Trial Outcomes & Findings for Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Older Adult Subjects With Overactive Bladder (OAB) (NCT NCT02216214)

Last Updated: 2024-11-22

Results Overview

A micturition was defined as any voluntary act of passing urine (excluding incontinence only episodes). The mean number of micturitions per 24 hours was calculated as the average number of times a participant urinated per day during the 3-day micturition diary period.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

888 participants

Primary outcome timeframe

Baseline and EOT (up to 12 weeks)

Results posted on

2024-11-22

Participant Flow

Participants who were ≥ 65 years who had symptoms of overactive bladder (OAB) were enrolled in 102 centers in 2 countries (US and Canada).

Eligible participants entered into a 2-week placebo run-in period. During this time, they were asked to complete a 3-day training micturition diary and in the 3 days prior to being randomized (and after, prior to each visit). Participants were randomized in a 1:1 ratio to either mirabegron or placebo, stratified by age (\< 75 years, ≥ 75 years).

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Overall Study STARTED	443	445
Overall Study Treated	442	445
Overall Study COMPLETED	400	409
Overall Study NOT COMPLETED	43	36

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Overall Study Randomized Never Received Study Drug	1	0
Overall Study Adverse Event	10	8
Overall Study Lack of Efficacy	2	2
Overall Study Lost to Follow-up	3	2
Overall Study Protocol Violation	4	2
Overall Study Withdrawal by Subject	22	20
Overall Study Study Terminated By Sponsor	0	1
Overall Study Miscellaneous	1	1

Baseline Characteristics

Full analysis set-incontinence (FAS-I): included all participants who took at least 1 dose of double-blind study drug after randomization, reported at least 1 micturition and at least 1 micturition post-baseline and reported at least 1 incontinence episode in the baseline diary, and with available data and excluded participants from one site.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=442 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=445 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Total n=887 Participants Total of all reporting groups
Age, Continuous	71.9 years STANDARD_DEVIATION 6 • n=442 Participants	71.7 years STANDARD_DEVIATION 5.5 • n=445 Participants	71.8 years STANDARD_DEVIATION 5.8 • n=887 Participants
Sex: Female, Male Female	324 Participants n=442 Participants	317 Participants n=445 Participants	641 Participants n=887 Participants
Sex: Female, Male Male	118 Participants n=442 Participants	128 Participants n=445 Participants	246 Participants n=887 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	43 Participants n=442 Participants	41 Participants n=445 Participants	84 Participants n=887 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	395 Participants n=442 Participants	401 Participants n=445 Participants	796 Participants n=887 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=442 Participants	3 Participants n=445 Participants	7 Participants n=887 Participants
Race White	357 Participants n=442 Participants	348 Participants n=445 Participants	705 Participants n=887 Participants
Race Black or African American	25 Participants n=442 Participants	33 Participants n=445 Participants	58 Participants n=887 Participants
Race Asian	54 Participants n=442 Participants	59 Participants n=445 Participants	113 Participants n=887 Participants
Race Other	6 Participants n=442 Participants	5 Participants n=445 Participants	11 Participants n=887 Participants
Age Categorical < 75 years	318 Participants n=442 Participants	320 Participants n=445 Participants	638 Participants n=887 Participants
Age Categorical ≥ 75 years	124 Participants n=442 Participants	125 Participants n=445 Participants	249 Participants n=887 Participants
Incontinence Episodes per 24 Hours	3.44 incontinence episodes/24 hours STANDARD_DEVIATION 3.21 • n=430 Participants • Full analysis set-incontinence (FAS-I): included all participants who took at least 1 dose of double-blind study drug after randomization, reported at least 1 micturition and at least 1 micturition post-baseline and reported at least 1 incontinence episode in the baseline diary, and with available data and excluded participants from one site.	3.45 incontinence episodes/24 hours STANDARD_DEVIATION 3.11 • n=437 Participants • Full analysis set-incontinence (FAS-I): included all participants who took at least 1 dose of double-blind study drug after randomization, reported at least 1 micturition and at least 1 micturition post-baseline and reported at least 1 incontinence episode in the baseline diary, and with available data and excluded participants from one site.	3.44 incontinence episodes/24 hours STANDARD_DEVIATION 3.16 • n=867 Participants • Full analysis set-incontinence (FAS-I): included all participants who took at least 1 dose of double-blind study drug after randomization, reported at least 1 micturition and at least 1 micturition post-baseline and reported at least 1 incontinence episode in the baseline diary, and with available data and excluded participants from one site.
Micturitions per 24 Hours	10.5 micturitions/24 hours STANDARD_DEVIATION 3.1 • n=430 Participants • The analysis population was the FAS-I, with available data.	10.6 micturitions/24 hours STANDARD_DEVIATION 2.4 • n=437 Participants • The analysis population was the FAS-I, with available data.	10.6 micturitions/24 hours STANDARD_DEVIATION 2.7 • n=867 Participants • The analysis population was the FAS-I, with available data.
Nocturia Episodes per 24 Hours	0.43 nocturia episodes/24 hours STANDARD_DEVIATION 0.71 • n=430 Participants • The analysis population was the FAS-I, with available data.	0.45 nocturia episodes/24 hours STANDARD_DEVIATION 0.81 • n=437 Participants • The analysis population was the FAS-I, with available data.	0.44 nocturia episodes/24 hours STANDARD_DEVIATION 0.77 • n=867 Participants • The analysis population was the FAS-I, with available data.
Urgency Episodes per 24 Hours (Grade 3-4)	5.84 urgency episodes/24 hours STANDARD_DEVIATION 3.87 • n=430 Participants • The analysis population was the FAS-I, with available data.	5.88 urgency episodes/24 hours STANDARD_DEVIATION 3.61 • n=437 Participants • The analysis population was the FAS-I, with available data.	5.86 urgency episodes/24 hours STANDARD_DEVIATION 3.74 • n=867 Participants • The analysis population was the FAS-I, with available data.

PRIMARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Particpants with available data at baseline and EOT are included in the analysis. Last observation carried forward (LOCF) was used for EOT.

Outcome measures

Outcome measures
Measure	Placebo n=427 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=435 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to End of Treatment (EOT) in Mean Number of Micturitions Per 24 Hours	-1.7 micturitions/24 hours Standard Error 0.2	-2.3 micturitions/24 hours Standard Error 0.2

PRIMARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

An incontinence episode was defined as the complaint of any involuntary leakage of urine. The mean number of incontinence episodes per 24 hours was calculated as the average number of times a participant recorded an incontinence episode per day during the 3-day micturition diary period.

Outcome measures

Outcome measures
Measure	Placebo n=427 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=435 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Mean Number of Incontinence Episodes Per 24 Hours	-1.45 incontinence episodes/24 hours Standard Error 0.13	-2.00 incontinence episodes/24 hours Standard Error 0.13

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The mean volume voided per micturition during 3 days of the 3-day micturition diary period.

Outcome measures

Outcome measures
Measure	Placebo n=319 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=326 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Mean Volume Voided Per Micturition	17.45 mL Standard Error 4.17	30.54 mL Standard Error 3.97

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQoL). The symptom bother portion consists of 8 questions, rated on a 6-point Likert scale (1 through 6). The total symptom bother score was calculated from the 8 answers and then transformed to range from 0 (least severity) to 100 (worst severity). A negative change from baseline indicated an improvement.

