Trial Outcomes & Findings for OnabotulinumtoxinA (BOTOX®) Treatment for Urinary Incontinence in Patients With Overactive Bladder (NCT NCT01945489)

NCT ID: NCT01945489

Last Updated: 2017-11-06

Results Overview

Urinary incontinence is defined as involuntary loss of urine as recorded by the participant in a bladder diary during the 3 consecutive days prior to the study visit in Treatment Cycle 1. The number of incontinence episodes were averaged daily during this period and compared to baseline to determine 100% reduction in episodes.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

254 participants

Primary outcome timeframe

Baseline, Week 12

Results posted on

2017-11-06

Participant Flow

Participant milestones

Participant milestones
Measure	OnabotulinumtoxinA OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).
Cycle 1 STARTED	129	125
Cycle 1 COMPLETED	116	121
Cycle 1 NOT COMPLETED	13	4
Cycle 2 STARTED	88	107
Cycle 2 COMPLETED	87	106
Cycle 2 NOT COMPLETED	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	OnabotulinumtoxinA OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).
Cycle 1 Adverse Event	2	0
Cycle 1 Lost to Follow-up	4	0
Cycle 1 Personal Reasons	4	2
Cycle 1 Protocol Violation	0	1
Cycle 1 Other Miscellaneous Reasons	3	1
Cycle 2 Adverse Event	1	0
Cycle 2 Lost to Follow-up	0	1

Baseline Characteristics

OnabotulinumtoxinA (BOTOX®) Treatment for Urinary Incontinence in Patients With Overactive Bladder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	OnabotulinumtoxinA n=129 Participants OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA n=125 Participants Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Total n=254 Participants Total of all reporting groups
Age, Continuous	60.8 years STANDARD_DEVIATION 12.73 • n=5 Participants	60.9 years STANDARD_DEVIATION 12.10 • n=7 Participants	60.8 years STANDARD_DEVIATION 12.40 • n=5 Participants
Sex: Female, Male Female	114 Participants n=5 Participants	112 Participants n=7 Participants	226 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants	13 Participants n=7 Participants	28 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: Participants from the Intent-to-Treat Population, all participants who were randomized to study drug, with data available at Baseline and Week 12.

Outcome measures

Outcome measures
Measure	OnabotulinumtoxinA n=128 Participants OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA n=125 Participants Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).
Percentage of Participants Who Achieve a 100% Reduction in Urinary Incontinence Episodes	32.0 percentage of participants	7.2 percentage of participants

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: Participants from the Intent-to-Treat Population, all participants who were randomized to study drug, with data available at Baseline and Week 12.

Urinary incontinence is defined as involuntary loss of urine as recorded by the participant in a bladder diary during the 3 consecutive days prior to the study visit in Treatment Cycle 1. The number of incontinence episodes were averaged daily during this period. A negative number change from Baseline indicates an improvement and a positive number change from Baseline indicates a worsening.

Outcome measures

Outcome measures
Measure	OnabotulinumtoxinA n=128 Participants OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA n=125 Participants Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).
Change From Baseline in the Daily Average Number of Episodes of Urinary Incontinence Baseline	5.4 incontinence episodes Standard Deviation 3.16	5.9 incontinence episodes Standard Deviation 3.75
Change From Baseline in the Daily Average Number of Episodes of Urinary Incontinence Change at Week 12	-3.4 incontinence episodes Standard Deviation 3.69	-1.7 incontinence episodes Standard Deviation 3.23

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: Intent-to-Treat Population included all participants who were randomized to study drug, "n" is the number of participants with available data at the given time-point.

The King's Health Questionnaire is a disease-specific questionnaire that measures the quality of life of participants with urinary incontinence. The questionnaire consists of 7 domains, including emotions, personal relationships, physical limitations, role limitations, severity (coping) measures, sleep/energy and social limitations. Domain scores range from 0 to 100, with a lower score indicating a preferable health status (absence of urinary incontinence impacts). A negative number change from Baseline indicates improvement and a positive number change from Baseline indicates a worsening.

