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Clinical Trial Results:
A PHASE 2/3, RANDOMIZED, DOUBLE-MASKED, SHAM-CONTROLLED TRIAL OF QPI-1007 DELIVERED BY SINGLE OR MULTI-DOSE INTRAVITREAL INJECTION(S) TO SUBJECTS WITH ACUTE NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY (NAION)

Summary
EudraCT number	2015-003079-31
Trial protocol	DE IT
Global end of trial date	14 Jun 2019

Results information
Results version number	v1(current)
This version publication date	22 Jul 2021
First version publication date	22 Jul 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

QRK207

ISRCTN number

US NCT number

NCT02341560

WHO universal trial number (UTN)

Sponsor organisation name

Quark Pharmaceuticals, Inc.

Sponsor organisation address

7999 Gateway Boulevard, Suite 310, Newark, California , United States, 94560

Public contact

Clinical Operations, Quark Pharmaceuticals Inc., +1 510424020, dcafaro@quarkpharma.com

Scientific contact

Clinical Operations, Quark Pharmaceuticals Inc., +1 510424020, dcafaro@quarkpharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

14 Jun 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 Jun 2019

Global end of trial reached?

Yes

Global end of trial date

14 Jun 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

1. To assess the safety and tolerability of QPI-1007 IVT injections in subjects with recent-onset NAION. 2. To determine the effect on visual function of QPI-1007 IVT injections in subjects with recent-onset NAION.

Protection of trial subjects

The trial was completed according to the International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice. Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Feb 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Italy: 23

Country: Number of subjects enrolled

Australia: 27

Country: Number of subjects enrolled

China: 34

Country: Number of subjects enrolled

India: 111

Country: Number of subjects enrolled

Israel: 47

Country: Number of subjects enrolled

Singapore: 4

Country: Number of subjects enrolled

United States: 463

Worldwide total number of subjects

732

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

480

From 65 to 84 years

252

85 years and over

Subject disposition

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Recruitment details

The study was conducted at a total of 80 sites, with sites in Australia, China, Germany, India, Israel, Italy, Singapore and the United States

Screening details

A total of 1,092 subjects with symptoms indicative of NAION were screened, of which 732 were randomized and 725 received test treatment within 16 days of onset of symptoms.

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

Blinding implementation details

Site study staff conducting and evaluating all ophthalmic evaluations will be masked to the treatment assignment, except those staff who perform the 30-minute post-dose assessments. Only masked staff should perform assessment of AEs for causality and relatedness to study treatment. Masked staff may not perform any Pharmacy tasks that compromise or could potentially compromise the study masking. The pharmacist, Investigator administering study treatment, unmasked coordinator will be unmasked.

Are arms mutually exclusive

Yes

Cohort 1 - ITT

Arm description

Single dose regime, 1.5mg dose of QPI-1007 on day 1. Sham dose administered at months 2 and 4.

Arm type

Experimental

Investigational medicinal product name

QPI-1007

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

1.5 mg QPI-1007 dose. Preparation of QPI-1007 for administration should be done using aseptic techniques. The IVT injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate topical anesthesia and a broad-spectrum topical microbicide should be given prior to the injection.

Cohort 2 - ITT

Arm description

Single dose regime. 3mg QPI-1007 administered on day 1. Sham administration on months 2 and 4.

Arm type

Experimental

Investigational medicinal product name

QPI-1007

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

3mg QPI-1007 dose. Preparation of QPI-1007 for administration should be done using aseptic techniques. The IVT injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate topical anesthesia and a broad-spectrum topical microbicide should be given prior to the injection.

Cohort 3 - ITT

Arm description

Multiple dose regimen. 1.5 mg QPI-1007 dose on day 1, and months 2 and 4.

Arm type

Experimental

Investigational medicinal product name

QPI-1007

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

1.5mg QPI-1007 dose. Preparation of QPI-1007 for administration should be done using aseptic techniques. The IVT injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate topical anesthesia and a broad-spectrum topical microbicide should be given prior to the injection.

Cohort 4 - ITT

Arm description

Multiple dose regimen. 3mg QPI-I007 administered on day 1, and months 2 and 4.

Arm type

Experimental

Investigational medicinal product name

QPI-1007

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

Cohort 5 - ITT

Arm description

Sham control. For subjects receiving the sham-procedure no study drug was prepared but an empty syringe was used. The IVT injection was simulated by touching the eye with the blunt end of a syringe; the globe is not penetrated

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Cohort 1 - ITT	Cohort 2 - ITT	Cohort 3 - ITT	Cohort 4 - ITT	Cohort 5 - ITT
Started	81	81	191	188	191
Completed	75	74	102	102	103
Not completed	6	7	89	86	88
Consent withdrawn by subject	1	4	6	4	3
Physician decision	-	-	1	-	-
Adverse event, non-fatal	1	1	2	-	2
Other	-	-	-	2	-
Study Terminated by Sponsor	-	-	75	76	77
Lost to follow-up	3	2	3	1	2
Lack of efficacy	1	-	-	-	3
Protocol deviation	-	-	2	3	1

Baseline characteristics

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Reporting group title

Cohort 1 - ITT

Reporting group description

Single dose regime, 1.5mg dose of QPI-1007 on day 1. Sham dose administered at months 2 and 4.

Reporting group title

Cohort 2 - ITT

Reporting group description

Single dose regime. 3mg QPI-1007 administered on day 1. Sham administration on months 2 and 4.

