50 mg tablets orally once a day for 12 weeks.
Total Total of all reporting groups

Baseline Measures
    Placebo     Mirabegron 25 mg     Mirabegron 50 mg     Solifenacin 2.5 mg     Solifenacin 5 mg     Solifenacin 10 mg     Solifenacin 2.5 mg +Mirabegron 25 mg     Solifenacin 2.5 mg + Mirabegron 50 mg     Solifenacin 5 mg + Mirabegron 25 mg     Solifenacin 5 mg + Mirabegron 50 mg     Solifenacin 10 mg + Mirabegron 25 mg     Solifenacin 10 mg + Mirabegron 50 mg     Total  
Number of Participants  
[units: participants]
  81     77     78     79     156     78     149     149     144     153     81     81     1306  
Age  
[units: years]
Mean (Standard Deviation)
  54.6  (13.37)     55.2  (14.45)     53.4  (13.98)     56.1  (11.71)     54.2  (15.53)     55.0  (12.82)     55.8  (13.82)     53.7  (14.55)     55.0  (14.57)     54.1  (14.09)     56.5  (12.34)     55.5  (13.82)     54.8  (13.97)  
Gender  
[units: participants]
                         
Female     54     52     52     51     103     53     100     100     95     101     52     54     867  
Male     27     25     26     28     53     25     49     49     49     52     29     27     439  
Race/Ethnicity, Customized  
[units: participants]
                         
White     81     77     78     78     156     77     149     148     143     153     81     81     1302  
Black or African American     0     0     0     1     0     0     0     1     0     0     0     0     2  
Asian     0     0     0     0     0     1     0     0     1     0     0     0     2  
Other     0     0     0     0     0     0     0     0     0     0     0     0     0  
Type of Overactive Bladder (OAB)  
[units: participants]
                         