Outcome measures

Outcome measures
Measure	Placebo n=431 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=434 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Overactive Bladder Questionnaire (OAB-q): Symptom Bother Score	-18.69 units on a scale Standard Error 1.33	-23.39 units on a scale Standard Error 1.29

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

Outcome measures

Outcome measures
Measure	Placebo n=431 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=434 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in OAB-q: Health Related Quality of Life (HRQL) Total Score	14.80 units on a scale Standard Error 1.04	17.18 units on a scale Standard Error 1.01

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The PPBC is a validated, global assessment tool using a 6-point Likert scale that asks participants to rate their subjective impression of their current bladder condition. Participants assessed their bladder condition using this scale: 1. Does not cause me any problems at all; 2. Causes me some very minor problems; 3. Causes me some minor problems; 4. Causes me (some) moderate problems; 5. Causes me severe problems; 6. Causes me many severe problems. A higher score indicated a worse perception of bladder condition.

Outcome measures

Outcome measures
Measure	Placebo n=428 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=431 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Patient Perception of Bladder Condition (PPBC)	-0.7 units on a scale Standard Error 0.1	-1.0 units on a scale Standard Error 0.1

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

Urgency was defined as a complaint of a sudden, compelling desire to pass urine, which is difficult to defer. An urgency episode was defined as any micturition or incontinence episode with a severity of grade 3 or 4, assessed by participants based on the PPIUS, where 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. The mean number of urgency episodes (grade 3 and/or 4) per 24 hours was calculated as the average number of times a participant recorded an urgency episode (grade 3 and/or 4) with or without incontinence per day during the 3-day micturition diary period.

Outcome measures

Outcome measures
Measure	Placebo n=427 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=435 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours	-2.81 urgency episodes/24 hours Standard Error 0.21	-3.66 urgency episodes/24 hours Standard Error 0.21

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

An urgency incontinence episode was defined as the involuntary leakage of urine accompanied by or immediately preceded by urgency. The mean number of urgency episodes was calculated as the average number of times a participant recorded an urgency incontinence episode per day during the 3-day micturition diary period.

Outcome measures

Outcome measures
Measure	Placebo n=427 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=435 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Mean Number of Urgency Incontinence Episodes Per 24 Hours	-1.37 urgency incontinence episodes/24 hours Standard Error 0.12	-1.93 urgency incontinence episodes/24 hours Standard Error 0.11

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

A nocturia episode was defined as waking at night one or more time to void (i.e., any voiding associated with sleep disturbance between the date/time the participant goes to bed with the intention to sleep until the date/time the participant gets up in the morning with the intention to stay awake). A night time episode of incontinence only is not considered a nocturia episode. The mean number of nocturia episodes per 24 hours was calculated as the average number of times a participant recorded a nocturia episode per day during the 3-day micturition diary period.

Outcome measures

Outcome measures
Measure	Placebo n=427 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=435 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From to EOT in Mean Number of Nocturia Episodes Per 24 Hours	-0.21 nocturia episodes/24 hours Standard Error 0.04	-0.29 nocturia episodes/24 hours Standard Error 0.04

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The Barthel Index consists of 10 items that measure a person's daily functioning; specifically the activities of daily living and mobility. The total possible score ranges from 0 to 20, with lower scores indicating increased disability.

Outcome measures

Outcome measures
Measure	Placebo n=415 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=420 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Barthel Index of Daily Living Score	0.4 units on a scale Standard Error 0.1	0.5 units on a scale Standard Error 0.1

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The VES-13 is a simple function-based tool for screening community-dwelling populations to identify older persons at risk for health deterioration. The VES-13 considers age, self-related health, limitation in physical function, and functional disabilities. The total possible score ranges from 0 to 10, with higher scores indicating increased disability.

Outcome measures

Outcome measures
Measure	Placebo n=177 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=176 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Vulnerable Elder Survey-13 (VES-13) Score	-0.1 units on a scale Standard Error 0.1	-0.3 units on a scale Standard Error 0.1

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The PPIUS is a 5-point categorical scale used by participants to rate the degree of associated urgency for each micturition and/or incontinence episode they experienced. categories include: 0 - No urgency, I felt no need to empty my bladder, but did so for other reasons; 1 - Mild urgency, I could postpone voiding as long as necessary, without fear of wetting myself; 2 - Moderate urgency, I could postpone voiding for a short while, without fear of wetting myself; 3 - Severe urgency, I could not postpone voiding, but had to rush to the toilet in order not to wet myself; 4 - Urge incontinence, I leaked before arriving at the toilet. Scores were recorded in the micturition diary.