Outcome measures

Outcome measures
Measure	OnabotulinumtoxinA n=129 Participants OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA n=125 Participants Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Severity (Coping) Measures, Baseline (n=128,124)	65.68 score on a scale Standard Deviation 21.347	69.18 score on a scale Standard Deviation 22.201
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Emotions, Baseline (n=128,123)	52.38 score on a scale Standard Deviation 30.982	53.60 score on a scale Standard Deviation 29.243
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Emotions, Change at Week 12 (n=121,118)	-21.98 score on a scale Standard Deviation 33.164	-6.63 score on a scale Standard Deviation 26.177
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Personal Relationships, Baseline (n=87,86)	42.91 score on a scale Standard Deviation 35.000	43.22 score on a scale Standard Deviation 36.638
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Personal Relationships,Change at Week 12 (n=71,74)	-18.31 score on a scale Standard Deviation 31.390	-6.98 score on a scale Standard Deviation 28.537
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Physical Limitations, Baseline (n=128,125)	66.41 score on a scale Standard Deviation 29.651	64.93 score on a scale Standard Deviation 30.145
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Physical Limitations,Change at Week 12 (n=121,120)	-32.37 score on a scale Standard Deviation 35.046	-10.00 score on a scale Standard Deviation 28.039
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Role Limitations, Baseline (n=127,123)	70.73 score on a scale Standard Deviation 27.516	71.95 score on a scale Standard Deviation 29.362
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Role Limitations, Change at Week 12 (n=117,117)	-37.75 score on a scale Standard Deviation 32.928	-16.67 score on a scale Standard Deviation 28.196
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Severity (Coping), Change at Week 12 (n=121,119)	-24.89 score on a scale Standard Deviation 29.558	-9.17 score on a scale Standard Deviation 19.925
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Sleep/Energy, Baseline (n=128,123)	71.35 score on a scale Standard Deviation 25.696	71.00 score on a scale Standard Deviation 25.053
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Sleep/Energy, Change at Week 12 (n=121,118)	-24.93 score on a scale Standard Deviation 26.885	-10.03 score on a scale Standard Deviation 25.796
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Social Limitations, Baseline (n=128,125)	43.69 score on a scale Standard Deviation 28.911	46.81 score on a scale Standard Deviation 32.065
Change From Baseline in King's Health Questionnaire (KHQ) Domain Scores Social Limitations, Change at Week 12 (n=120,120)	-20.40 score on a scale Standard Deviation 32.634	-5.97 score on a scale Standard Deviation 25.332

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: Participants from the Intent-to-Treat Population, all participants who were randomized to study drug, with data available at Baseline and Week 12.

The number of micturition episodes (the number of times a patient urinates into the toilet) in Treatment Cycle 1 was recorded by the participant in a bladder diary during the 3 consecutive days prior to the study visit in Treatment Cycle 1. The number of micturition episodes were averaged daily during this period A negative number change from Baseline indicates an improvement and a positive number change from Baseline indicates a worsening.

Outcome measures

Outcome measures
Measure	OnabotulinumtoxinA n=128 Participants OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA n=125 Participants Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).
Change From Baseline in the Daily Average Number of Micturition Episodes Baseline	10.2 micturition episodes Standard Deviation 2.99	11.1 micturition episodes Standard Deviation 3.43
Change From Baseline in the Daily Average Number of Micturition Episodes Change at Week 12	-2.6 micturition episodes Standard Deviation 2.71	-1.3 micturition episodes Standard Deviation 2.62

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: Participants from the Intent-to-Treat Population, all participants who were randomized to study drug, with data available at Baseline and Week 12.

The number of daily urgency episodes (the number of times a patient experiences the urgency to urinate) in Treatment Cycle 1 was recorded by the patient in a bladder diary during the 3 consecutive days prior to the study visit in Treatment Cycle 1. The number of urgency episodes were averaged daily during this period A negative number change from Baseline indicates an improvement and a positive number change from Baseline indicates a worsening.

