Trial Outcomes & Findings for Safety and Efficacy of Intravenous Natalizumab in Acute Ischemic Stroke (NCT NCT02730455)

Last Updated: 2019-01-08

Results Overview

The composite global measure of functional disability excellent outcome was based on a score of 0 or 1 on the modified Rankin Scale (mRS) and a score of \>=95 on the Barthel Index (BI). mRS measures independence, rather than neurological function, with specific tasks pre- and post-stroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death. BI consists of 10 items that measure a participant's daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. The scores for each of the items are summed to create a total score of 0 to 100. The higher the score, the more "independent" the participant is.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

277 participants

Primary outcome timeframe

Day 90

Results posted on

2019-01-08

Participant Flow

Participants were recruited from 19 sites in Germany, 4 sites in the United Kingdom (UK), 12 sites in Spain, and 18 sites in the United States (US).

A total of 277 participants with acute ischemic stroke were randomized into the study (94 participants in the placebo group, 91 participants in the natalizumab 300 milligram (mg) group, and 92 participants in the natalizumab 600 mg group).

Participant milestones

Participant milestones
Measure	Placebo Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Overall Study STARTED	94	91	92
Overall Study Safety Population	91	90	89
Overall Study Participants Dosed	91	88	91
Overall Study Who Received Total Volume of Study Drug	90	88	89
Overall Study COMPLETED	81	77	81
Overall Study NOT COMPLETED	13	14	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Overall Study Death	5	6	4
Overall Study Consent withdrawn	2	4	1
Overall Study Lost to Follow-up	3	1	4
Overall Study Other	2	2	0

Baseline Characteristics

Safety and Efficacy of Intravenous Natalizumab in Acute Ischemic Stroke

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=94 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=91 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=92 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Total n=277 Participants Total of all reporting groups
Age, Continuous	67.1 years STANDARD_DEVIATION 9.54 • n=5 Participants	66.1 years STANDARD_DEVIATION 10.47 • n=7 Participants	65.6 years STANDARD_DEVIATION 11.09 • n=5 Participants	66.2 years STANDARD_DEVIATION 10.36 • n=4 Participants
Sex: Female, Male Female	29 Participants n=5 Participants	36 Participants n=7 Participants	37 Participants n=5 Participants	102 Participants n=4 Participants
Sex: Female, Male Male	65 Participants n=5 Participants	55 Participants n=7 Participants	55 Participants n=5 Participants	175 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants n=5 Participants	24 Participants n=7 Participants	24 Participants n=5 Participants	76 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	64 Participants n=5 Participants	65 Participants n=7 Participants	65 Participants n=5 Participants	194 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	2 count of participants n=5 Participants	1 count of participants n=7 Participants	1 count of participants n=5 Participants	4 count of participants n=4 Participants
Race/Ethnicity, Customized White	27 count of participants n=5 Participants	25 count of participants n=7 Participants	25 count of participants n=5 Participants	77 count of participants n=4 Participants
Race/Ethnicity, Customized Not Reported Due to Confidentiality Regulations	64 count of participants n=5 Participants	65 count of participants n=7 Participants	65 count of participants n=5 Participants	194 count of participants n=4 Participants
Race/Ethnicity, Customized Missing	1 count of participants n=5 Participants	0 count of participants n=7 Participants	1 count of participants n=5 Participants	2 count of participants n=4 Participants

PRIMARY outcome

Timeframe: Day 90

Population: Modified Intent-to-Treat (MITT) population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is the number of participants with data available for analysis.

Outcome measures

Outcome measures
Measure	Placebo n=90 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=88 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=89 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Percentage of Participants With Composite Global Measure of Functional Disability Excellent Outcome at Day 90	54.1 percentage of participants	41.5 percentage of participants	39.9 percentage of participants

SECONDARY outcome

Timeframe: Day 90

Population: MITT population: all randomized participants who had received entire infusion of study treatment. Participants who were accidentally enrolled based on conditions that mimicked stroke symptom at presentation were excluded from MITT population. Number analyzed is number of participants with data available for analysis.

