Trial Outcomes & Findings for Study of DU-176b Aged 80 Years or Older (NCT NCT02801669)

Last Updated: 2020-11-19

Results Overview

Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

984 participants

Primary outcome timeframe

Randomization up to the time of onset of the initial composite event of stroke or systemic embolic event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Results posted on

2020-11-19

Participant Flow

A total of 984 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment at 164 clinic centers in Japan. Of the 984 participants, 982 received treatment.

Participants were assigned to the DU-176b or placebo group in a 1:1 ratio using a stratified randomization method with the CHADS2 index score (≤2, ≥3) as a stratification factor.

Participant milestones

Participant milestones
Measure	DU-176b 15 mg Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo Participants who were randomized to oral placebo administered once daily.
Overall Study STARTED	492	492
Overall Study Received at Least 1 Dose of Study Drug	492	490
Overall Study COMPLETED	341	340
Overall Study NOT COMPLETED	151	152

Reasons for withdrawal

Reasons for withdrawal
Measure	DU-176b 15 mg Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo Participants who were randomized to oral placebo administered once daily.
Overall Study Death	66	69
Overall Study Withdrawal by Subject	81	77
Overall Study Other	4	6

Baseline Characteristics

Study of DU-176b Aged 80 Years or Older

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=492 Participants Participants who were randomized to oral placebo administered once daily.	Total n=984 Participants Total of all reporting groups
Age, Continuous	86.7 years STANDARD_DEVIATION 4.22 • n=5 Participants	86.4 years STANDARD_DEVIATION 4.27 • n=7 Participants	86.6 years STANDARD_DEVIATION 4.24 • n=5 Participants
Age, Customized <85 years	173 Participants n=5 Participants	181 Participants n=7 Participants	354 Participants n=5 Participants
Age, Customized 85 to <90 years	190 Participants n=5 Participants	184 Participants n=7 Participants	374 Participants n=5 Participants
Age, Customized 90 to <95 years	110 Participants n=5 Participants	106 Participants n=7 Participants	216 Participants n=5 Participants
Age, Customized 95 years or older	19 Participants n=5 Participants	21 Participants n=7 Participants	40 Participants n=5 Participants
Sex: Female, Male Female	280 Participants n=5 Participants	285 Participants n=7 Participants	565 Participants n=5 Participants
Sex: Female, Male Male	212 Participants n=5 Participants	207 Participants n=7 Participants	419 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	492 Participants n=5 Participants	492 Participants n=7 Participants	984 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Japan	492 participants n=5 Participants	492 participants n=7 Participants	984 participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization up to the time of onset of the initial composite event of stroke or systemic embolic event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: The primary outcome was assessed in the Intent-to-Treat (ITT) analysis set.

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=492 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With a Composite Endpoint of Stroke and Systemic Embolic Events (SEE) in Participants Who Were Administered DU-176b Compared With Placebo	15 Participants	44 Participants

PRIMARY outcome

Population: The primary outcome was assessed in the Intent-to-Treat (ITT) analysis set.

Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. Subcomponents of stroke (ischemic and hemorrhagic) were also reported. A systemic embolic event (SEE) was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation).

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=492 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo Stroke	12 Participants	40 Participants
Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo Systemic Embolic Events (SEE)	3 Participants	6 Participants
Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo Ischaemic Stroke	12 Participants	39 Participants
Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo Hemorrhagic Stroke	0 Participants	2 Participants
Number of Participants With Stroke and Systemic Embolic Events (SEE), Including Subcomponents of Stroke and Composite Event of Ischemic Stroke and SEE in Participants Who Were Administered DU-176b Compared With Placebo Ischemic Stroke/SEE	15 Participants	43 Participants

SECONDARY outcome

Timeframe: Randomization up to the time of onset of the initial composite event of stroke, systemic embolic event, or death due to CV, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=492 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and Death Due to Cardiovascular in Participants Who Were Administered DU-176b Compared With Placebo	52 Participants	72 Participants

SECONDARY outcome

Timeframe: Randomization up to the time of onset of the initial MACE event, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.

