Trial Outcomes & Findings for Evaluation of an Alternative Injection Paradigm for OnabotulinumtoxinA (BOTOX®) in the Treatment of Overactive Bladder in Patients With Urinary Incontinence (NCT NCT03052764)

Last Updated: 2019-12-24

Results Overview

The participant recorded urinary incontinence in a 3-day bladder diary. Data for the three days was averaged. A negative change from Baseline indicates improvement. An analysis of covariance (ANCOVA) model with treatment as a factor at 2 levels, and the number of Urgency Urinary Incontinence (UUI) episodes reported at Baseline (\<= 9 versus \> 9 daily episodes) and Baseline daily average number of episodes of incontinence as covariates was used for analyses.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

120 participants

Primary outcome timeframe

Baseline (3 consecutive days during the Screening Period; within 35 days prior to Day 1) to 3 consecutive days prior to Week 12

Results posted on

2019-12-24

Participant Flow

Participant milestones

Participant milestones
Measure	BOTOX® 100 U/BOTOX® 100 U BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.
Double-Blind Treatment Period STARTED	80	40
Double-Blind Treatment Period mITT	78	39
Double-Blind Treatment Period COMPLETED	70	37
Double-Blind Treatment Period NOT COMPLETED	10	3
Open-Label Re-Treatment Period STARTED	58	33
Open-Label Re-Treatment Period COMPLETED	58	33
Open-Label Re-Treatment Period NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	BOTOX® 100 U/BOTOX® 100 U BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.
Double-Blind Treatment Period Adverse Event	2	0
Double-Blind Treatment Period Lack of Efficacy	1	0
Double-Blind Treatment Period Protocol Violation	2	1
Double-Blind Treatment Period Withdrawal by Subject	3	1
Double-Blind Treatment Period Reason not Specified	2	1

Baseline Characteristics

Modified Intent-to-treat (mITT) Population included all randomized participants who had at least one efficacy assessment at Baseline and a postbaseline visit.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BOTOX® 100 U/BOTOX® 100 U n=80 Participants BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U n=40 Participants Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Total n=120 Participants Total of all reporting groups
Age, Continuous	60.5 years STANDARD_DEVIATION 11.91 • n=80 Participants	61.9 years STANDARD_DEVIATION 11.26 • n=40 Participants	61.0 years STANDARD_DEVIATION 11.67 • n=120 Participants
Sex: Female, Male Female	75 Participants n=80 Participants	40 Participants n=40 Participants	115 Participants n=120 Participants
Sex: Female, Male Male	5 Participants n=80 Participants	0 Participants n=40 Participants	5 Participants n=120 Participants
Race/Ethnicity, Customized Caucasian	65 Participants n=80 Participants	39 Participants n=40 Participants	104 Participants n=120 Participants
Race/Ethnicity, Customized Black	9 Participants n=80 Participants	1 Participants n=40 Participants	10 Participants n=120 Participants
Race/Ethnicity, Customized Asian	3 Participants n=80 Participants	0 Participants n=40 Participants	3 Participants n=120 Participants
Race/Ethnicity, Customized Other	3 Participants n=80 Participants	0 Participants n=40 Participants	3 Participants n=120 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	75 Participants n=80 Participants	38 Participants n=40 Participants	113 Participants n=120 Participants
Race/Ethnicity, Customized Hispanic or Latino	5 Participants n=80 Participants	2 Participants n=40 Participants	7 Participants n=120 Participants
Daily Average Number of Urinary Incontinence Episodes	6.31 incontinence episodes per day STANDARD_DEVIATION 4.341 • n=78 Participants • Modified Intent-to-treat (mITT) Population included all randomized participants who had at least one efficacy assessment at Baseline and a postbaseline visit.	6.34 incontinence episodes per day STANDARD_DEVIATION 3.061 • n=39 Participants • Modified Intent-to-treat (mITT) Population included all randomized participants who had at least one efficacy assessment at Baseline and a postbaseline visit.	6.32 incontinence episodes per day STANDARD_DEVIATION 3.947 • n=117 Participants • Modified Intent-to-treat (mITT) Population included all randomized participants who had at least one efficacy assessment at Baseline and a postbaseline visit.