Excellent mRS is defined as mRS score of 0 or 1. mRS measures independence, rather than neurological function, with specific tasks pre- and poststroke. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death.

Outcome measures

Outcome measures
Measure	Placebo n=86 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=83 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=82 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Percentage of Participants With Excellent Outcome in mRS Score at Day 90	41 percentage of participants	29 percentage of participants	26 percentage of participants

SECONDARY outcome

Timeframe: Day 90

Excellent BI outcome is defined as a score of \>=95. BI consists of 10 items that measure a participant's daily functioning, specifically the activities of daily living and mobility. The items include feeding, moving from wheelchair to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder. The scores for each of the items are summed to create a total score of 0 to 100. The higher the score, the more "independent" the participant is.

Outcome measures

Outcome measures
Measure	Placebo n=86 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=81 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=81 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Percentage of Participants With Excellent Outcome in BI Score at Day 90	67 percentage of participants	54 percentage of participants	54 percentage of participants

SECONDARY outcome

Timeframe: Day 90

The SIS-16 is a 16-item physical dimension instrument that was developed as a brief, stand-alone tool for measuring the physical aspects of stroke recovery. The 16 physical aspects are rated on a 1 to 5 scale as follows: not difficult at all (5), a little difficult (4), somewhat difficult (3), very difficult (2), and could not do at all (1). Total score range is 16 to 80, with higher scores indicating higher levels of health-related quality of life and function.

Outcome measures

Outcome measures
Measure	Placebo n=84 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=80 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=77 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Stroke Impact Scale-16 (SIS-16) Score Using a Repeated Measures Mixed Effects Model at Day 90	76.21 score on a scale Standard Deviation 30.783	66.96 score on a scale Standard Deviation 35.493	68.10 score on a scale Standard Deviation 31.461

SECONDARY outcome

Timeframe: Day 90

The MoCA is a global cognitive screening test with favorable psychometric properties It screens 8 domains: visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, and orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 0 to 30 points; a score of 26 or above is considered normal, \<10 (severe cognitive impairment), 10-17 (moderate cognitive impairment) and \>=18 (mild cognitive impairment).

Outcome measures

Outcome measures
Measure	Placebo n=69 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=74 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=69 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Montreal Cognitive Assessment (MoCA) Score at Day 90	21.23 score on a scale Standard Deviation 8.412	20.73 score on a scale Standard Deviation 8.141	20.90 score on a scale Standard Deviation 8.223

SECONDARY outcome

Timeframe: Baseline, Day 90

The NIHSS is a reliable tool for rapidly evaluating the effects of acute cerebral infarction. A trained observer rates the participant's ability to answer questions and perform activities relating to level of consciousness, language, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, sensory loss, and extinction and inattention (formerly neglect). There are 15 items. Total score ranges from 0 as normal to a maximum possible total severity score of 42 for all items. Higher the score, more the severity. A negative change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=77 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=76 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=71 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Change From Baseline in National Institute of Health Stroke Scale (NIHSS) Score at Day 90	-6.14 score on a scale Standard Deviation 6.920	-5.17 score on a scale Standard Deviation 7.937	-6.28 score on a scale Standard Deviation 6.510

SECONDARY outcome

Timeframe: Baseline up to Day 90

Population: The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.

An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=90 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=89 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Number of Participants Experiencing Adverse Events (AE)	84 participants	81 participants	82 participants

SECONDARY outcome

Timeframe: Baseline up to Day 90

Population: The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.

A SAE is any untoward medical occurrence that at any dose results in death, is a life-threatening event, requires inpatient hospitalization, results in a significant disability/incapacity or congenital anomaly.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=90 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=89 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Number of Participants Experiencing Serious Adverse Events (SAE)	19 participants	23 participants	29 participants

SECONDARY outcome

Timeframe: Day 90

Percentage of participants with dose response was evaluated in proportion of excellent outcome on mRS and BI.