Outcome measures

Outcome measures
Measure	Placebo n=427 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=435 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in PPIUS	-0.37 units on a scale Standard Error 0.04	-0.54 units on a scale Standard Error 0.04

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQoL). The HRQoL portion consists of 25 HRQoL items comprising 4 HRQoL subscales (Coping, Concern, Sleep, and Social Interaction), each item was scored 1-6. The Coping score has 8 items, the Concern score has 7 items, the Sleep and Social score has 5 items each. Each subscale score was calculated by adding each score's items and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A positive change from baseline indicated an improvement.

Outcome measures

Outcome measures
Measure	Placebo n=431 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=434 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in OAB-q HRQL Subscale Scores Coping	16.36 units on a scale Standard Error 1.23	18.95 units on a scale Standard Error 1.20
Change From Baseline to EOT in OAB-q HRQL Subscale Scores Concern	16.89 units on a scale Standard Error 1.19	19.72 units on a scale Standard Error 1.16
Change From Baseline to EOT in OAB-q HRQL Subscale Scores Sleep	13.46 units on a scale Standard Error 1.38	16.82 units on a scale Standard Error 1.35
Change From Baseline to EOT in OAB-q HRQL Subscale Scores Social	11.15 units on a scale Standard Error 0.78	11.47 units on a scale Standard Error 0.76

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The TS-VAS is a visual analog scale that asks participants to rate their satisfaction with the treatment by placing a vertical mark on a line that runs from 0 (No, not at all) to 100 (Yes, completely).

Outcome measures

Outcome measures
Measure	Placebo n=427 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=429 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Treatment Satisfaction Visual Analog Scale (TS-VAS)	14.455 units on a scale Standard Error 2.058	20.110 units on a scale Standard Error 2.007

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The UAB-LSA measures mobility in terms of the spatial extent of a person's life. Life space is defined based upon the distance a person routinely travels to perform activities over this time frame. The UAB-LSA includes determining how far and how often the person leaves his or her place of residence and the degree of independence the person has. Each level of life space represents a distance further from the room where one sleeps: 0 - Mobility limited to the room where one sleeps; 1 - Mobility limited to within one's dwelling; 2 - Mobility limited to the space just proximal to one's personal living space (for instance, a porch, patio, or yard just outside the home or hallway outside of an apartment); 3 - Mobility limited to one's neighborhood; 4 - Mobility limited to one's town; 5 - Mobility outside one's town. The total scores ranges from 0-120, where a higher score indicates greater mobility.

Outcome measures

Outcome measures
Measure	Placebo n=429 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=433 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in University of Alabama, Birmingham - Life Space Assessment (UAB-LSA)	1.33 units on a scale Standard Error 1.20	1.14 units on a scale Standard Error 1.17

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8 and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at all time points are included in the analysis. LOCF was used for EOT.

An incontinence episode was defined as the complaint of any involuntary leakage of urine. The number of incontinence episodes were calculated as the total number of the incontinence episodes recorded during the 3-day micturition diary period.

Outcome measures

Outcome measures
Measure	Placebo n=431 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=437 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline in Number of Incontinence Episodes Reported During 3-Day Diary Prior to Each Visit Week 4	-1.03 incontinence episodes Standard Error 0.12	-1.44 incontinence episodes Standard Error 0.10
Change From Baseline in Number of Incontinence Episodes Reported During 3-Day Diary Prior to Each Visit Week 8	-1.36 incontinence episodes Standard Error 0.11	-1.77 incontinence episodes Standard Error 0.11
Change From Baseline in Number of Incontinence Episodes Reported During 3-Day Diary Prior to Each Visit EOT	-1.40 incontinence episodes Standard Error 0.13	-1.94 incontinence episodes Standard Error 0.11

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the FAS-I.

