Trial Outcomes & Findings for Comparison of 23 mg Donepezil Sustained Release (SR) to 10 mg Donepezil Immediate Release (IR) in Patients With Moderate to Severe Alzheimer's Disease (NCT NCT00478205)

NCT ID: NCT00478205

Last Updated: 2014-07-11

Results Overview

The SIB is an assessment of cognitive dysfunction across nine domains such as memory, language, and orientation. The score ranges from 0 (worst) to 100 (best). This outcome was calculated using the LOCF (last observation carried forward) method.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1467 participants
• Primary outcome timeframe: Baseline and Week 24
• Results posted on: 2014-07-11

Participant Flow

Participant milestones

Measure	Donepezil SR 23 mg Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.
Overall Study STARTED	981	486
Overall Study COMPLETED	685	399
Overall Study NOT COMPLETED	296	87

Reasons for withdrawal

Measure	Donepezil SR 23 mg Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.
Overall Study Adverse Event	182	39
Overall Study Medication Non-compliance	9	4
Overall Study Protocol Violation	15	5
Overall Study Request of Investigator or Sponsor	4	5
Overall Study Withdrawal by Subject	61	22
Overall Study Lack of Efficacy	1	0
Overall Study Other	24	12

Baseline Characteristics

Comparison of 23 mg Donepezil Sustained Release (SR) to 10 mg Donepezil Immediate Release (IR) in Patients With Moderate to Severe Alzheimer's Disease

Baseline characteristics by cohort

Measure	Donepezil SR 23 mg n=963 Participants Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg n=471 Participants Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.	Total n=1434 Participants Total of all reporting groups
Age, Continuous	73.9 Years STANDARD_DEVIATION 8.53 • n=5 Participants	73.8 Years STANDARD_DEVIATION 8.56 • n=7 Participants	73.8 Years STANDARD_DEVIATION 8.53 • n=5 Participants
Sex: Female, Male Female	607 Participants 63.0 • n=5 Participants	294 Participants 62.4 • n=7 Participants	901 Participants 62.8 • n=5 Participants
Sex: Female, Male Male	356 Participants 37.0 • n=5 Participants	177 Participants 37.6 • n=7 Participants	533 Participants 37.2 • n=5 Participants
Race/Ethnicity, Customized Black	22 Participants n=5 Participants	9 Participants n=7 Participants	31 Participants n=5 Participants
Race/Ethnicity, Customized White	708 Participants n=5 Participants	346 Participants n=7 Participants	1054 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	67 Participants n=5 Participants	26 Participants n=7 Participants	93 Participants n=5 Participants
Race/Ethnicity, Customized Native American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian/Pacific	161 Participants n=5 Participants	87 Participants n=7 Participants	248 Participants n=5 Participants
Race/Ethnicity, Customized Other	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 24

Population: Intent-to-treat (ITT) population: All Randomized patients in Safety Population and Severe Impairment Battery (SIB) or Clinician Interview-Based Impression of Severity Plus Caregiver Input (CIBIS+) data available at Baseline and SIB or Clinician Interview-Based Impression of Change Plus caregiver Input (CIBIC+ ) data available post-Baseline; LOCF

The SIB is an assessment of cognitive dysfunction across nine domains such as memory, language, and orientation. The score ranges from 0 (worst) to 100 (best). This outcome was calculated using the LOCF (last observation carried forward) method.

Outcome measures

Measure	Donepezil SR 23 mg n=909 Participants Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg n=462 Participants Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.
Change From Baseline to Week 24 in SIB Total Score	2.6 Scores on a scale Standard Error 0.58	0.4 Scores on a scale Standard Error 0.66

PRIMARY outcome

Timeframe: Baseline and Week 24

Population: ITT population, LOCF

The CIBIC+ is a rating scale derived from an interview with the patient and caregiver with an independent rater designed to measure several domains of patient function, such as mental/cognitive state, behavior, and activities of daily living. The scores range from 1 (marked improvement) to 7 (marked worsening).

Outcome measures

Measure	Donepezil SR 23 mg n=909 Participants Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg n=462 Participants Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.
Overall Change From Baseline in Modified CIBIC+ to Week 24	4.23 Scores on a scale Standard Deviation 1.07	4.29 Scores on a scale Standard Deviation 1.07

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT population, LOCF

The ADCS-ADL (Alzhemier's Disease Cooperative Study-Activities of Daily Living) is a 19-item assessment scale used to measure a patient's basic functional abilities, such as walking, grooming, and bathing.Scores range from 0 to 54, with a higher score indicating greater functional ability.

Outcome measures

Measure	Donepezil SR 23 mg n=909 Participants Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg n=462 Participants Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.
Change From Baseline to Week 24 in ADCS-ADL Total Score	-1.2 Scores on a scale Standard Deviation 6.83	-1.2 Scores on a scale Standard Deviation 6.78

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT population, LOCF

The MMSE (Mini-Mental State Examination) is a 30-item test that evaluates 5 domains of cognitive function (orientation to time and place, immediate and delayed recall, attention, calculation, and language). The scores range from 0 (most impaired) to 30 (no impaiment).