Reporting group title

Cohort 3 - ITT

Reporting group description

Multiple dose regimen. 1.5 mg QPI-1007 dose on day 1, and months 2 and 4.

Reporting group title

Cohort 4 - ITT

Reporting group description

Multiple dose regimen. 3mg QPI-I007 administered on day 1, and months 2 and 4.

Reporting group title

Cohort 5 - ITT

Reporting group description

Reporting group values	Cohort 1 - ITT	Cohort 2 - ITT	Cohort 3 - ITT	Cohort 4 - ITT	Cohort 5 - ITT	Total
Number of subjects	81	81	191	188	191	732
Age categorical
Units: Subjects
Adults (18-64 years)	53	60	124	122	121	480
From 65-84 years	28	21	67	66	70	252
Age continuous
Units: years
arithmetic mean (full range (min-max))	61.2 (50 to 80)	60.3 (50 to 77)	61.7 (50 to 80)	61.3 (50 to 80)	61.7 (50 to 79)	-
Gender categorical
Units: Subjects
Female	25	33	58	56	58	230
Male	56	48	133	132	133	502

Subject analysis set title

Cohort 1 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Single dose regime, 1.5mg dose of QPI-1007 on day 1. Sham dose administered at months 2 and 4. mITT ≤ 12days analysis set include subjects who were randomized within 12 days of the onset of symptoms.

Subject analysis set title

Cohort 2 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Single dose regime. 3mg QPI-1007 administered on day 1. Sham administration on months 2 and 4. mITT ≤ 12days analysis set include subjects who were randomized within 12 days of the onset of symptoms.

Subject analysis set title

Cohort 3 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Multiple dose regimen. 1.5 mg QPI-1007 dose on day 1, and months 2 and 4. mITT ≤ 12days analysis set include subjects who were randomized within 12 days of the onset of symptoms.

Subject analysis set title

Cohort 4 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Multiple dose regimen. 3mg QPI-I007 administered on day 1, and months 2 and 4. mITT ≤ 12days analysis set include subjects who were randomized within 12 days of the onset of symptoms.

Subject analysis set title

Cohort 5 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Sham control. mITT ≤ 12days analysis set include subjects who were randomized within 12 days of the onset of symptoms.

Subject analysis set title

Cohort 1 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Single dose regime, 1.5mg dose of QPI-1007 on day 1. Sham dose administered at months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis set title

Cohort 2 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Single dose regime. 3mg QPI-1007 administered on day 1. Sham administration on months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis set title

Cohort 3 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Multiple dose regimen. 1.5 mg QPI-1007 dose on day 1, and months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis set title

Cohort 4 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Multiple dose regimen. 3mg QPI-I007 administered on day 1, and months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis set title

Cohort 5 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Sham control. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis sets values	Cohort 1 - mITT ≤ 12days	Cohort 2 - mITT ≤ 12days	Cohort 3 - mITT ≤ 12days	Cohort 4 - mITT ≤ 12days	Cohort 5 - mITT ≤ 12days	Cohort 1 - As treated	Cohort 2 - As treated	Cohort 3 - As treated	Cohort 4 - As treated	Cohort 5 - As treated
Number of subjects	101	100	168	166	190	57	55	146	142	144
Age categorical
Units: Subjects
Adults (18-64 years)	67	70	110	111	120
From 65-84 years	34	30	58	55	70
Age continuous
Units: years
arithmetic mean (full range (min-max))						61.3 (50 to 80)	61.0 (50 to 80)	61.5 (50 to 80)	60.9 (50 to 80)	61.8 (50 to 79)
Gender categorical
Units: Subjects
Female	29	38	54	49	58	16	18	46	41	46
Male	72	62	114	117	132	41	37	100	101	98

End points

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Reporting group title

Cohort 1 - ITT

Reporting group description

Single dose regime, 1.5mg dose of QPI-1007 on day 1. Sham dose administered at months 2 and 4.

Reporting group title

Cohort 2 - ITT

Reporting group description

Single dose regime. 3mg QPI-1007 administered on day 1. Sham administration on months 2 and 4.

Reporting group title

Cohort 3 - ITT

Reporting group description

Multiple dose regimen. 1.5 mg QPI-1007 dose on day 1, and months 2 and 4.

Reporting group title

Cohort 4 - ITT

Reporting group description

Multiple dose regimen. 3mg QPI-I007 administered on day 1, and months 2 and 4.

Reporting group title

Cohort 5 - ITT

Reporting group description

Subject analysis set title

Cohort 1 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Cohort 2 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Cohort 3 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Multiple dose regimen. 1.5 mg QPI-1007 dose on day 1, and months 2 and 4. mITT ≤ 12days analysis set include subjects who were randomized within 12 days of the onset of symptoms.

Subject analysis set title

Cohort 4 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Multiple dose regimen. 3mg QPI-I007 administered on day 1, and months 2 and 4. mITT ≤ 12days analysis set include subjects who were randomized within 12 days of the onset of symptoms.

Subject analysis set title

Cohort 5 - mITT ≤ 12days

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Sham control. mITT ≤ 12days analysis set include subjects who were randomized within 12 days of the onset of symptoms.

Subject analysis set title

Cohort 1 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Single dose regime, 1.5mg dose of QPI-1007 on day 1. Sham dose administered at months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis set title

Cohort 2 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Single dose regime. 3mg QPI-1007 administered on day 1. Sham administration on months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis set title

Cohort 3 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Multiple dose regimen. 1.5 mg QPI-1007 dose on day 1, and months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis set title

Cohort 4 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Multiple dose regimen. 3mg QPI-I007 administered on day 1, and months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Subject analysis set title

Cohort 5 - As treated

Subject analysis set type

Per protocol

Subject analysis set description

Sham control. As treated analysis set includes all subjects who received the correct test treatment.