PRIMARY outcome

Timeframe: Baseline (3 consecutive days during the Screening Period; within 35 days prior to Day 1) to 3 consecutive days prior to Week 12

Population: Modified Intent-to-treat (mITT) Population included all randomized participants who had at least one efficacy assessment at Baseline and a postbaseline visit.

Outcome measures

Outcome measures
Measure	BOTOX® 100 U/BOTOX® 100 U n=78 Participants BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U n=39 Participants Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.
Change From Baseline in Daily Average Number of Urinary Incontinence Episodes	-2.99 incontinence episodes per day Standard Error 0.488	-0.42 incontinence episodes per day Standard Error 0.612

SECONDARY outcome

Timeframe: Baseline (3 consecutive days during the Screening Period; within 35 days prior to Day 1) to 3 consecutive days prior to Week 12]

Population: mITT Population included all randomized participants who had at least one efficacy assessment at Baseline and a postbaseline visit. Number analyzed is the number of participants with data available for analyses at the given timepoint.

Complete continence is defined as 100% reduction in urinary incontinence from Baseline.

Outcome measures

Outcome measures
Measure	BOTOX® 100 U/BOTOX® 100 U n=72 Participants BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U n=37 Participants Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.
Percentage of Participants Who Achieved Complete Continence	13.9 percentage of participants	2.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline (3 consecutive days during the Screening Period; within 35 days prior to Day 1) to 3 consecutive days prior to Week 12

The participant recorded the number of micturition episodes in a 3-day bladder diary. Data for the three days was averaged. A negative change from Baseline indicates improvement. An ANCOVA model with treatment as a factor at 2 levels, and the number of UUI episodes reported at Baseline (\<= 9 versus \> 9 daily episodes) and Baseline daily average number of micturition as covariates was used for analyses.

Outcome measures

Outcome measures
Measure	BOTOX® 100 U/BOTOX® 100 U n=72 Participants BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U n=37 Participants Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.
Change From Baseline in Daily Average Number of Micturition Episodes	-2.25 micturition episodes per day Standard Error 0.421	-0.01 micturition episodes per day Standard Error 0.525

SECONDARY outcome

Timeframe: Baseline (3 consecutive days during the Screening Period; within 35 days prior to Day 1) to 3 consecutive days prior to Week 12

The participant recorded the number of urgency episode in a 3-day bladder diary. Data for the three days was averaged. A negative change from Baseline indicates improvement. An ANCOVA model with treatment as a factor at 2 levels, and the number of UUI episodes reported at Baseline (\<= 9 versus \> 9 daily episodes) and Baseline daily average number of urgency episodes as covariates was used for analyses.

Outcome measures

Outcome measures
Measure	BOTOX® 100 U/BOTOX® 100 U n=72 Participants BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U n=37 Participants Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.
Change From Baseline in Daily Average Number of Urgency Episodes	-2.79 urgency episodes per day Standard Error 0.491	-0.23 urgency episodes per day Standard Error 0.618

SECONDARY outcome

Timeframe: Baseline (3 consecutive days during the Screening Period; within 35 days prior to Day 1) to, 3 consecutive days prior to Week 12

The participants recorded the number of nocturia episodes in a 3-day bladder diary. Data for the three days was averaged. A negative change from Baseline indicates improvement. An ANCOVA model with treatment as a factor at 2 levels, and the number of UUI episodes reported at Baseline (\<= 9 versus \> 9 daily episodes) and Baseline daily average number of nocturia episodes as covariates was used for analyses.

Outcome measures

Outcome measures
Measure	BOTOX® 100 U/BOTOX® 100 U n=72 Participants BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U n=37 Participants Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.
Change From Baseline in Daily Average Number of Nocturia Episodes	-0.53 nocturia episodes per day Standard Error 0.154	0.17 nocturia episodes per day Standard Error 0.193

SECONDARY outcome

Timeframe: Week 12

The participant rated their condition during treatment using the TBS 4-point scale where: 1=greatly improved, 2=improved, 3=not changed or 4=worsened. A positive treatment response is either as score of 1=greatly improved or 2=improved.