The number of pads were calculated as the number of times a participant records a new pad used during the 3-day micturition diary period. No data were collected for the number of pads used due to a failure in the programming of the diary used for data collection.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: End of treatment (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. Non-responder imputation (NRI) was used for EOT.

Participants who achieved micturition frequency normalization were defined as participants who had at least 8 micturitions per 24 hours at baseline and less than 8 micturitions per 24 hours post-baseline.

Outcome measures

Outcome measures
Measure	Placebo n=431 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=437 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Percentage of Participants Who Achieved Micturition Frequency Normalization	36.0 percentage of participants	44.6 percentage of participants

SECONDARY outcome

Timeframe: End of treatment (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. NRI was used for EOT.

An incontinence episode was defined as the complaint of any involuntary leakage of urine. Participants with 50% reduction in mean number of incontinence episodes per 24 hours were defined as participants with at least 50% decrease from baseline in mean number of incontinence episodes per 24 hours during the treatment period at each visit.

Outcome measures

Outcome measures
Measure	Placebo n=428 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=435 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Percentage of Participants With 50% Reduction in Mean Number of Incontinence Episodes Per 24 Hours	60.0 percentage of participants	72.4 percentage of participants

SECONDARY outcome

Timeframe: End of treatment (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. NRI was used for EOT.

An incontinence episode was defined as the complaint of any involuntary leakage of urine. Participants with zero incontinence episodes per 24 hours were defined as participants who had no incontinence episodes per 24 hours during the treatment period at each visit.

Outcome measures

Outcome measures
Measure	Placebo n=428 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=435 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Percentage of Participants With Zero Incontinence Episodes Per 24 Hours	30.4 percentage of participants	38.4 percentage of participants

SECONDARY outcome

Timeframe: End of treatment (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. NRI was used for EOT.

The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQoL). The HRQoL portion consists of 25 HRQoL items comprising 4 HRQoL subscales (Coping, Concern, Sleep, and Social Interaction), each item was scored 1-6. The Coping score has 8 items, the Concern score has 7 items, the Sleep and Social score has 5 items each. Each subscale score was calculated by adding each score's items and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. Participants with ≥ 10-point improvement from baseline in OAB-q HRQL subscales were defined as participants with at least 10-point improvement from baseline in OAB-q Subscales at each visit.

Outcome measures

Outcome measures
Measure	Placebo n=431 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=436 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Percentage of Participants With ≥ 10-Point Improvement From Baseline in OAB-q HRQL Subscales Coping	58.7 percentage of participants	66.1 percentage of participants
Percentage of Participants With ≥ 10-Point Improvement From Baseline in OAB-q HRQL Subscales Concern	56.6 percentage of participants	62.2 percentage of participants
Percentage of Participants With ≥ 10-Point Improvement From Baseline in OAB-q HRQL Subscales Sleep	53.1 percentage of participants	60.1 percentage of participants
Percentage of Participants With ≥ 10-Point Improvement From Baseline in OAB-q HRQL Subscales Social	34.1 percentage of participants	36.9 percentage of participants

SECONDARY outcome

Timeframe: End of treatment (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. NRI was used for EOT.

Outcome measures

Outcome measures
Measure	Placebo n=428 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=433 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Percentage of Participants With ≥ 1-Point Improvement From Baseline in PPBC	54.4 percentage of participants	64.7 percentage of participants

SECONDARY outcome

Timeframe: End of treatment (up to 12 weeks)

Population: The analysis population was the FAS-I. Participants with available data at baseline and EOT are included in the analysis. NRI was used for EOT.