Major adverse cardiovascular events (MACE) included a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal systemic embolic events (SEE), and deaths due to cardiovascular (CV) or bleeding. Stroke was defined as an abrupt onset, over minutes to hours, of symptoms representing focal neurological deficit in the domain supplied by a single brain artery (including the retinal artery) and that was not due to an identifiable non-vascular cause (such as brain tumor or trauma). The deficit symptoms had to either last for more than 24 hours or result in death within 24 hours of symptom onset. A SEE was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis and instrumentation).

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=492 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With a Composite Endpoint of a Major Adverse Cardiovascular Event (MACE) in Participants Who Were Administered DU-176b Compared With Placebo	51 Participants	72 Participants

SECONDARY outcome

Timeframe: Randomization up to the time of onset of the initial composite event of stroke, SEE, all-cause mortality, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=492 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With a Composite Endpoint of Stroke, Systemic Embolic Events (SEE), and All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo	74 Participants	98 Participants

SECONDARY outcome

Timeframe: Randomization up to the time of onset of the initial composite event of stroke, SEE, major bleeding, all-cause mortality, or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.

Net clinical benefit included a composite of stroke, systemic embolic events (SEE), major bleeding, and all-cause mortality. Stroke was defined as an abrupt onset of symptoms representing focal neurological deficit in the domain supplied by a single brain artery that was not due to an identifiable non-vascular cause. The deficit symptoms had to either last \>24 hours or result in death within 24 hours of symptom onset. A SEE was defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms. Major bleeding was defined as overt bleeding that met at least 1 of the following criteria: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intraarticular, or pericardial bleeding, or symptomatic intramuscular bleeding accompanied by compartment syndrome; or clinically overt bleeding that decreased hemoglobin by at least 2.0 g/dL and required blood transfusion.

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=492 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With Net Clinical Benefit in Participants Who Were Administered DU-176b Compared With Placebo	87 Participants	103 Participants

SECONDARY outcome

Timeframe: Randomization up to death (due to any cause), or study discontinuation, or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: Secondary outcomes were assessed in the Intent-to-Treat (ITT) analysis set.

All-cause mortality was defined as death due to cardiovascular and mortality due to all other causes.

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=492 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With All-Cause Mortality in Participants Who Were Administered DU-176b Compared With Placebo	66 Participants	69 Participants

SECONDARY outcome

Timeframe: Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: Safety outcomes were assessed in the Safety analysis set.

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=490 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Major bleeding	20 Participants	11 Participants
Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Major bleeding, Intracranial haemorrhage	2 Participants	4 Participants
Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Fatal bleeding	0 Participants	2 Participants
Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Fatal bleeding, Intracranial haemorrhage	0 Participants	1 Participants
Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Fatal bleeding, Non-Intracranial haemorrhage	0 Participants	1 Participants
Number of Participants With Major Bleeding During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Life-threatening bleeding	8 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: Safety outcomes were assessed in the Safety analysis set.

Major bleeding was defined as overt bleeding that met at least 1 of the following criteria: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intraarticular, or pericardial bleeding, or symptomatic intramuscular bleeding accompanied by compartment syndrome; or clinically overt bleeding that decreased hemoglobin by at least 2.0 g/dL and required blood transfusion. Clinically overt bleeding that required treatment was taken to be clinically relevant non-major bleeding, including for example (but was not limited to) the bleeding that led to the diagnostic tests and treatments as specified in the protocol. The clinically overt bleeding requiring treatment did not include outpatient examinations that did not involve any of the medical procedures (diagnostic tests or treatments) as specified in the protocol.

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=490 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With Major Bleeding or Clinically Relevant Non-major Bleedings During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Major or clinically relevant non-major bleeding	97 Participants	62 Participants
Number of Participants With Major Bleeding or Clinically Relevant Non-major Bleedings During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Clinically relevant non-major bleeding	81 Participants	52 Participants

SECONDARY outcome

Timeframe: Baseline up to study discontinuation or end of study (whichever comes first), up to 3 years 2 months postdose (maximum follow-up time)

Population: Safety outcomes were assessed in the Safety analysis set.

