Clinical Trial Results:
A Phase 2b/3 Multicenter, Randomized, Double-Masked, Dose-Ranging Study Comparing the Efficacy and Safety of Emixustat Hydrochloride (ACU-4429) with Placebo for the Treatment of Geographic Atrophy Associated with Dry Age-Related Macular Degeneration

Trial information Top of page
Trial identification
Sponsor protocol code	4429-202
Additional study identifiers
ISRCTN number	-
US NCT number	NCT01802866
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Acucela Inc.
Sponsor organisation address	600 University Street, Suite 2900, Seattle, United States, 98101
Public contact	Acucela Clinical Trials Helpdesk, Acucela Inc., +1 2068058310, clinicaltrials@acucela.com
Scientific contact	Acucela Clinical Trials Helpdesk, Acucela Inc., 2068058300 2068058310, clinicaltrials@acucela.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	15 Apr 2016
Is this the analysis of the primary completion data?	Yes
Primary completion date	15 Apr 2016
Global end of trial reached?	Yes
Global end of trial date	15 Apr 2016
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To determine if ACU-4429 reduces the rate of progression of geographic atrophy (GA) compared to placebo in subjects with dry age-related macular degeneration (AMD).
Protection of trial subjects	All subjects were required to read and sign an informed consent form.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	18 Jan 2013
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Germany: 57
Country: Number of subjects enrolled	United States: 451
Worldwide total number of subjects	508
EEA total number of subjects	57
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	28
From 65 to 84 years	382
85 years and over	98

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	A total of 503 subjects were randomized and received study drug at 49 sites in the United States and 7 sites in Germany from February 2013 to April 2016.
Pre-assignment
Screening details	A total of 968 subjects were screened, and 508 subjects were randomized. The most common reason for failing screening was the total area of GA not meeting an inclusioncriterion (n = 219/460 screen failures).
Period 1
Period 1 title	Overall Trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Monitor, Data analyst, Carer, Assessor
Arms
Are arms mutually exclusive	Yes
Arm title	Emixustat 2.5 mg
Arm description	Subjects took one oral tablet of emixustat 2.5 mg per day for 24 months.
Arm type	Experimental
Investigational medicinal product name	emixustat hydrochloride
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Emixustat 2.5 mg oral tablet taken once daily
Arm title	Emixustat 5 mg
Arm description	Subjects took one oral tablet of emixustat 5 mg per day for 24 months.
Arm type	Experimental
Investigational medicinal product name	emixustat hydrochloride
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Emixustat 5 mg oral tablet taken once daily
Arm title	Emixustat 10 mg
Arm description	Subjects took one oral tablet of emixustat 5 mg per day for 1 month, then one oral tablet of emixustat 7.5 mg per day for 1 month, and then one oral tablet of emixustat 10 mg per day for 22 months.
Arm type	Experimental
Investigational medicinal product name	emixustat hydrochloride
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	One oral tablet of emixustat 5 mg per day for 1 month, then one oral tablet of emixustat 7.5 mg per day for 1 month, and then one oral tablet of emixustat 10 mg per day for 22 months.
Arm title	Placebo
Arm description	Subjects took one oral tablet of placebo per day for 24 months.
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	1 tablet taken by mouth each day
Number of subjects in period 1 Emixustat 2.5 mg Emixustat 5 mg Emixustat 10 mg Placebo Started 134 135 103 136 Completed 78 81 53 108 Not completed 56 54 50 28      Adverse event, serious fatal 3 2 1 -      Consent withdrawn by subject 16 8 9 6      Physician decision 1 - - 2      Randomized in error, did not receive study drug 1 - - 3      Adverse event, non-fatal 33 44 39 15      Lost to follow-up 2 - 1 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Emixustat 2.5 mg
Reporting group description	Subjects took one oral tablet of emixustat 2.5 mg per day for 24 months.
Reporting group title	Emixustat 5 mg
Reporting group description	Subjects took one oral tablet of emixustat 5 mg per day for 24 months.
Reporting group title	Emixustat 10 mg
Reporting group description	Subjects took one oral tablet of emixustat 5 mg per day for 1 month, then one oral tablet of emixustat 7.5 mg per day for 1 month, and then one oral tablet of emixustat 10 mg per day for 22 months.
Reporting group title	Placebo
Reporting group description	Subjects took one oral tablet of placebo per day for 24 months.
