Study to Test the Long Term Safety and Efficacy of the Beta-3 Agonist Mirabegron (YM178) in Patients With Symptoms of Overactive Bladder (TAURUS)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Astellas Pharma Inc

ClinicalTrials.gov Identifier:

NCT00688688

First received: May 29, 2008

Last updated: March 19, 2013

Last verified: March 2013

History of Changes

Results First Received: July 23, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Urinary Bladder, Overactive
Interventions:	Drug: Mirabegron Drug: Tolterodine Drug: Placebo to Mirabegron Drug: Placebo to Tolterodine

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
Patients who completed the 12-week treatment and safety follow-up periods of studies 178-CL-046 (NCT00689104) or 178-CL-047 (NCT00662909), as well as patients that did not participate in these studies were enrolled into this study if they met all inclusion criteria and none of the exclusion criteria.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
After screening, 2792 patients took placebo run-in study drug in a 2-week, single-blind, placebo run-in period. On completion of the run-in period, 2452 eligible patients were randomly assigned to receive mirabegron 50 mg, or mirabegron 100 mg or tolterodine ER 4 mg once daily for 12 months.

Reporting Groups

	Description
Mirabegron 50 mg	Participants received mirabegron 50 mg tablets and matching tolterodine extended release (ER) placebo capsules orally once a day for 12 months.
Mirabegron 100 mg	Participants received mirabegron 100 mg tablets and matching tolterodine ER placebo capsules orally once a day for 12 months.
Tolterodine ER 4 mg	Participants received tolterodine ER 4 mg capsules and matching mirabegron placebo tablets orally once a day for 12 months.

Participant Flow: Overall Study

	Mirabegron 50 mg	Mirabegron 100 mg	Tolterodine ER 4 mg
STARTED	815	824	813
Safety Analysis Set (SAF)	812 ^[1]	820 ^[1]	812 ^[1]
Full Analysis Set (FAS)	789 ^[2]	802 ^[2]	791 ^[2]
Full Analysis Set Incontinence (FAS-I)	479 ^[3]	483 ^[3]	488 ^[3]
COMPLETED	629	645	621
NOT COMPLETED	186	179	192
Eligibility criterion not met	7	7	10
Adverse Event	52	51	50
Lack of Efficacy	34	25	45
Withdrawal by Subject	66	75	65
Lost to Follow-up	14	7	7
Protocol Violation	6	9	11
Randomized but never received study drug	1	0	0
Non-compliance with study procedures	5	3	4
Taking exclusionary medications	1	0	0
Site closure	0	1	0
Violation of exclusion criterion	0	1	0

[1]	All randomized patients who took at least 1 dose of double-blind study drug.
[2]	All treated patients with a baseline and at least 1 post-baseline micturition measurement.
[3]	All FAS patients who had at least 1 incontinence episode at Baseline.

Baseline Characteristics

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Reporting Groups

	Description
Mirabegron 50 mg	Participants received mirabegron 50 mg tablets and matching tolterodine extended release (ER) placebo capsules orally once a day for 12 months.
Mirabegron 100 mg	Participants received mirabegron 100 mg tablets and matching tolterodine ER placebo capsules orally once a day for 12 months.
Tolterodine ER 4 mg	Participants received tolterodine ER 4 mg capsules and matching mirabegron placebo tablets orally once a day for 12 months.
Total	Total of all reporting groups