Outcome measures

Outcome measures
Measure	BOTOX® 100 U/BOTOX® 100 U n=50 Participants BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.	Placebo/BOTOX® 100 U n=17 Participants Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period and a second injection BOTOX® 100 U after Week 12 if applicable in the Open-Label Re-Treatment Period.
Percentage of Participants Who Have a Positive Treatment Response on the Treatment Benefit Scale (TBS)	74.0 percentage of participants	17.6 percentage of participants

Adverse Events

Double Blind: BOTOX® 100 U

Serious events: 5 serious events

Other events: 31 other events

Deaths: 0 deaths

Double Blind: Placebo

Serious events: 2 serious events

Other events: 13 other events

Deaths: 0 deaths

Open Label: BOTOX® 100 U/BOTOX® 100 U

Serious events: 2 serious events

Other events: 14 other events

Deaths: 0 deaths

Open Label: Placebo/BOTOX® 100 U

Serious events: 1 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Double Blind: BOTOX® 100 U n=78 participants at risk BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period.	Double Blind: Placebo n=39 participants at risk Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period.	Open Label: BOTOX® 100 U/BOTOX® 100 U n=58 participants at risk BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder in the Open-Label Re-Treatment Period in participants who previously received BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1.	Open Label: Placebo/BOTOX® 100 U n=33 participants at risk BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder in the Open-Label Re-Treatment Period in participants who previously received Placebo (saline) injection into the bladder on Day 1.
Renal and urinary disorders Dysuria	5.1% 4/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	2.6% 1/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	6.1% 2/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Respiratory, thoracic and mediastinal disorders Productive cough	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	5.1% 2/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Infections and infestations Urinary tract infection	35.9% 28/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	28.2% 11/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	24.1% 14/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	42.4% 14/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.

Additional Information

Therapeutic Area, Head

Allergan

Phone: 714-246-4500

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee A 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 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
Publication restrictions are in place

Restriction type: OTHER

Measure	Double Blind: BOTOX® 100 U n=78 participants at risk BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1 in the Double-Blind Treatment Period.	Double Blind: Placebo n=39 participants at risk Placebo (saline) injection into the bladder on Day 1 in the Double-Blind Treatment Period.	Open Label: BOTOX® 100 U/BOTOX® 100 U n=58 participants at risk BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder in the Open-Label Re-Treatment Period in participants who previously received BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder on Day 1.	Open Label: Placebo/BOTOX® 100 U n=33 participants at risk BOTOX® (onabotulinumtoxinA) 100 U injection into the bladder in the Open-Label Re-Treatment Period in participants who previously received Placebo (saline) injection into the bladder on Day 1.
Blood and lymphatic system disorders Anaemia	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Cardiac disorders Acute coronary syndrome	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Gastrointestinal disorders Haematochezia	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Infections and infestations Cellulitis	0.00% 0/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	2.6% 1/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Infections and infestations Post procedural cellulitis	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Infections and infestations Pyelonephritis	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Infections and infestations Urosepsis	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer recurrent	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Nervous system disorders Sciatica	1.3% 1/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Renal and urinary disorders Urinary bladder haemorrhage	0.00% 0/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	2.6% 1/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Cardiac disorders Arteriosclerosis coronary artery	0.00% 0/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	1.7% 1/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
General disorders Chest pain	0.00% 0/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	1.7% 1/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Investigations Troponin increased	0.00% 0/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	3.0% 1/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	1.7% 1/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.
Nervous system disorders Syncope	0.00% 0/78 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/39 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	0.00% 0/58 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.	3.0% 1/33 • Randomization to the Study Exit Visit (Up to 70 Weeks) ITT population, all randomized participants, was used to determine the number at risk for All-Cause Mortality. Safety Population, all participants who received study drug, was used to determine the number of participants at risk for Adverse Events.