Reporting group values Emixustat 2.5 mg Emixustat 5 mg Emixustat 10 mg Placebo Total Number of subjects 134 135 103 136 508 Age categorical Units: Subjects     In utero 0     Preterm newborn infants (gestational age < 37 wks) 0     Newborns (0-27 days) 0     Infants and toddlers (28 days-23 months) 0     Children (2-11 years) 0     Adolescents (12-17 years) 0     Adults (18-64 years) 0     From 65-84 years 0     85 years and over 0 Age continuous Units: years     arithmetic mean (standard deviation) 78.2 ( 7.11 ) 78.2 ( 7.79 ) 77.2 ( 7.96 ) 77.1 ( 8.13 ) - Gender categorical Units: Subjects     Female 79 73 61 77 290     Male 55 62 42 59 218

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Emixustat 2.5 mg
Reporting group description	Subjects took one oral tablet of emixustat 2.5 mg per day for 24 months.
Reporting group title	Emixustat 5 mg
Reporting group description	Subjects took one oral tablet of emixustat 5 mg per day for 24 months.
Reporting group title	Emixustat 10 mg
Reporting group description	Subjects took one oral tablet of emixustat 5 mg per day for 1 month, then one oral tablet of emixustat 7.5 mg per day for 1 month, and then one oral tablet of emixustat 10 mg per day for 22 months.
Reporting group title	Placebo
Reporting group description	Subjects took one oral tablet of placebo per day for 24 months.

End points Top of page

Primary: Mean rate of change from Baseline in the total area of geographic atrophy in the study eye Top of page
End point title	Mean rate of change from Baseline in the total area of geographic atrophy in the study eye
End point description
End point type	Primary
End point timeframe	24 Months
End point values Emixustat 2.5 mg Emixustat 5 mg Emixustat 10 mg Placebo Number of subjects analysed 133 134 103 133 Units: mm^2 per year     least squares mean (standard error) 1.69 ( 0.115 ) 1.83 ( 0.116 ) 1.84 ( 0.143 ) 1.69 ( 0.108 )
Statistical analysis title	Least square mean difference against placebo
Comparison groups	Emixustat 2.5 mg v Emixustat 5 mg v Emixustat 10 mg v Placebo
Number of subjects included in analysis	503
Analysis specification	Pre-specified
Analysis type	superiority
P-value	≥ 0.81 [1]
Method	Mixed models analysis
Parameter type	Mean difference (final values)
Point estimate	0.15
Confidence interval
level	95%
sides	2-sided
lower limit	-0.2
upper limit	0.5
Variability estimate	Standard error of the mean
Dispersion value	0.18
Notes [1] - 2.5 mg group vs. placebo group -- p = 0.99 5 mg group vs. placebo group -- p = 0.81 10 mg group vs. placebo group -- p = 0.81

Primary: Mean rate of change from Baseline in the total area of geographic atrophy in the study eye Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	24 months
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	19.0
Reporting groups
Reporting group title	Emixustat 2.5 mg
Reporting group description	Subjects took one oral tablet of emixustat 2.5 mg per day for 24 months.
Reporting group title	Emixustat 5 mg
Reporting group description	Subjects took one oral tablet of emixustat 5 mg per day for 24 months.
Reporting group title	Emixustat 10 mg
Reporting group description	Subjects took one oral tablet of emixustat 5 mg per day for 1 month, then one oral tablet of emixustat 7.5 mg per day for 1 month, and then one oral tablet of emixustat 10 mg per day for 22 months.
Reporting group title	Placebo
Reporting group description	Subjects took one oral tablet of placebo per day for 24 months.