Baseline Measures

	Mirabegron 50 mg	Mirabegron 100 mg	Tolterodine ER 4 mg	Total
Number of Participants [units: participants]	812	820	812	2444
Age ^[1] [units: years] Mean ± Standard Deviation	59.2 ± 12.56	60.1 ± 11.92	59.6 ± 12.47	59.6 ± 12.32
Gender [units: participants]
Female	602	608	600	1810
Male	210	212	212	634
Type of overactive bladder (OAB) [units: participants]
Urge incontinence	296	305	317	918
Mixed	232	228	210	670
Frequency	284	287	285	856
Duration of OAB symptoms [units: months] Mean ± Standard Deviation	87.4 ± 96.28	87.9 ± 91.52	83.8 ± 87.34	86.4 ± 91.77
Summary of previous treatment [units: participants]
Placebo	190	174	180	544
Mirabegron 50 mg	170	180	171	521
Mirabegron 100 mg	183	198	197	578
Tolterodine ER 4 mg	130	107	108	345
Naive	139	161	156	456
Mean number of micturitions per 24 Hours ^[2] [units: micturitions] Mean ± Standard Deviation	11.12 ± 2.809	11.16 ± 2.917	10.94 ± 2.668	11.08 ± 2.801
Mean volume voided per micturition ^[3] [units: mL] Mean ± Standard Deviation	160.4 ± 58.80	164.6 ± 58.62	160.8 ± 56.98	162.0 ± 58.15
Mean number of urgency episodes (grade 3 or 4) per 24 hours ^[4] [units: urgency episodes] Mean ± Standard Deviation	5.66 ± 3.601	5.61 ± 3.722	5.44 ± 3.453	5.57 ± 3.594
Mean level of urgency ^[5] [units: scores on a scale] Mean ± Standard Deviation	2.45 ± 0.544	2.44 ± 0.525	2.43 ± 0.519	2.44 ± 0.529
Mean number of nocturia episodes per 24 hours ^[6] [units: nocturia episodes] Mean ± Standard Deviation	1.83 ± 1.361	1.85 ± 1.404	1.77 ± 1.388	1.82 ± 1.384
Mean number of pads used per 24 hours ^[3] [units: pads] Mean ± Standard Deviation	1.06 ± 1.872	0.98 ± 1.769	0.98 ± 1.759	1.01 ± 1.800

[1]	Baseline Measure data are provided for all randomized patients who took at least 1 dose of double-blind study drug (Safety Analysis Set).
[2]	The average number of micturitions (urinations) per 24 hours recorded by the patient in a micturition diary for 3 days prior to the Baseline visit.
[3]	Recorded by the patient in a micturition diary for 3 days prior to the Baseline visit.
[4]	Urgency episodes were those classified by the patient 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.
[5]	Average of patients’ 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.
[6]	The average number of times a patient woke at night to urinate (excluding incontinence only episodes) recorded for 3 days prior to the Baseline visit in the patient micturition diary.

Outcome Measures

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1. Primary:

Number of Participants With and Severity of Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From the first dose of double-blind study drug up until 30 days after the last dose of study drug, up to 13 months. ]

Show Outcome Measure 1

2. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Mean Number of Micturitions Per 24 Hours [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 2

3. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Mean Number of Incontinence Episodes Per 24 Hours [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 3

4. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Mean Volume Voided Per Micturition [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 4

5. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Mean Number of Urgency Incontinence Episodes Per 24 Hours [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 5

6. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 6

7. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Mean Level of Urgency [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 7

8. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in the Mean Number of Pads Used Per 24 Hours [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 8

9. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Mean Number of Nocturia Episodes Per 24 Hours [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 9

10. Secondary:

Percentage of Participants With Zero Incontinence Episodes at Months 1, 3, 6, 9 and 12 and the Final Visit [ Time Frame: Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 10

11. Secondary:

Percentage of Participants With ≥ 50% Reduction in Incontinence Episodes at Months 1, 3, 6, 9 and 12 and the Final Visit [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 11

12. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Symptom Bother Score [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 12

13. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Health-related Quality of Life (HRQL) Total Score [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 13

14. Secondary:

Change From Baseline to Month 12 and Final Visit in Patient Perception of Bladder Condition (PPBC) [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 14

15. Secondary:

Change From Baseline to Month 12 and Final Visit in Treatment Satisfaction-visual Analog Scale (TS-VAS) [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 15

16. Secondary:

Change From Baseline to Months 3, 6, 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Work Time Missed [ Time Frame: Baseline and Months 3, 6 and 12 ]