Outcome measures

Outcome measures
Measure	Placebo n=90 Participants Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=88 Participants Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=89 Participants Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Percentage of Participants With Dose Response at Day 90 mRS (0, 1)	41 percentage of participants	29 percentage of participants	26 percentage of participants
Percentage of Participants With Dose Response at Day 90 BI (>=95)	67 percentage of participants	54 percentage of participants	54 percentage of participants

Adverse Events

Placebo

Serious events: 19 serious events

Other events: 67 other events

Deaths: 5 deaths

Natalizumab 300 mg IV

Serious events: 23 serious events

Other events: 69 other events

Deaths: 6 deaths

Natalizumab 600 mg IV

Serious events: 29 serious events

Other events: 65 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Biogen Study Medical Director

Biogen

Phone: 866-633-4636

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=91 participants at risk Single dose of matching placebo intravenous (IV) to natalizumab on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 300 mg IV n=90 participants at risk Single 300 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).	Natalizumab 600 mg IV n=89 participants at risk Single 600 mg natalizumab IV on Day 1 at one of two treatment windows, either within 9 hours or between 9-24 hours from when the participant was last known normal (LKN).
Blood and lymphatic system disorders Anaemia	3.3% 3/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	3.3% 3/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Cardiac disorders Atrial fibrillation	8.8% 8/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	6.7% 6/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	7.9% 7/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Gastrointestinal disorders Abdominal pain	1.1% 1/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	1.1% 1/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Gastrointestinal disorders Constipation	19.8% 18/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	21.1% 19/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	25.8% 23/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Gastrointestinal disorders Diarrhoea	4.4% 4/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	3.4% 3/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Gastrointestinal disorders Dysphagia	1.1% 1/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	6.7% 6/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	2.2% 2/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Gastrointestinal disorders Nausea	4.4% 4/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	7.8% 7/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	6.7% 6/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Gastrointestinal disorders Vomiting	3.3% 3/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	7.8% 7/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	1.1% 1/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
General disorders Fatigue	5.5% 5/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	1.1% 1/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	1.1% 1/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
General disorders Pain	3.3% 3/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	7.8% 7/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	2.2% 2/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
General disorders Pyrexia	12.1% 11/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	21.1% 19/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	15.7% 14/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Infections and infestations Pneumonia	3.3% 3/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	2.2% 2/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	9.0% 8/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Infections and infestations Urinary tract infection	12.1% 11/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	15.6% 14/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	16.9% 15/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Injury, poisoning and procedural complications Fall	5.5% 5/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	7.8% 7/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Metabolism and nutrition disorders Hypokalaemia	6.6% 6/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	13.3% 12/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	6.7% 6/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	1.1% 1/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Musculoskeletal and connective tissue disorders Pain in extremity	2.2% 2/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	2.2% 2/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Nervous system disorders Haemorrhagic transformation stroke	4.4% 4/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	4.4% 4/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Nervous system disorders Headache	16.5% 15/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	17.8% 16/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	22.5% 20/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Psychiatric disorders Agitation	8.8% 8/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	0.00% 0/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Psychiatric disorders Anxiety	4.4% 4/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	2.2% 2/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	7.9% 7/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Psychiatric disorders Depression	17.6% 16/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	14.4% 13/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	11.2% 10/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Psychiatric disorders Insomnia	4.4% 4/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	12.2% 11/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	11.2% 10/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Renal and urinary disorders Haematuria	5.5% 5/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	3.3% 3/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	3.4% 3/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Renal and urinary disorders Urinary retention	6.6% 6/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	4.4% 4/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	3.4% 3/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	5.5% 5/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	5.6% 5/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	1.1% 1/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Vascular disorders Hypertension	6.6% 6/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	7.8% 7/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	9.0% 8/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.
Vascular disorders Hypotension	5.5% 5/91 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	4.4% 4/90 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.	7.9% 7/89 • Baseline up to Day 90 The safety population was defined as participants who had received any study treatment, including cases of complete or incomplete infusion.