Serious adverse events Emixustat 2.5 mg Emixustat 5 mg Emixustat 10 mg Placebo Total subjects affected by serious adverse events      subjects affected / exposed 34 / 133 (25.56%) 41 / 134 (30.60%) 20 / 103 (19.42%) 30 / 133 (22.56%)      number of deaths (all causes) 3 2 1 0      number of deaths resulting from adverse events 3 2 1 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Plasma cell myeloma      subjects affected / exposed 2 / 133 (1.50%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Prostate cancer      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 2 / 103 (1.94%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Breast cancer      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Chronic lymphocytic leukaemia      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Intestinal adenocarcinoma      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Laryngeal cancer recurrent      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lung adenocarcinoma      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lung cancer metastatic      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Lung neoplasm malignant      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Prostate cancer recurrent      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Salivary gland cancer      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Breast cancer metastatic      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Small cell lung cancer limited stage      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Vascular disorders Hypotension      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Orthostatic hypotension      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Peripheral artery occlusion      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Accelerated hypertension      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Temporal arteritis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 General disorders and administration site conditions Asthenia      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Chest pain      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Death      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 Systemic inflammatory response syndrome      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Reproductive system and breast disorders Cystocele      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Adnexa uteri mass      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease      subjects affected / exposed 3 / 133 (2.26%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 3 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Acute respiratory failure      subjects affected / exposed 2 / 133 (1.50%) 0 / 134 (0.00%) 0 / 103 (0.00%) 2 / 133 (1.50%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Asthma      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Dyspnoea      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Dyspnoea exertional      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pleural effusion      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pneumonia aspiration      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Pulmonary embolism      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 2 / 133 (1.50%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 hypoxia      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Investigations Cardiac murmur      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Transaminases increased      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Injury, poisoning and procedural complications Fall      subjects affected / exposed 0 / 133 (0.00%) 6 / 134 (4.48%) 2 / 103 (1.94%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 7 1 / 2 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Femur fracture      subjects affected / exposed 1 / 133 (0.75%) 2 / 134 (1.49%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hip fracture      subjects affected / exposed 0 / 133 (0.00%) 2 / 134 (1.49%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 3 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Road traffic accident      subjects affected / exposed 1 / 133 (0.75%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0 Cervical vertebral fracture      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Concussion      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Delayed recovery from anaesthesia      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Foot fracture      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Infusion related reaction      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lumbar vertebral fracture      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 pubis fracture      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Rib fracture      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Spinal compression fracture      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Subdural haematoma      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Eyelid injury      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Facial bones fracture      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Tendon rupture      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac disorders Atrial fibrillation      subjects affected / exposed 3 / 133 (2.26%) 1 / 134 (0.75%) 2 / 103 (1.94%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 3 0 / 1 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Myocardial infarction      subjects affected / exposed 2 / 133 (1.50%) 1 / 134 (0.75%) 1 / 103 (0.97%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 2 0 / 1 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac failure congestive      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 2 / 103 (1.94%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0 Sinus node dysfunction      subjects affected / exposed 1 / 133 (0.75%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Angina unstable      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Aortic valve incompetence      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Aortic valve stenosis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardiac arrest      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Cardiac failure acute      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cardio-respiratory arrest      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Coronary artery disease      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Coronary artery