Primary: Number of subjects who lose 15 letters or more in Best Corrected Visual Acuity (BCVA) score as measured by ETDRS visual acuity protocol in the study eye from Baseline to Month 6.

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End point title

Number of subjects who lose 15 letters or more in Best Corrected Visual Acuity (BCVA) score as measured by ETDRS visual acuity protocol in the study eye from Baseline to Month 6.

End point description

Number of subjects who lose 15 letters or more in BCVA at Month 6 from Baseline. Results given as number of patients who have altered BCVA.

End point type

Primary

End point timeframe

6 months post treatment

End point values	Cohort 1 - mITT ≤ 12days	Cohort 2 - mITT ≤ 12days	Cohort 3 - mITT ≤ 12days	Cohort 4 - mITT ≤ 12days	Cohort 5 - mITT ≤ 12days
Number of subjects analysed	57	55	146	142	144
Units: Subjects	17	17	23	27	21

Percentage difference from control

Comparison groups

Cohort 1 - mITT ≤ 12days v Cohort 5 - mITT ≤ 12days

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0217

Method

Regression, Logistic

Parameter type

Percentage difference

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Percentage difference from control

Comparison groups

Cohort 2 - mITT ≤ 12days v Cohort 5 - mITT ≤ 12days

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0146

Method

Regression, Logistic

Parameter type

Percentage difference

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Percentage difference from control

Comparison groups

Cohort 3 - mITT ≤ 12days v Cohort 5 - mITT ≤ 12days

Number of subjects included in analysis

290

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7808

Method

Regression, Logistic

Parameter type

Percentage difference

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Percentage difference from control

Comparison groups

Cohort 4 - mITT ≤ 12days v Cohort 5 - mITT ≤ 12days

Number of subjects included in analysis

286

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.293

Method

Regression, Logistic

Parameter type

Percentage difference

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Adverse events

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Timeframe for reporting adverse events

All AEs and SAEs will be recorded from the time of first study drug administration/sham procedure through 12 months post treatment or early termination

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Cohort 1 - As treated

Reporting group description

Single dose regime, 1.5mg dose of QPI-1007 on day 1. Sham dose administered at months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Reporting group title

Cohort 2 - As treated

Reporting group description

Single dose regime. 3mg QPI-1007 administered on day 1. Sham administration on months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Reporting group title

Cohort 3 - As treated

Reporting group description

Multiple dose regimen. 1.5 mg QPI-1007 dose on day 1, and months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Reporting group title

Cohort 4 - As treated

Reporting group description

Multiple dose regimen. 3mg QPI-I007 administered on day 1, and months 2 and 4. As treated analysis set includes all subjects who received the correct test treatment.

Reporting group title

Cohort 5 - As treated

Reporting group description

Sham control. As treated analysis set includes all subjects who received the correct test treatment.