Urge Incontinence     14     27     19     18     39     19     42     33     35     35     23     20     324  
Mixed     9     10     10     10     27     11     22     20     19     18     14     10     180  
Frequency     56     39     48     50     89     48     84     95     90     100     44     50     793  
Missing     2     1     1     1     1     0     1     1     0     0     0     1     9  
Duration of OAB Symptoms  
[units: months]
Mean (Standard Deviation)
  48.3  (38.37)     61.2  (68.03)     56.9  (66.62)     60.2  (67.85)     61.8  (78.21)     52.4  (56.98)     57.7  (68.91)     57.0  (66.85)     56.3  (84.78)     57.4  (81.53)     64.9  (100.57)     57.4  (80.12)     57.8  (73.82)  
Mean Number of Micturitions per 24 Hours [1]
[units: micturitions]
Mean (Standard Deviation)
  10.36  (2.036)     11.29  (2.581)     10.78  (2.254)     11.10  (3.056)     11.34  (3.158)     11.29  (2.896)     11.25  (3.643)     11.00  (2.260)     10.92  (2.386)     11.25  (3.171)     11.14  (2.268)     11.24  (2.453)     11.10  (2.794)  
Mean Volume Voided per Micturition [2]
[units: mL]
Mean (Standard Deviation)
  156.4  (52.80)     152.7  (56.70)     156.8  (52.33)     162.4  (57.59)     145.5  (59.34)     148.0  (52.74)     156.8  (61.97)     149.8  (50.05)     155.0  (55.55)     153.1  (51.88)     141.4  (51.29)     155.3  (62.13)     152.5  (55.65)  
Mean Number of Urgency Episodes per 24 Hours [3]
[units: urgency episodes]
Mean (Standard Deviation)
  5.26  (3.079)     6.25  (3.332)     6.58  (3.981)     6.20  (3.870)     6.41  (4.154)     6.37  (4.530)     6.05  (3.749)     6.78  (3.419)     6.26  (3.928)     6.49  (4.238)     6.91  (4.319)     6.81  (4.312)     6.37  (3.931)  
Mean Level of Urgency [4]
[units: units on a scale]
Mean (Standard Deviation)
  2.45  (0.503)     2.53  (0.439)     2.55  (0.508)     2.53  (0.539)     2.49  (0.508)     2.48  (0.503)     2.49  (0.445)     2.59  (0.446)     2.50  (0.491)     2.51  (0.441)     2.57  (0.493)     2.53  (0.473)     2.52  (0.479)  
Mean Number of Nocturia Episodes per 24 Hours [5]
[units: nocturia episodes]
Mean (Standard Deviation)
  2.19  (1.584)     2.18  (1.392)     2.31  (1.517)     2.46  (1.852)     2.19  (1.399)     2.50  (1.859)     2.64  (2.259)     2.05  (1.219)     2.28  (1.449)     2.27  (1.305)     2.65  (2.525)     2.41  (2.001)     2.33  (1.701)  
Mean Number of Incontinence Episodes per 24 Hours [6]
[units: incontinence episodes]
Mean (Standard Deviation)
  0.95  (0.765)     1.87  (1.578)     1.26  (1.000)     1.80  (1.167)     1.33  (1.242)     1.40  (1.280)     1.27  (1.096)     1.14  (0.791)     1.24  (1.108)     1.17  (1.196)     1.53  (1.235)     1.25  (0.858)     1.31  (1.109)  
Mean Number of Urgency Incontinence Episodes per 24 Hours [7]
[units: urgency incontinence episodes]
Mean (Standard Deviation)
  0.78  (0.807)     1.54  (1.337)     1.19  (1.043)     1.56  (1.052)     1.32  (1.227)     1.18  (1.308)     0.96  (0.903)     1.06  (0.757)     1.23  (1.118)     1.08  (1.193)     1.51  (1.247)     1.20  (0.901)     1.20  (1.072)  
[1] The average number of micturitions (urinations) a day recorded by the participant in a micturition diary for 3 days prior to the Baseline visit. Data available for 81, 76, 78, 79, 155, 78, 149, 148, 144, 152, 81 and 81 participants in each treatment arm respectively.
[2] Recorded by the patient in a micturition diary for 3 days prior to the Baseline visit. Data available for 81, 76, 78, 79, 155, 78, 149, 148, 144, 152, 81 and 81 participants in each treatment arm respectively.
[3] Urgency episodes were those classified by the participant in a 3-day micturition diary as 3 or 4 on the Patient Perception of Intensity of Urgency (PPIUS) scale: 0: No urgency; 1: Mild urgency; 2: Moderate urgency, could delay voiding a short while; 3: Severe urgency, could not delay voiding; 4: Urge incontinence, leaked before arriving to the toilet. Data available for 81, 76, 78, 79, 155, 78, 149, 148, 144, 152, 81 and 81 participants in each treatment arm respectively.
[4] Average of participants’ ratings on the degree of associated urgency for each micturition and/or incontinence episode recorded in a 3-day micturition diary according to the following 5-point categorical scale (Patient Perception of Intensity of Urgency Scale): 0: No urgency; 1: Mild urgency; 2: Moderate urgency, could delay voiding a short while; 3: Severe urgency, could not delay voiding; 4: Urge incontinence, leaked before arriving to the toilet. Data available for 81, 76, 78, 79, 155, 78, 149, 148, 144, 152, 81 and 81 participants in each treatment arm respectively.
[5] The average number of times a participant woke at night to urinate (excluding incontinence only episodes) recorded for 3 days prior to the Baseline visit in the patient micturition diary. Data available for 81, 76, 78, 79, 155, 78, 149, 148, 144, 152, 81 and 81 participants in each treatment arm respectively.
[6] The average number of incontinence episodes (any involuntary leakage of urine) a day recorded by the participant in a micturition diary for 3 days prior to the Baseline visit. Data are reported for participants who took at least 1 dose of double-blind study medication with available primary efficacy data who reported at least 1 incontinence episode in the Baseline diary (Full Analysis Set-Incontinence): 17, 13, 18, 15, 35, 15, 35, 33, 32, 24, 24, 20 participants in each treatment arm respectively.
[7] The average number of urgency incontinence episodes (involuntary urine leakage accompanied by or immediately preceded by urgency) a day recorded by the participant in a micturition diary for 3 days prior to the Baseline visit. Data are reported for participants who took at least 1 dose of double-blind study medication with available primary efficacy data who reported at least 1 incontinence episode in the Baseline diary (Full Analysis Set-Incontinence): 17, 13, 18, 15, 35, 15, 35, 33, 32, 24, 24, and 20 participants in each treatment arm respectively.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change From Baseline to End of Treatment (EOT) in Mean Volume Voided Per Micturition   [ Time Frame: Baseline and Week 12 ]

2.  Secondary:   Change From Baseline to End of Treatment in Mean Number of Micturitions Per 24 Hours   [ Time Frame: Baseline and Week 12 ]

3.  Secondary:   Change From Baseline to End of Treatment in Mean Number of Incontinence Episodes Per 24 Hours   [ Time Frame: Baseline and Week 12 ]

4.  Secondary:   Change From Baseline to Each Visit in Mean Volume Voided Per Micturition   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

5.  Secondary:   Change From Baseline to Each Visit in Mean Number of Micturitions Per 24 Hours   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

6.  Secondary:   Percentage of Participants With a Micturition Response   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