stenosis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Ischaemic cardiomyopathy      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Sinus bradycardia      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Acute myocardial infarction      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Angina pectoris      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Atrioventricular block      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Ventricular tachycardia      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Nervous system disorders Syncope      subjects affected / exposed 2 / 133 (1.50%) 0 / 134 (0.00%) 1 / 103 (0.97%) 4 / 133 (3.01%)      occurrences causally related to treatment / all 0 / 2 0 / 0 0 / 1 0 / 4      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cerebrovascular accident      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 2 / 103 (1.94%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 2 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Carotid artery stenosis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Dizziness      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Seizure      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Subarachnoid haemorrhage      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cerebral infarction      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Transient ischaemic attack      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 3 / 133 (2.26%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 3 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Coagulopathy      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Ear and labyrinth disorders Vertigo positional      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Eye disorders Optic ischaemic neuropathy      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Optic neuropathy      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Retinal artery occlusion      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastrointestinal disorders Small intestinal obstruction      subjects affected / exposed 0 / 133 (0.00%) 2 / 134 (1.49%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Abdominal hernia      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Diverticulum intestinal haemorrhagic      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastric ulcer      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastrointestinal haemorrhage      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Intestinal obstruction      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lower gastrointestinal haemorrhage      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pancreatitis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Rectal haemorrhage      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Upper gastrointestinal haemorrhage      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Colitis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 2 / 133 (1.50%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Inguinal hernia      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Intra-abdominal haematoma      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Hepatobiliary disorders Bile duct obstruction      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cholecystitis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cholelithiasis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Skin and subcutaneous tissue disorders Angioedema      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Renal and urinary disorders Acute kidney injury      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 2 / 103 (1.94%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Ureterolithiasis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Renal failure      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Musculoskeletal and connective tissue disorders Osteoarthritis      subjects affected / exposed 2 / 133 (1.50%) 2 / 134 (1.49%) 1 / 103 (0.97%) 4 / 133 (3.01%)      occurrences causally related to treatment / all 0 / 2 0 / 2 0 / 1 0 / 4      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Spinal pain      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Back pain      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Lumbar spinal stenosis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Spondylolisthesis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Infections and infestations Pneumonia      subjects affected / exposed 2 / 133 (1.50%) 2 / 134 (1.49%) 0 / 103 (0.00%) 3 / 133 (2.26%)      occurrences causally related to treatment / all 0 / 2 0 / 2 0 / 0 0 / 3      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Sepsis      subjects affected / exposed 2 / 133 (1.50%) 2 / 134 (1.49%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Cellulitis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Appendicitis perforated      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Arthritis bacterial      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Atypical pneumonia      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Bronchitis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Bronchopulmonary aspergillosis allergic      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Clostridium difficile colitis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Diverticulitis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Endocarditis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Enterocolitis infectious      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Gastroenteritis      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Influenza      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Parainfluenzae virus infection      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pneumonia pseudomonal      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pyelonephritis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Pyelonephritis acute      subjects affected / exposed 0 / 133 (0.00%) 1 / 134 (0.75%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 1 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Streptococcal sepsis      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Appendicitis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Escherichia sepsis      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Escherichia urinary tract infection      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Herpes zoster      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Urinary tract infection      