Serious adverse events	Cohort 1 - As treated	Cohort 2 - As treated	Cohort 3 - As treated	Cohort 4 - As treated	Cohort 5 - As treated
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 101 (10.89%)	17 / 100 (17.00%)	17 / 168 (10.12%)	22 / 166 (13.25%)	19 / 190 (10.00%)
number of deaths (all causes)	0	0	1	0	0
number of deaths resulting from adverse events	0	0	1	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
Additional description: Abdominal Aortic Aneurysm
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
Additional description: Reaction to medication given for fall. reaction was altered mental state
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
C-Reactive Protein Increase
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative ileus
Additional description: post operative
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cataract traumatic
Additional description: retraumatic cataract
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body in eye
Additional description: foreign body in cornea
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
Additional description: Hemorrhagic contusion
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
Additional description: fracture of left hip
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Hypertensive crisis
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
Additional description: non-ST segment elevation myocardial infarction
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
Additional description: Chronic total occlusion of the coronary artery
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular insufficiency
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Visual field defect
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
Additional description: worsening of anaemia
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
Additional description: Vertigo of unknown etiology
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Vitreous floaters
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Macular hole
Additional description: Stage 4 macular hole
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Age-related macular degeneration
Additional description: Wet age-related macular degeneration
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Corneal perforation
Additional description: retraumatic corneal perforation
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Optic ischaemic neuropathy
Additional description: Progressive Anterior Optic Neuropathy Bilateral Sequential
subjects affected / exposed	2 / 101 (1.98%)	2 / 100 (2.00%)	1 / 168 (0.60%)	4 / 166 (2.41%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blindness unilateral
Additional description: severe visual loss
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Papilloedema
Additional description: Marked increase in Optic Nerve Edema OS due to NAION
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Photophobia
Additional description: Loss of vision to light perception OS
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Visual impairment
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	2 / 190 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Visual acuity reduced
subjects affected / exposed	2 / 101 (1.98%)	8 / 100 (8.00%)	6 / 168 (3.57%)	7 / 166 (4.22%)	9 / 190 (4.74%)
occurrences causally related to treatment / all	0 / 2	0 / 8	0 / 6	0 / 7	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Optic atrophy
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Peptic ulcer
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erosive oesophagitis
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
Additional description: Prolapsed Inter vertebral disc
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis viral
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leptospirosis
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Cohort 1 - As treated	Cohort 2 - As treated	Cohort 3 - As treated	Cohort 4 - As treated	Cohort 5 - As treated
Total subjects affected by non serious adverse events
subjects affected / exposed	78 / 101 (77.23%)	75 / 100 (75.00%)	133 / 168 (79.17%)	125 / 166 (75.30%)	134 / 190 (70.53%)
Vascular disorders
Arterial occlusive disease
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Hypertension
subjects affected / exposed	3 / 101 (2.97%)	2 / 100 (2.00%)	7 / 168 (4.17%)	10 / 166 (6.02%)	10 / 190 (5.26%)
occurrences all number	3	2	7	10	10
Hypotension
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	0	0	1	0
Hyperaemia
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	0	0	1	0
Surgical and medical procedures
Oral surgery
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 101 (0.00%)	2 / 100 (2.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	4 / 190 (2.11%)
occurrences all number	0	2	1	2	4
Facial pain
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Fatigue
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	1	1	1	2	1
Influenza like illness
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	1	1	0	1
Glassy eyes
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Injection site pain
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	1	1	1	0
Injection site discomfort
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Injection site erythema
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	2	0	0	0	1
Pain
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	2 / 168 (1.19%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	1	0	2	2	1
Peripheral swelling
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	0	2	0	1
Pyrexia
subjects affected / exposed	1 / 101 (0.99%)	4 / 100 (4.00%)	3 / 168 (1.79%)	1 / 166 (0.60%)	2 / 190 (1.05%)
occurrences all number	1	4	3	1	2
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	2	0	0	0	0
Hypersensitivity
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	1	0	0	1
Seasonal allergy
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	5 / 190 (2.63%)
occurrences all number	0	1	1	2	5
Bronchitis
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	6 / 168 (3.57%)	4 / 166 (2.41%)	2 / 190 (1.05%)
occurrences all number	1	1	6	4	2
Rhinitis
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Social circumstances
Menopause
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Reproductive system and breast disorders
Breast cyst
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Benign prostatic hyperplasia
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	0	0	0	1	1
Prostatitis
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	2 / 101 (1.98%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	2	1	0	0	0
Cough
subjects affected / exposed	3 / 101 (2.97%)	2 / 100 (2.00%)	7 / 168 (4.17%)	5 / 166 (3.01%)	4 / 190 (2.11%)
occurrences all number	3	2	7	5	4
Nasal congestion
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	3 / 168 (1.79%)	1 / 166 (0.60%)	2 / 190 (1.05%)
occurrences all number	0	0	3	1	2
Epistaxis
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	1	0	1	0
Hiccups
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Nasal oedema
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Nasal polyps
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	1	0	0
Respiratory tract congestion
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	1	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	3 / 168 (1.79%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	0	3	1	0
Paranasal sinus discomfort
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	0	1	0	0
Rhinorrhoea
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	1	1	1	0
Sleep apnoea syndrome
subjects affected / exposed	6 / 101 (5.94%)	4 / 100 (4.00%)	3 / 168 (1.79%)	5 / 166 (3.01%)	5 / 190 (2.63%)
occurrences all number	6	4	3	5	5
Asthma
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	1	0	0	1
Upper airway obstruction
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Upper respiratory tract congestion
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 101 (2.97%)	2 / 100 (2.00%)	2 / 168 (1.19%)	1 / 166 (0.60%)	2 / 190 (1.05%)
occurrences all number	3	2	2	1	2
Depression
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	3 / 190 (1.58%)
occurrences all number	1	0	0	0	3
Insomnia
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	1	0	1	0
Stress
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Investigations
Blood calcium increased
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Blood cholesterol increased
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	2 / 168 (1.19%)	2 / 166 (1.20%)	5 / 190 (2.63%)
occurrences all number	1	0	2	2	5
Blood homocysteine increased
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Blood pressure increased
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	3 / 190 (1.58%)
occurrences all number	0	1	1	2	3
Blood urea increased