Outcome measures

Measure	Donepezil SR 23 mg n=909 Participants Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg n=462 Participants Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.
Change From Baseline to Week 24 in MMSE Total Score	0.6 Scores on a scale Standard Deviation 2.93	0.4 Scores on a scale Standard Deviation 3.20

Adverse Events

Donepezil SR 23 mg

Serious events: 80 serious events

Other events: 233 other events

Deaths: 0 deaths

Donepezil IR 10 mg

Serious events: 45 serious events

Other events: 50 other events

Deaths: 0 deaths

Serious adverse events

Measure	Donepezil SR 23 mg n=963 participants at risk Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg n=471 participants at risk Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.
Blood and lymphatic system disorders Anaemia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Blood and lymphatic system disorders Leukocytosis	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Acute coronary syndrome	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Acute myocardial infarction	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Angina pectoris	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Atrial fibrillation	0.42% 4/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Bradycardia	0.42% 4/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Cardiac failure	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Cardiac failure congestive	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Cardio-respiratory arrest	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Cardiopulmonary failure	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Cardiovascular disorder	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Coronary artery occlusion	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Myocardial infarction	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Myocardial ischaemia	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Tachycardia	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Cardiac disorders Ventricular tachycardia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Eye disorders Diplopia	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Abdominal discomfort	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Abdominal pain	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Diarrhoea	0.42% 4/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Diarrhoea haemorrhagic	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Dyspepsia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Gastric ulcer haemorrhage	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Gastritis	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Haematochezia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Hiatus hernia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Inguinal hernia	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Nausea	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Oesophageal ulcer	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Rectal haemorrhage	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Vomiting	0.31% 3/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
General disorders Asthenia	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
General disorders Drowning	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
General disorders General physical health deterioration	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
General disorders Hypothermia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.42% 2/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
General disorders Irritability	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
General disorders Pyrexia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Hepatobiliary disorders Bile duct stenosis	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Hepatobiliary disorders Bile duct stone	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Hepatobiliary disorders Cholangitis acute	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Hepatobiliary disorders Cholecystitis chronic	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Hepatobiliary disorders Cholelithiasis	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Bronchitis	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Cellulitis	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Diverticulitis	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Gastroenteritis	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Gastrointestinal infection	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Pneumonia	0.31% 3/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.64% 3/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Sepsis	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Septic shock	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Infections and infestations Urinary tract infection	0.62% 6/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.42% 2/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Burns first degree	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Burns second degree	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Contusion	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Facial bones fracture	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Fall	0.62% 6/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.42% 2/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Femoral neck fracture	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Femur fracture	0.42% 4/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Hip fracture	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Neck injury	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Overdose	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Pelvic fracture	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Procedural complication	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Rib fracture	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Road traffic accident	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Skin laceration	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Subdural haematoma	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Injury, poisoning and procedural complications Wrist fracture	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Investigations Blood pressure increased	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Investigations Electrocardiogram QT prolonged	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Investigations Weight decreased	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Metabolism and nutrition disorders Anorexia	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Metabolism and nutrition disorders Dehydration	0.31% 3/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Musculoskeletal and connective tissue disorders Arthritis	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Musculoskeletal and connective tissue disorders Back pain	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Musculoskeletal and connective tissue disorders Mobility decreased	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Abdominal neoplasm	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer recurrent	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Balance disorder	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Cerebellar infarction	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Cerebrovascular accident	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Convulsion	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.42% 2/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Dementia	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Dizziness	0.42% 4/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Grand mal convulsion	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Headache	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Presyncope	0.31% 3/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Somnolence	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Subarachnoid haemorrhage	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Syncope	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	1.1% 5/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Thalamic infarction	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Transient ischaemic attack	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Nervous system disorders Unresponsive to stimuli	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Abnormal behaviour	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Aggression	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.85% 4/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Behavioural and psychiatric symptoms of dementia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Confusional state	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.64% 3/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Delusion	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Depression	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Hallucination	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Insomnia	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Mental status changes	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Paranoia	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Poriomania	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Psychiatric disorders Suicide attempt	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Renal and urinary disorders Calculus ureteric	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Renal and urinary disorders Renal failure	0.00% 0/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Renal and urinary disorders Renal failure acute	0.31% 3/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Renal and urinary disorders Urinary retention	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Reproductive system and breast disorders Breast mass	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Respiratory, thoracic and mediastinal disorders Cough	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Respiratory, thoracic and mediastinal disorders Pneumomediastinum	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.31% 3/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Vascular disorders Deep vein thrombosis	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Vascular disorders Hypotension	0.21% 2/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.21% 1/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Vascular disorders Orthostatic hypotension	0.10% 1/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	0.00% 0/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.

Other adverse events

Measure	Donepezil SR 23 mg n=963 participants at risk Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period.	Donepezil IR 10 mg n=471 participants at risk Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period.
Gastrointestinal disorders Diarrhoea	7.9% 76/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	5.3% 25/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Nausea	11.7% 113/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	3.4% 16/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Gastrointestinal disorders Vomiting	8.9% 86/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	2.5% 12/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.
Metabolism and nutrition disorders Anorexia	5.3% 51/963 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.	1.7% 8/471 • All adverse events (AEs) were recorded from the time of informed consent until after the Final Visit or Early Termination. Serious adverse events (SAEs) were monitored through the termination visit and through 30 days after study drug discontinuation, whichever was longer.

Additional Information

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Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place