7.  Secondary:   Change From Baseline to Each Visit in Mean Number of Incontinence Episodes Per 24 Hours   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

8.  Secondary:   Percentage of Participants With Zero Incontinence Episodes Post-baseline   [ Time Frame: Weeks 2, 4, 8 and 12 ]

9.  Secondary:   Percentage of Participants With 50% Reduction in Incontinence Episodes   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

10.  Secondary:   Change From Baseline to Each Visit in Mean Number of Urgency Incontinence Episodes Per 24 Hours   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

11.  Secondary:   Change From Baseline to Each Visit in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

12.  Secondary:   Change From Baseline to Each Visit in Mean Level of Urgency   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

13.  Secondary:   Change From Baseline to Each Visit in Mean Number of Pads Used Per 24 Hours   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

14.  Secondary:   Change From Baseline to Each Visit in Mean Number of Nocturia Episodes Per 24-Hours   [ Time Frame: Baseline and Weeks 2, 4, 8 and 12 ]

15.  Secondary:   Change From Baseline to End of Treatment in Patient Perception of Bladder Condition (PPBC)   [ Time Frame: Baseline and Week 12 ]

16.  Secondary:   Percentage of Participants With Improvement in PPBC   [ Time Frame: Baseline and Week 12 ]

17.  Secondary:   Percentage of Participants With Major Improvement in PPBC   [ Time Frame: Baseline and Week 12 ]

18.  Secondary:   Percentage of Participants With Deterioration in PPBC   [ Time Frame: Baseline and Week 12 ]

19.  Secondary:   Change From Baseline to End of Treatment in Symptom Bother Score as Assessed by the Overactive Bladder Questionnaire (OAB-q)   [ Time Frame: Baseline and Week 12 ]

20.  Secondary:   Percentage of Participants With a Symptom Bother Response   [ Time Frame: Baseline and Week 12 ]

21.  Secondary:   Change From Baseline to End of Treatment in Health-related Quality of Life (HRQL) Total Score   [ Time Frame: Baseline and Week 12 ]

22.  Secondary:   Percentage of Participants With a Health-related Quality of Life Total Score Response   [ Time Frame: Baseline and Week 12 ]

23.  Secondary:   Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Mobility Score   [ Time Frame: Baseline and Week 12 ]

24.  Secondary:   Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Self-care Score   [ Time Frame: Baseline and Week 12 ]

25.  Secondary:   Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Usual Activities Score   [ Time Frame: Baseline and Week 12 ]

26.  Secondary:   Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Pain/Discomfort Score   [ Time Frame: Baseline and Week 12 ]

27.  Secondary:   Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Anxiety/Depression Score   [ Time Frame: Baseline and Week 12 ]

28.  Secondary:   Change From Baseline to End of Treatment in European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS)   [ Time Frame: Baseline and Week 12 ]

29.  Secondary:   Change From Baseline to End of Treatment in Work Productivity and Activity Impairment (WPAI)   [ Time Frame: Baseline and Week 12 ]

30.  Secondary:   Change From Baseline to End of Treatment in Treatment Satisfaction on Visual Analog Scale (TS-VAS)   [ Time Frame: Baseline and Week 12 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Company makes no warranties or representations of any kind as to the posting, expressed or implied, including warranties of merchantability and fitness for a particular purpose, and shall not be liable for any damages.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Director
Organization: Astellas Pharma Europe, B.V.
e-mail: Astellas.resultsdisclosure@astellas.com


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Astellas Pharma Inc ( Astellas Pharma Europe B.V. )
ClinicalTrials.gov Identifier: NCT01340027     History of Changes
Other Study ID Numbers: 178-CL-100
2010-020601-32 ( EudraCT Number )
Study First Received: April 20, 2011
Results First Received: June 23, 2015
Last Updated: July 27, 2015
Health Authority: Austria : Federal Ministry for Labour, Health, and Social Affairs
Belarus: Ministry of Health
Belgium: Federal Agency for Medicinal Products and Health Products
Czech Republic: State Institute for Drug Control
Denmark: Ministry of Health
Finland: Finnish Medicines Agency
France: Ministry of Health
Germany: Ministry of Health
Hungary: Research Ethics Medical Committee
Italy: Ministry of Health
Netherlands: Ministry of Health, Welfare and Sport
Norway: Ministry of Health and Care Services
Poland: Ministry of Health
Portugal: Ethics Committee for Clinical Research
Romania: Ministry of Public Health
Russia: Ministry of Health of the Russian Federation
Slovakia: State Institute for Drug Control
Spain: Ministry of Health
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Ukraine: Ministry of Health