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	3 / 168 (1.79%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	0	3	1	0
Blood triglycerides increased
subjects affected / exposed	4 / 101 (3.96%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	3 / 190 (1.58%)
occurrences all number	4	1	1	0	3
Injury, poisoning and procedural complications
Toothache
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	4 / 168 (2.38%)	3 / 166 (1.81%)	1 / 190 (0.53%)
occurrences all number	1	0	5	3	1
Tooth abscess
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	1	0	0	0	1
Arthropod bite
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	0	1	0	1	1
Conjunctival abrasion
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Corneal abrasion
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	1	0	1	2	1
Contusion
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	0	1	0	2	0
Fall
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	3 / 190 (1.58%)
occurrences all number	0	1	1	1	3
Foreign body in eye
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	2 / 190 (1.05%)
occurrences all number	0	0	1	1	2
Ligament sprain
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	1	1	0	0	1
Foot fracture
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	0	0	1	0
Hand fracture
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	1	0	0
Injection related reaction
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	0	0	1	0
Injury
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Joint swelling
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	0	0	0	2	0
Joint injury
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	3 / 168 (1.79%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	0	3	0	1
Joint dislocation
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	0	0	0	2	0
Limb injury
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	1	1	1	0
Muscle rupture
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	0	2	0	0
Muscle strain
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	2 / 168 (1.19%)	1 / 166 (0.60%)	3 / 190 (1.58%)
occurrences all number	2	0	2	1	3
Lumbar vertebral fracture
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Post procedural haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	1	0	0
Product administration error
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	2 / 190 (1.05%)
occurrences all number	1	0	1	2	2
Rib fracture
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	1	0	1	2	1
Stress fracture
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Skin laceration
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	3 / 190 (1.58%)
occurrences all number	1	0	0	1	3
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	2 / 190 (1.05%)
occurrences all number	1	0	0	2	2
Congenital, familial and genetic disorders
Methylenetetrahydrofolate reductase gene mutation
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	1	0	1	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	1	0	0	1	1
Left ventricular hypertrophy
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Cardiomyopathy
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Nervous system disorders
Visual field defect
subjects affected / exposed	3 / 101 (2.97%)	3 / 100 (3.00%)	4 / 168 (2.38%)	10 / 166 (6.02%)	4 / 190 (2.11%)
occurrences all number	3	3	4	10	4
Nerve compression
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	0	0	0	2	0
Blood and lymphatic system disorders
anaemia
subjects affected / exposed	1 / 101 (0.99%)	2 / 100 (2.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	1	2	0	1	1
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Ear pain
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	0	2	1	0
Tinnitus
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	2	0	1	1	0
Vertigo
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	2	0	0	0	0
Eye disorders
Abnormal sensation in eye
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	1	0	0	0
Anterior chamber cell
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Blepharitis
subjects affected / exposed	1 / 101 (0.99%)	2 / 100 (2.00%)	3 / 168 (1.79%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	1	2	3	2	1
Blepharospasm
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	1	0	0
Cataract
subjects affected / exposed	3 / 101 (2.97%)	2 / 100 (2.00%)	2 / 168 (1.19%)	3 / 166 (1.81%)	4 / 190 (2.11%)
occurrences all number	3	2	2	3	4
Cataract nuclear
subjects affected / exposed	1 / 101 (0.99%)	2 / 100 (2.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	1	2	1	1	1
Cataract subcapsular
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	3 / 166 (1.81%)	0 / 190 (0.00%)
occurrences all number	0	1	1	3	0
Conjunctival haemorrhage
subjects affected / exposed	13 / 101 (12.87%)	11 / 100 (11.00%)	24 / 168 (14.29%)	18 / 166 (10.84%)	4 / 190 (2.11%)
occurrences all number	13	11	24	18	4
Conjunctival hyperaemia
subjects affected / exposed	1 / 101 (0.99%)	3 / 100 (3.00%)	3 / 168 (1.79%)	0 / 166 (0.00%)	4 / 190 (2.11%)
occurrences all number	1	3	3	0	4
Corneal epithelial microcysts
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Cyanopsia
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Dermatochalasis
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Conjunctivitis allergic
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	1	0	0	0	1
Cystoid macular oedema
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Diplopia
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	2 / 168 (1.19%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	1	2	1	0
Dry eye
subjects affected / exposed	3 / 101 (2.97%)	6 / 100 (6.00%)	7 / 168 (4.17%)	6 / 166 (3.61%)	6 / 190 (3.16%)
occurrences all number	3	6	7	6	6
Eye disorder
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	1	0	1	0
Eye allergy
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	2 / 190 (1.05%)
occurrences all number	1	0	0	1	2
Eye irritation
subjects affected / exposed	2 / 101 (1.98%)	3 / 100 (3.00%)	4 / 168 (2.38%)	8 / 166 (4.82%)	1 / 190 (0.53%)
occurrences all number	2	3	4	8	1
Eye pain
subjects affected / exposed	5 / 101 (4.95%)	5 / 100 (5.00%)	19 / 168 (11.31%)	8 / 166 (4.82%)	10 / 190 (5.26%)
occurrences all number	5	5	19	8	10
Eye swelling
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	0	2	1	0
Eyelid oedema
subjects affected / exposed	0 / 101 (0.00%)	2 / 100 (2.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	2	0	0	1
Eyelid pain
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	10 / 190 (5.26%)
occurrences all number	0	1	0	0	10
Eye pruritus
subjects affected / exposed	0 / 101 (0.00%)	2 / 100 (2.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	6 / 190 (3.16%)
occurrences all number	0	2	1	2	6
swelling of the eyelid
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	3 / 166 (1.81%)	0 / 190 (0.00%)
occurrences all number	0	0	0	3	0
Eyelid irritation
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	0	0	1	0
Foreign body sensation in eyes
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	2 / 190 (1.05%)
occurrences all number	2	0	0	1	2
Glare
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	0	0	0	2	0
Macular fibrosis
subjects affected / exposed	1 / 101 (0.99%)	2 / 100 (2.00%)	0 / 168 (0.00%)	3 / 166 (1.81%)	1 / 190 (0.53%)
occurrences all number	1	2	0	3	1
Iritis
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	0	0	1	2	1
Lacrimation increased
subjects affected / exposed	0 / 101 (0.00%)	2 / 100 (2.00%)	2 / 168 (1.19%)	4 / 166 (2.41%)	4 / 190 (2.11%)
occurrences all number	0	2	2	4	4
Macular detachment
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Macular oedema
subjects affected / exposed	1 / 101 (0.99%)	3 / 100 (3.00%)	2 / 168 (1.19%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	1	3	2	2	1
Metamorphopsia
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	0	1	1	2	0
Meibomian gland dysfunction
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	1	0	1	1	1
Ocular discomfort
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	1	0	1	0
Ocular hypertension
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	0	0	1	2	0
Ocular hyperaemia
subjects affected / exposed	2 / 101 (1.98%)	1 / 100 (1.00%)	3 / 168 (1.79%)	3 / 166 (1.81%)	6 / 190 (3.16%)
occurrences all number	2	1	3	3	6
Optic atrophy
subjects affected / exposed	2 / 101 (1.98%)	2 / 100 (2.00%)	2 / 168 (1.19%)	5 / 166 (3.01%)	1 / 190 (0.53%)
occurrences all number	2	2	2	5	1
Optic disc disorder
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	2 / 190 (1.05%)
occurrences all number	1	0	1	1	2
Optic disc haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	5 / 168 (2.98%)	3 / 166 (1.81%)	0 / 190 (0.00%)
occurrences all number	0	0	5	3	0
Optic ischaemic neuropathy
subjects affected / exposed	7 / 101 (6.93%)	4 / 100 (4.00%)	2 / 168 (1.19%)	10 / 166 (6.02%)	8 / 190 (4.21%)
occurrences all number	7	4	2	10	8