Show Outcome Measure 16

17. Secondary:

Change From Baseline to Months 3, 6, 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Impairment While Working [ Time Frame: Baseline and Months 3, 6 and 12 ]

Show Outcome Measure 17

18. Secondary:

Change From Baseline to Months 3, 6, 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Overall Work Impairment [ Time Frame: Baseline and Months 3, 6 and 12 ]

Show Outcome Measure 18

19. Secondary:

Change From Baseline to Months 3, 6, 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Activity Impairment [ Time Frame: Baseline and Months 3, 6 and 12 ]

Show Outcome Measure 19

20. Secondary:

Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Mobility Score [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 20

21. Secondary:

Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Self-Care Score [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 21

22. Secondary:

Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Usual Activities Score [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 22

23. Secondary:

Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Pain/Discomfort Score [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 23

24. Secondary:

Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Anxiety/Depression Score [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 24

25. Secondary:

Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in the European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) [ Time Frame: Baseline and Months 1, 3, 6, 9 and 12 ]

Show Outcome Measure 25

26. Secondary:

Change From Baseline to Months 3, 6, 12 and Final Visit in Number of Non-study Related Visits to Physician [ Time Frame: Baseline and Months 3, 6 and 12 ]

Show Outcome Measure 26

27. Secondary:

Percentage of Participants With Improvement in Patient Perception of Bladder Condition (PPBC) [ Time Frame: Baseline and Month 12 ]

Show Outcome Measure 27

28. Secondary:

Safety as Assessed by Adverse Events (AEs), Vital Signs, Laboratory Tests, Physical Examination and Electrocardiogram [ Time Frame: From the first dose of double-blind study drug up until 30 days after the last dose of study drug, up to 13 months. ]

Show Outcome Measure 28

Serious Adverse Events

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Other Adverse Events

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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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site’s manuscript at least 30 days prior to publication to ensure that no confidential information of Sponsor is included in the document. Sponsor may delay the publication for an additional 60 days to seek patent protection.

Limitations and Caveats

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.

Results Point of Contact:

Name/Title: Medical Director, Global Medical Sciences
Organization: Astellas Pharma Global Development, Inc.
e-mail: ClinicalTrials.Disclosure@us.astellas.com

Publications:

Chapple CR, Kaplan SA, Mitcheson D, Klecka J, Cummings J, Drogendijk T, Dorrepaal C, Martin N. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder. Eur Urol. 2013 Feb;63(2):296-305. doi: 10.1016/j.eururo.2012.10.048. Epub 2012 Nov 6.

Responsible Party:	Astellas Pharma Inc
ClinicalTrials.gov Identifier:	NCT00688688 History of Changes
Other Study ID Numbers:	178-CL-049, 2007-001452-39
Study First Received:	May 29, 2008
Results First Received:	July 23, 2012
Last Updated:	March 19, 2013
Health Authority:	United States: Food and Drug Administration Australia: Department of Health and Ageing Therapeutic Goods Administration Austria: Federal Office for Safety in Health Care Belarus: Ministry of Health Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment Bulgaria: Bulgarian Drug Agency Czech Republic: State Institute for Drug Control Denmark: Danish Medicines Agency Finland: Finnish Medicines Agency France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Germany: Federal Institute for Drugs and Medical Devices Greece: National Organization of Medicines Hungary: National Institute of Pharmacy Iceland: Icelandic Medicines Control Agency Ireland: Irish Medicines Board Italy: Ethics Committee Latvia: State Agency of Medicines Lithuania: State Medicine Control Agency - Ministry of Health Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) Norway: Norwegian Medicines Agency Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Portugal: National Pharmacy and Medicines Institute Romania: National Medicines Agency Russia: Ministry of Health of the Russian Federation Slovakia: State Institute for Drug Control South Africa: Medicines Control Council Spain: Spanish Agency of Medicines Sweden: Medical Products Agency Switzerland: Swissmedic Ukraine: Ministry of Health United Kingdom: Medicines and Healthcare Products Regulatory Agency Canada: Health Canada Morocco: Ministry of Public Health

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