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 2 / 133 (1.50%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0 Metabolism and nutrition disorders Hyponatraemia      subjects affected / exposed 1 / 133 (0.75%) 0 / 134 (0.00%) 0 / 103 (0.00%) 0 / 133 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 1 0 / 0 0 / 0 0 / 0 Dehydration      subjects affected / exposed 0 / 133 (0.00%) 0 / 134 (0.00%) 0 / 103 (0.00%) 1 / 133 (0.75%)      occurrences causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Emixustat 2.5 mg Emixustat 5 mg Emixustat 10 mg Placebo Total subjects affected by non serious adverse events      subjects affected / exposed 127 / 133 (95.49%) 131 / 134 (97.76%) 101 / 103 (98.06%) 127 / 133 (95.49%) Investigations Visual acuity tests abnormal      subjects affected / exposed 9 / 133 (6.77%) 19 / 134 (14.18%) 14 / 103 (13.59%) 9 / 133 (6.77%)      occurrences all number 9 25 16 9 Injury, poisoning and procedural complications Fall      subjects affected / exposed 7 / 133 (5.26%) 14 / 134 (10.45%) 8 / 103 (7.77%) 20 / 133 (15.04%)      occurrences all number 7 16 13 26 Vascular disorders Hypertension      subjects affected / exposed 12 / 133 (9.02%) 11 / 134 (8.21%) 5 / 103 (4.85%) 17 / 133 (12.78%)      occurrences all number 13 14 6 20 Cardiac disorders Atrial fibrillation      subjects affected / exposed 6 / 133 (4.51%) 3 / 134 (2.24%) 0 / 103 (0.00%) 7 / 133 (5.26%)      occurrences all number 6 4 0 8 Nervous system disorders Visual field defect      subjects affected / exposed 7 / 133 (5.26%) 10 / 134 (7.46%) 12 / 103 (11.65%) 2 / 133 (1.50%)      occurrences all number 8 13 13 2 Headache      subjects affected / exposed 5 / 133 (3.76%) 11 / 134 (8.21%) 6 / 103 (5.83%) 13 / 133 (9.77%)      occurrences all number 6 13 8 18 Dizziness      subjects affected / exposed 5 / 133 (3.76%) 7 / 134 (5.22%) 2 / 103 (1.94%) 9 / 133 (6.77%)      occurrences all number 5 9 2 11 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 7 / 133 (5.26%) 4 / 134 (2.99%) 5 / 103 (4.85%) 1 / 133 (0.75%)      occurrences all number 7 4 6 1 General disorders and administration site conditions Oedema peripheral      subjects affected / exposed 6 / 133 (4.51%) 2 / 134 (1.49%) 1 / 103 (0.97%) 14 / 133 (10.53%)      occurrences all number 7 2 1 17 Eye disorders Delayed dark adaptation      subjects affected / exposed 48 / 133 (36.09%) 88 / 134 (65.67%) 69 / 103 (66.99%) 13 / 133 (9.77%)      occurrences all number 56 105 87 15 Chromatopsia      subjects affected / exposed 13 / 133 (9.77%) 30 / 134 (22.39%) 22 / 103 (21.36%) 4 / 133 (3.01%)      occurrences all number 13 35 23 4 Visual impairment      subjects affected / exposed 12 / 133 (9.02%) 25 / 134 (18.66%) 20 / 103 (19.42%) 19 / 133 (14.29%)      occurrences all number 14 42 25 32 Erythropsia      subjects affected / exposed 12 / 133 (9.02%) 26 / 134 (19.40%) 16 / 103 (15.53%) 6 / 133 (4.51%)      occurrences all number 15 33 19 6 Visual acuity reduced      subjects affected / exposed 18 / 133 (13.53%) 18 / 134 (13.43%) 13 / 103 (12.62%) 18 / 133 (13.53%)      occurrences all number 22 22 15 24 Vision blurred      subjects affected / exposed 10 / 133 (7.52%) 17 / 134 (12.69%) 16 / 103 (15.53%) 10 / 133 (7.52%)      occurrences all number 10 18 18 11 Choroidal neovascularisation      subjects affected / exposed 17 / 133 (12.78%) 10 / 134 (7.46%) 8 / 103 (7.77%) 17 / 133 (12.78%)      occurrences all number 19 11 10 30 Retinal haemorrhage      subjects affected / exposed 8 / 133 (6.02%) 15 / 134 (11.19%) 8 / 103 (7.77%) 11 / 133 (8.27%)      occurrences all number 10 16 10 15 Posterior capsule opacification      subjects affected / exposed 5 / 133 (3.76%) 13 / 134 (9.70%) 9 / 103 (8.74%) 7 / 133 (5.26%)      occurrences all number 6 16 11 10 Vitreous detachment      subjects affected / exposed 10 / 133 (7.52%) 10 / 134 (7.46%) 5 / 103 (4.85%) 11 / 133 (8.27%)      occurrences all number 12 11 5 14 Cataract nuclear      subjects affected / exposed 9 / 133 (6.77%) 11 / 134 (8.21%) 4 / 103 (3.88%) 13 / 133 (9.77%)      occurrences all number 13 16 4 22 Xanthopsia      subjects affected / exposed 2 / 133 (1.50%) 10 / 134 (7.46%) 9 / 103 (8.74%) 1 / 133 (0.75%)      occurrences all number 3 10 9 1 Night blindness      subjects affected / exposed 4 / 133 (3.01%) 3 / 134 (2.24%) 10 / 103 (9.71%) 1 / 133 (0.75%)      occurrences all number 4 3 14 1 Cataract cortical      subjects affected / exposed 6 / 133 (4.51%) 6 / 134 (4.48%) 4 / 103 (3.88%) 7 / 133 (5.26%)      occurrences all number 11 9 7 9 Blepharitis      subjects affected / exposed 2 / 133 (1.50%) 7 / 134 (5.22%) 3 / 103 (2.91%) 4 / 133 (3.01%)      occurrences all number 2 8 3 5 Cyanopsia      subjects affected / exposed 2 / 133 (1.50%) 9 / 134 (6.72%) 1 / 103 (0.97%) 0 / 133 (0.00%)      occurrences all number 2 9 1 0 Dry age-related macular degeneration      subjects affected / exposed 3 / 133 (2.26%) 2 / 134 (1.49%) 6 / 103 (5.83%) 6 / 133 (4.51%)      occurrences all number 3 2 6 6 Punctate keratitis      subjects affected / exposed 3 / 133 (2.26%) 3 / 134 (2.24%) 3 / 103 (2.91%) 7 / 133 (5.26%)      occurrences all number 3 3 3 9 Gastrointestinal disorders Nausea      subjects affected / exposed 4 / 133 (3.01%) 6 / 134 (4.48%) 5 / 103 (4.85%) 11 / 133 (8.27%)      occurrences all number 5 6 6 12 Diarrhoea      subjects affected / exposed 4 / 133 (3.01%) 6 / 134 (4.48%) 2 / 103 (1.94%) 15 / 133 (11.28%)      occurrences all number 4 7 2 25 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 8 / 133 (6.02%) 7 / 134 (5.22%) 3 / 103 (2.91%) 12 / 133 (9.02%)      occurrences all number 10 7 3 13 Musculoskeletal and connective tissue disorders Back pain      subjects affected / exposed 7 / 133 (5.26%) 5 / 134 (3.73%) 6 / 103 (5.83%) 5 / 133 (3.76%)      occurrences all number 7 6 6 8 Arthralgia      subjects affected / exposed 2 / 133 (1.50%) 6 / 134 (4.48%) 2 / 103 (1.94%) 7 / 133 (5.26%)      occurrences all number 3 8 2 8 Infections and infestations Nasopharyngitis      subjects affected / exposed 15 / 133 (11.28%) 12 / 134 (8.96%) 7 / 103 (6.80%) 27 / 133 (20.30%)      occurrences all number 21 12 8 38 Bronchitis      subjects affected / exposed 11 / 133 (8.27%) 5 / 134 (3.73%) 8 / 103 (7.77%) 8 / 133 (6.02%)      occurrences all number 12 5 8 8 Urinary tract infection      subjects affected / exposed 7 / 133 (5.26%) 4 / 134 (2.99%) 6 / 103 (5.83%) 17 / 133 (12.78%)      occurrences all number 12 6 7 18 Herpes zoster      subjects affected / exposed 2 / 133 (1.50%) 1 / 134 (0.75%) 2 / 103 (1.94%) 7 / 133 (5.26%)      occurrences all number 2 1 2 8