Optic nerve disorder
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	1	1	1	0
Optic nerve sheath haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	0	2	0	0
Papilloedema
subjects affected / exposed	6 / 101 (5.94%)	3 / 100 (3.00%)	3 / 168 (1.79%)	9 / 166 (5.42%)	2 / 190 (1.05%)
occurrences all number	6	3	3	9	2
Photopsia
subjects affected / exposed	3 / 101 (2.97%)	2 / 100 (2.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	3	2	1	1	1
Photophobia
subjects affected / exposed	0 / 101 (0.00%)	3 / 100 (3.00%)	1 / 168 (0.60%)	4 / 166 (2.41%)	0 / 190 (0.00%)
occurrences all number	0	3	1	4	0
Punctate keratitis
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	6 / 168 (3.57%)	4 / 166 (2.41%)	4 / 190 (2.11%)
occurrences all number	1	1	6	4	4
Pupillary reflex impaired
subjects affected / exposed	2 / 101 (1.98%)	2 / 100 (2.00%)	1 / 168 (0.60%)	3 / 166 (1.81%)	1 / 190 (0.53%)
occurrences all number	2	2	1	3	1
Retinal degeneration
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	1	0	0	0
Retinal disorder
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	2 / 190 (1.05%)
occurrences all number	0	0	1	2	2
Retinal detachment
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Retinal exudates
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	2 / 168 (1.19%)	2 / 166 (1.20%)	4 / 190 (2.11%)
occurrences all number	1	0	2	2	4
Retinal haemorrhage
subjects affected / exposed	1 / 101 (0.99%)	2 / 100 (2.00%)	2 / 168 (1.19%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	1	2	2	1	1
Retinal neovascularisation
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Retinoschisis
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Vision blurred
subjects affected / exposed	2 / 101 (1.98%)	1 / 100 (1.00%)	2 / 168 (1.19%)	4 / 166 (2.41%)	5 / 190 (2.63%)
occurrences all number	2	1	2	4	5
Visual acuity reduced
subjects affected / exposed	11 / 101 (10.89%)	18 / 100 (18.00%)	15 / 168 (8.93%)	21 / 166 (12.65%)	18 / 190 (9.47%)
occurrences all number	11	18	15	21	18
Visual impairment
subjects affected / exposed	5 / 101 (4.95%)	6 / 100 (6.00%)	7 / 168 (4.17%)	3 / 166 (1.81%)	4 / 190 (2.11%)
occurrences all number	5	6	7	3	4
Vitreous detachment
subjects affected / exposed	0 / 101 (0.00%)	3 / 100 (3.00%)	2 / 168 (1.19%)	8 / 166 (4.82%)	7 / 190 (3.68%)
occurrences all number	0	3	2	8	7
Vitreous floaters
subjects affected / exposed	5 / 101 (4.95%)	8 / 100 (8.00%)	5 / 168 (2.98%)	5 / 166 (3.01%)	3 / 190 (1.58%)
occurrences all number	5	8	5	5	3
Vitritis
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	1	0	0	1
Vitreous opacities
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	1	0	0
Asthenopia
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	0 / 190 (0.00%)
occurrences all number	0	0	1	2	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	3 / 166 (1.81%)	2 / 190 (1.05%)
occurrences all number	1	0	1	3	2
Abdominal pain
subjects affected / exposed	2 / 101 (1.98%)	3 / 100 (3.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	2	3	0	2	1
Abdominal pain upper
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Constipation
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	3 / 168 (1.79%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	1	3	0	1
Chronic gastritis
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Dental caries
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	2	0	0	1	0
Duodenal polyp
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Inflammatory bowel disease
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Paraesthesia oral
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Nausea
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	2	0	1	1	1
Vomiting
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	2 / 190 (1.05%)
occurrences all number	0	0	0	1	2
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	0	0	1	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Blister
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	1	0	0
Dermatitis allergic
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	1	0	0
Psoriasis
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Eczema
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Actinic keratosis
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	0	0	1	0
Rash
subjects affected / exposed	2 / 101 (1.98%)	1 / 100 (1.00%)	2 / 168 (1.19%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	2	1	2	2	1
Rash pruritic
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Pruritus
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	0	0	0	1	0
Skin lesion
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	1	0	0
Impaired driving ability
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	1	0	0
Splinter haemorrhages
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	0	0	0	2	1
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Diabetic retinopathy
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	2 / 168 (1.19%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	1	2	0	0
Vitreous degeneration
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	2 / 190 (1.05%)
occurrences all number	0	1	0	0	2
Infections and infestations
Asymptomatic bacteriuria
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Bronchiolitis
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Cellulitis
subjects affected / exposed	1 / 101 (0.99%)	1 / 100 (1.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	1	0	1	0
Conjunctivitis
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	3 / 166 (1.81%)	3 / 190 (1.58%)
occurrences all number	0	1	1	3	3
Cystitis
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	0 / 168 (0.00%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	0	0	0	2	1
Conjunctivitis viral
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	1	0	0
Eye infection
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal infection
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Gastroenteritis viral
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	1 / 168 (0.60%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	1	0	1	1	1
Helicobacter infection
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Herpes zoster
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	1	0	0	1	1
Hordeolum
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	1 / 168 (0.60%)	2 / 166 (1.20%)	1 / 190 (0.53%)
occurrences all number	0	0	1	2	1
Influenza
subjects affected / exposed	2 / 101 (1.98%)	2 / 100 (2.00%)	5 / 168 (2.98%)	2 / 166 (1.20%)	5 / 190 (2.63%)
occurrences all number	2	2	5	2	5
Lower respiratory tract infection
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	1	1	0	1
Labyrinthitis
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
lung infection
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	1 / 166 (0.60%)	0 / 190 (0.00%)
occurrences all number	1	0	0	1	0
Nail infection
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Nasopharyngitis
subjects affected / exposed	8 / 101 (7.92%)	11 / 100 (11.00%)	18 / 168 (10.71%)	12 / 166 (7.23%)	17 / 190 (8.95%)
occurrences all number	8	11	18	12	17
Otitis externa
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	0	2	0	0
Oral herpes
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Pharyngitis
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	1 / 166 (0.60%)	1 / 190 (0.53%)
occurrences all number	0	0	2	1	1
Pneumonia
subjects affected / exposed	0 / 101 (0.00%)	2 / 100 (2.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	2 / 190 (1.05%)
occurrences all number	0	2	1	0	2
Postoperative wound infection
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Root canal infection
subjects affected / exposed	1 / 101 (0.99%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	1	0	0	0	0
Sinusitis
subjects affected / exposed	6 / 101 (5.94%)	0 / 100 (0.00%)	9 / 168 (5.36%)	5 / 166 (3.01%)	12 / 190 (6.32%)
occurrences all number	6	0	9	5	12
Tooth infection
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	1 / 168 (0.60%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	0	1	1	0	1
Upper respiratory tract infection
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	2 / 168 (1.19%)	10 / 166 (6.02%)	5 / 190 (2.63%)
occurrences all number	2	0	2	10	5
Urinary tract infection
subjects affected / exposed	4 / 101 (3.96%)	1 / 100 (1.00%)	1 / 168 (0.60%)	4 / 166 (2.41%)	2 / 190 (1.05%)
occurrences all number	4	1	1	4	2
Viral infection
subjects affected / exposed	2 / 101 (1.98%)	0 / 100 (0.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	1 / 190 (0.53%)
occurrences all number	2	0	0	0	1
Vulval abscess
subjects affected / exposed	0 / 101 (0.00%)	1 / 100 (1.00%)	0 / 168 (0.00%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	1	0	0	0
Chemical burns of eye
subjects affected / exposed	0 / 101 (0.00%)	0 / 100 (0.00%)	2 / 168 (1.19%)	0 / 166 (0.00%)	0 / 190 (0.00%)
occurrences all number	0	0	2	0	0

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Were there any global substantial amendments to the protocol? Yes

13 Jan 2014

Added language to note this is a Pivotal Phase II/III study Language added from provided reference regarding disease population. Revised confirmation of eligibility for subjects <50 and >80 years of age. Language modified to exclude subjects previously exposed to QPI-1007. Language added to note VF assessment at Month 2. Language added for AE and SAE reporting to cover local regulatory authority requirements for global protocol Language added for concomitant treatment collection to cover local regulatory authority requirements for global protocol. Added language to note that confirmation of enrollment eligibility to occur prior to Day 0. Language added for SAE notification Optional interim analysis deleted due to revised study design. Language added to global protocol to capture video consent requirements where applicable, per local regulatory authorities.

11 Mar 2015

Clarified language to note dose options. Corrected language as not all subjects will receive three bi-monthly IVT injections. Interim analysis plan for the study was modified to include a futility analysis after 40 subjects in each treatment group complete Month 6 visit. Month 9 study visit added for safety follow-up. Language added to define afferent papillary defect inclusion criteria; Enrollment Adjudication Board removed and inclusion criteria confirmed that subjects must be 50 to 80 years of age. Added language to note Indian requirements, criterion for study eye, low dose aspirin therapy dose is per local standard. Added language to clarify exclusion criterion for diabetic retinopathy, concomitant disease and uveitis Language Added to allow basal cell carcinoma allowed only if adequately treated. Removal of FSH testing and ECG testing. Reference to diluted study drug removed as study drug will not be diluted. Correction of sample size determination and primary end point analysis, added multiple comparison procedure and futility analysis. Language added to note Key Secondary Endpoints and Secondary Efficacy Endpoints. Overall Summary of Related AEs table removed Contrast sensitivity added as an ophthalmologic assessment at Day 0 and Months 2, 4, 6, 9, and 12/ET. CRP and Westergren sedimentation rate added Entry criteria added for study eye, Instructions added for Day 0/Post-dose. Information added for adverse events in case of early treatment discontinuation Allocation of treatment groups defined for randomization Information on sensitivity and subgroup analysis was included.

09 Sep 2015

Changed all references for concomitant medications and treatments collection from 7 days to 14 days. Removed “differential” from WBC laboratory collection. Changed all references of Day “0” to Day “1” and Day “7” to Day “8.” Added Europe to increase diversity of patient population. Adverse events, regardless of severity, must be collected for the entire study for all regions Added ganglion cell layer to Secondary objective. Study changed from 4-arm to 5-arm study. As such, study design was updated Reduced Screening window from 28 days to 14 days, Removed Contrast Sensitivity procedure/exam from protocol. Removed all mentions of 96 hours screening period and related references that stated Screening and Day 1 could occur on the same day.

16 Oct 2015

Updated: to reflect current understanding of disease process and number of subjects to accommodate recalculation of statistical hypothesis. Increased total number of study sites from 50 to 60. Removed aspirin requirement as background therapy. Added “OCT image and VF pattern compatible with the diagnosis of NAION, as determined by a Central Reading Center” image and VF pattern compatibility” to Screening visit task list. Changed inclusion criterion to allow Best-Corrected Visual Acuity score in the study eye to be better than or equal to 15 letter score without an upper limit Added exclusion criterion: “history of amiodarone use in the 12 months prior to the Day 1/Randomization visit.” and “NAION secondary to acute blood loss' and “any intravitreal injection within 3 months prior to Day 1 in the study eye only:” and “diffuse pale swelling of the optic disc.” and “bilateral (simultaneous) disc swelling Additional exclusion criteria added included: “Visual Field exclusions at Screening Visit (inconclusive visual fields should be sent to the Reading Center for adjudication) Updated study background to include new information and related references Added information regarding QRK208 study, 5th dosing cohort added in Changed “other efficacy endpoints.” Allows for Screening and Day 1 to occur on same day. Change made to provide better understanding of per-visit procedures as not all procedures occur at all visits.

06 Oct 2016

To explain purpose of and plan for newly-added sub-study. Clarification of global site distribution Clarification that there will be an earlier safety look, in addition to the already-listed interim analysis to be conducted after 40 subjects per group complete their Month 6 visit. It is not always the injecting physician who performs the 30-minute post-dose evaluations. Per German Regulatory Authority recommendation, removed barrier method as acceptable method of birth control Clarification of excluded ophthalmic surgeries. Clarification that subjects may be excluded by any visual field exclusions listed; subjects not required to meet ALL VF exclusions in order to be excluded. Clarified only study eye relevant to this criterion. Clarification that mild blepharitis, although considered an inflammatory condition, is NOT exclusionary. Correction to clarify potential subjects may be lactating and may not be actively nursing (lactating and nursing are not inclusive of one another). PDE5 inhibitors use is a risk for developing NAION and should not be used during the study. Updated to include new terms and correct existing list, to provide current information and status of QRK208 study. Spot size III using SITA standard 24-2 protocol is not done at Day 1, so this endpoint needs to be measured from Screening. Reduced requirement to avoid patient fatigue. Clarified spot size III requirement by name (previous version did not specify spot size).

15 Mar 2018

Sample size adjustment. The sample size has been recalculated to be consistent with the observed 20% overall rate of subjects losing 15-letters or more in visual acuity from 106 subjects to 213. Added language that another DMC will occur due to increased sample size Addition of ERG (for China sites only) to global protocol for Day 1 Pre-Dose, Month 2, and Month 6. Defined when 24-hour period starts (at first procedure after ICF, so any procedure after ICF). Added language found elsewhere in the protocol related to preferred time frame for study drug administration. Change type of stopper for study drug vial to "FuroTec-coated," instead of "Teflon-coated." Added statement that after the interim analysis, subjects already enrolled in the dropped regimen will continue until they have completed study participation Replaced duplicate IA information (already present in Sections 10.2 and 10.9) with definition of DMC purpose.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical Trial Results:
A PHASE 2/3, RANDOMIZED, DOUBLE-MASKED, SHAM-CONTROLLED TRIAL OF QPI-1007 DELIVERED BY SINGLE OR MULTI-DOSE INTRAVITREAL INJECTION(S) TO SUBJECTS WITH ACUTE NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY (NAION)

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End points

Primary: Number of subjects who lose 15 letters or more in Best Corrected Visual Acuity (BCVA) score as measured by ETDRS visual acuity protocol in the study eye from Baseline to Month 6.

Primary: Number of subjects who lose 15 letters or more in Best Corrected Visual Acuity (BCVA) score as measured by ETDRS visual acuity protocol in the study eye from Baseline to Month 6.

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Clinical trials

Clinical Trial Results: A PHASE 2/3, RANDOMIZED, DOUBLE-MASKED, SHAM-CONTROLLED TRIAL OF QPI-1007 DELIVERED BY SINGLE OR MULTI-DOSE INTRAVITREAL INJECTION(S) TO SUBJECTS WITH ACUTE NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY (NAION)

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects who lose 15 letters or more in Best Corrected Visual Acuity (BCVA) score as measured by ETDRS visual acuity protocol in the study eye from Baseline to Month 6.

Primary: Number of subjects who lose 15 letters or more in Best Corrected Visual Acuity (BCVA) score as measured by ETDRS visual acuity protocol in the study eye from Baseline to Month 6.

Adverse events

Adverse events

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Substantial protocol amendments (globally)

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Clinical Trial Results:
A PHASE 2/3, RANDOMIZED, DOUBLE-MASKED, SHAM-CONTROLLED TRIAL OF QPI-1007 DELIVERED BY SINGLE OR MULTI-DOSE INTRAVITREAL INJECTION(S) TO SUBJECTS WITH ACUTE NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY (NAION)