All bleeding events include major and clinically relevant non-major bleeding events. Other overt bleeding events that did not meet the criteria for major bleeding or clinically relevant non-major bleeding were taken to be minor bleeding (for example, epistaxis that did not require treatment). All events other than the above (such as a decrease in hemoglobin without overt bleeding) were classified as "non-bleeding event."

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=492 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=490 Participants Participants who were randomized to oral placebo administered once daily.
Number of Participants With All Bleeding Events and Minor Bleeding Events During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo All bleeding	241 Participants	202 Participants
Number of Participants With All Bleeding Events and Minor Bleeding Events During On-Treatment Period in Participants Who Were Administered DU-176b Compared With Placebo Minor bleeding	190 Participants	177 Participants

SECONDARY outcome

Timeframe: Week 8: Predose,1-3 hours (h) and 4-8 h postdose

Population: Plasma concentration was assessed in the Pharmacokinetic Analysis Set.

Outcome measures

Outcome measures
Measure	DU-176b 15 mg n=451 Participants Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo Participants who were randomized to oral placebo administered once daily.
Plasma Concentration of DU-176 in Participants Who Were Administered DU-176b Week 8: Predose (trough)	17.3 ng/mL Standard Deviation 13.9	—
Plasma Concentration of DU-176 in Participants Who Were Administered DU-176b Week 8: 1-3 h	93.3 ng/mL Standard Deviation 57.8	—
Plasma Concentration of DU-176 in Participants Who Were Administered DU-176b Week 8: 4-8 h	93.4 ng/mL Standard Deviation 37.5	—

Adverse Events

DU-176b 15 mg

Serious events: 220 serious events

Other events: 461 other events

Deaths: 66 deaths

Placebo

Serious events: 238 serious events

Other events: 454 other events

Deaths: 69 deaths

Serious adverse events

Other adverse events

Additional Information

Contact for Clinical Trial Information

Daiichi Sankyo

Phone: 908-992-6400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	DU-176b 15 mg n=492 participants at risk Participants who were randomized to oral DU-176b administered at a dose of 15 mg once daily.	Placebo n=490 participants at risk Participants who were randomized to oral placebo administered once daily.
Respiratory, thoracic and mediastinal disorders Epistaxis	8.5% 42/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	3.3% 16/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Skin and subcutaneous tissue disorders Haemorrhage subcutaneous	14.8% 73/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	18.0% 88/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Renal and urinary disorders Haematuria	8.9% 44/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	2.9% 14/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Infections and infestations Nasopharyngitis	22.6% 111/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	24.7% 121/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Infections and infestations Pneumonia	9.6% 47/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	10.8% 53/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Infections and infestations Urinary tract infection	5.5% 27/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	5.5% 27/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Infections and infestations Bronchitis	7.1% 35/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	3.7% 18/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Blood and lymphatic system disorders Anaemia	7.9% 39/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	4.3% 21/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Metabolism and nutrition disorders Dehydration	7.5% 37/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	6.5% 32/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Cardiac disorders Cardiac failure congestive	8.5% 42/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	10.4% 51/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Vascular disorders Hypertension	5.3% 26/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	4.1% 20/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Gastrointestinal disorders Constipation	10.6% 52/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	9.2% 45/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Gastrointestinal disorders Diarrhoea	6.9% 34/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	9.2% 45/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Musculoskeletal and connective tissue disorders Back pain	10.0% 49/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	6.3% 31/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Injury, poisoning and procedural complications Contusion	8.7% 43/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	10.0% 49/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.
Cardiac disorders Cardiac failure	9.1% 45/492 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.	8.4% 41/490 • Treatment-emergent adverse events (TEAEs) were collected from baseline up to 3 years 2 months postdose. A treatment-emergent adverse event (TEAE) was defined as an adverse event that first appears during treatment, which is absent before treatment or which worsens relative to pre-treatment state. TEAEs are reported in the Safety Analysis Set.