Outcome measures

Outcome measures
Measure	OnabotulinumtoxinA n=128 Participants OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA n=125 Participants Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).
Change From Baseline in the Daily Average Number of Urgency Episodes Baseline	4.9 urgency episodes Standard Deviation 3.09	5.3 urgency episodes Standard Deviation 3.47
Change From Baseline in the Daily Average Number of Urgency Episodes Change at Week 12	-3.3 urgency episodes Standard Deviation 3.49	-1.7 urgency episodes Standard Deviation 3.24

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: Participants from the Intent-to-Treat Population, all participants who were randomized to study drug, with data available at Baseline and Week 12.

Nocturia episodes were recorded by the participant in a bladder diary during the 3 consecutive days prior to the study visit in Treatment Cycle 1. The number of nocturia episodes were averaged daily during this period. A nocturia episode is a void (urinating into the toilet) that interrupts one's sleep. A negative number change from Baseline indicates an improvement and a positive number change from baseline indicates a worsening.

Outcome measures

Outcome measures
Measure	OnabotulinumtoxinA n=128 Participants OnabotulinumtoxinA (BOTOX®) 100U injected into the detrusor at Day 1, followed by a repeat injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).	Placebo/OnabotulinumtoxinA n=125 Participants Placebo (Normal saline) injected into the detrusor on Day 1, followed by an injection of onabotulinumtoxinA 100U after a minimum of 12 weeks (if applicable).
Change From Baseline in the Daily Average Number of Nocturia Episodes Baseline	2.2 nocturia episodes Standard Deviation 1.43	2.1 nocturia episodes Standard Deviation 1.43
Change From Baseline in the Daily Average Number of Nocturia Episodes Change at Week 12	-0.7 nocturia episodes Standard Deviation 1.34	-0.4 nocturia episodes Standard Deviation 1.28

Adverse Events

OnabotulinumtoxinA (Cycle 1)

Serious events: 6 serious events

Other events: 51 other events

Deaths: 0 deaths

Placebo (Cycle 1)

Serious events: 8 serious events

Other events: 34 other events

Deaths: 0 deaths

OnabotulinumtoxinA (Cycle 2)

Serious events: 3 serious events

Other events: 75 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Vice President Medical Affairs

Allergan, Inc

Phone: 1-877-277-8566

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	OnabotulinumtoxinA (Cycle 1) n=128 participants at risk OnabotulinumtoxinA (BOTOX®) 100 U injected into the detrusor at Day 1 in Cycle 1.	Placebo (Cycle 1) n=125 participants at risk Placebo (Normal saline) injected into the detrusor on Day 1 of Cycle 1.	OnabotulinumtoxinA (Cycle 2) n=195 participants at risk OnabotulinumtoxinA (BOTOX®) 100 U injected into the detrusor at Day 1 in Cycle 2.
Cardiac disorders Cardiac failure congestive	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.80% 1/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Gastrointestinal disorders Gastritis erosive	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Gastrointestinal disorders Haematemesis	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Gastrointestinal disorders Melaena	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
General disorders Hernia obstructive	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Infections and infestations Urinary tract infection	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Infections and infestations Appendicitis	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.80% 1/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Metabolism and nutrition disorders Hyponatraemia	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.80% 1/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Metabolism and nutrition disorders Dehydration	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.51% 1/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Metabolism and nutrition disorders Hypokalaemia	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.80% 1/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.80% 1/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) B-cell lymphoma	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.80% 1/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.80% 1/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Nervous system disorders Cerebrovascular accident	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Nervous system disorders Hemiparesis	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Nervous system disorders Syncope	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Nervous system disorders Transient ischaemic attack	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Psychiatric disorders Mental status changes	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.80% 1/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.51% 1/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
General disorders Non-cardiac chest pain	0.00% 0/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.51% 1/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.
Vascular disorders Hypotension	0.78% 1/128 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.00% 0/125 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.	0.51% 1/195 The Safety Population, all participants who received at least one dose of study drug, was used to determine the number of participants at risk for Serious Adverse Events and Adverse Events.