Outcome measures

Outcome measures
Measure	Placebo n=428 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=433 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Percentage of Participants Major (≥ 2-Point) Improvement From Baseline in PPBC	27.1 percentage of participants	36.5 percentage of participants

SECONDARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)

Population: The analysis population was the SAF.

Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. AEs were considered as serious if resulted in in death, was life-threatening resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required inpatient hospitalization or led to prolongation of hospitalization and other medically important events.

Outcome measures

Outcome measures
Measure	Placebo n=442 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=445 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Number of Participants With Adverse Events (AEs) AEs Leading to Study Drug Discont.	14 Participants	14 Participants
Number of Participants With Adverse Events (AEs) Drug-Related SAEs	2 Participants	0 Participants
Number of Participants With Adverse Events (AEs) AEs	174 Participants	209 Participants
Number of Participants With Adverse Events (AEs) Related AEs	57 Participants	84 Participants
Number of Participants With Adverse Events (AEs) AEs Leading to Deaths	0 Participants	0 Participants
Number of Participants With Adverse Events (AEs) SAEs	12 Participants	15 Participants
Number of Participants With Adverse Events (AEs) Drug-related AEs Leading to Study Drug Discont.	7 Participants	10 Participants

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the SAF. Participants with available data at baseline and EOT are included in the analysis. LOCF was used for EOT.

The MoCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points, with lower scores indicating worse cognitive function.

Outcome measures

Outcome measures
Measure	Placebo n=411 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=425 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline to EOT in Montreal Cognitive Assessment (MoCA) Score	-0.07 units on a scale Standard Error 0.14	-0.16 units on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: Baseline and EOT (up to 12 weeks)

Population: The analysis population was the SAF. Participants with available data are included in the analysis. LOCF was used for EOT.

PVR was assessed by ultrasonography or bladder scan.

Outcome measures

Outcome measures
Measure	Placebo n=380 Participants Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=377 Participants Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Change From Baseline in Post-void Residual Volume (PVR)	-3.1 mL Standard Deviation 40.3	2.6 mL Standard Deviation 56.2

Adverse Events

Placebo

Serious events: 12 serious events

Other events: 12 other events

Deaths: 0 deaths

Mirabegron

Serious events: 15 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=442 participants at risk Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=445 participants at risk Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Nervous system disorders Headache	2.7% 12/442 • Number of events 12 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	5.2% 23/445 • Number of events 23 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)

Additional Information

Clinical Trial Disclosure

Astellas Pharma Global Development, Inc.

Phone: 800-888-7704

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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 prior to publication for review and comment as specified in the Investigator Agreement.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=442 participants at risk Participants received placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.	Mirabegron n=445 participants at risk Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug.
Cardiac disorders Acute myocardial infarction	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Cardiac disorders Angina pectoris	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Cardiac disorders Atrial fibrillation	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Gastrointestinal disorders Diverticulum	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Gastrointestinal disorders Flatulence	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Gastrointestinal disorders Intestinal perforation	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Gastrointestinal disorders Vomiting	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
General disorders Asthenia	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
General disorders Chest pain	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
General disorders Chills	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
General disorders Non-cardiac chest pain	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
General disorders Oedema peripheral	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
General disorders Systemic inflammatory response syndrome	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Immune system disorders Allergy to arthropod bite	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Infections and infestations Arthritis infective	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Infections and infestations Cellulitis	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Infections and infestations Pneumonia	0.45% 2/442 • Number of events 2 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Infections and infestations Soft tissue infection	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Injury, poisoning and procedural complications Fall	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Injury, poisoning and procedural complications Femur fracture	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Injury, poisoning and procedural complications Scapula fracture	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Intraductal proliferative breast lesion	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tonsil cancer	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Nervous system disorders Cerebrovascular accident	0.45% 2/442 • Number of events 2 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Nervous system disorders Transient ischaemic attack	0.23% 1/442 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.00% 0/445 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)
Surgical and medical procedures Knee operation	0.00% 0/442 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)	0.22% 1/445 • Number of events 1 • From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks)