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Clinical Trial Results:
An open-label proof-of-concept study with a double-masked, dose-ranging component to assess the effects of AIN457 in patients with noninfectious uveitis

Summary
EudraCT number	2011-001243-67
Trial protocol	DE
Global end of trial date	13 Sep 2013

Results information
Results version number	v1(current)
This version publication date	13 Jul 2016
First version publication date	31 Jul 2015
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

CAIN457A2208

ISRCTN number

US NCT number

NCT00685399

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

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

13 Sep 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Sep 2013

Global end of trial reached?

Yes

Global end of trial date

13 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

To assess the safety and tolerability of intravenous AIN457 in patients with uveitis.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

10 Jun 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 72

Country: Number of subjects enrolled

Germany: 7

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Cohort 4 was originally comprised of patients from all other core cohorts of this study whose uveitis was in remission at the end of study observation (Cohorts 1, 2, and 3).

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Cohort 1

Arm description

Cohort 1-300mg s.c. bi-weekly (q2wks)

Arm type

Experimental

Investigational medicinal product name

Sekukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cohort 1-300mg s.c. bi-weekly (q2wks)

Cohort 2

Arm description

(300mg s.c. bi-weekly (q2wks)), 3 patients from cohort 1 rolled into this cohort

Arm type

Experimental

Investigational medicinal product name

Sekukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

(300mg s.c. bi-weekly (q2wks)), 3 patients from cohort 1 rolled into this cohort

Cohort 3

Arm description

10 mg/kg i.v. every 4 weeks (q4 wks)

Arm type

Experimental

Investigational medicinal product name

Sekukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

10 mg/kg i.v. every 4 weeks (q4 wks)

Cohort 5

Arm description

30 mg/kg AIN457 IV q4 weeks

Arm type

Experimental

Investigational medicinal product name

Sekukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

30 mg/kg AIN457 IV q4 weeks

Cohort 6 Arm 1

Arm description

300mg sc q 2wks

Arm type

Experimental

Investigational medicinal product name

Sekukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

300mg sc q 2wks

Cohort 6 Arm 2

Arm description

10mg/kg i.v. q2wks

Arm type

Experimental

Investigational medicinal product name

Sekukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

10mg/kg i.v. q2wks

Cohort 6 Arm 3

Arm description

30mg/kg i.v. q4wks

Arm type

Experimental

Investigational medicinal product name

Sekukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

30mg/kg i.v. q4wks

Number of subjects in period 1	Cohort 1	Cohort 2	Cohort 3	Cohort 5	Cohort 6 Arm 1	Cohort 6 Arm 2	Cohort 6 Arm 3
Started	16	17	5	4	12	13	12
Completed	10	3	2	4	10	13	10
Not completed	6	14	3	0	2	0	2
Consent withdrawn by subject	2	1	-	-	-	-	2
Adverse event, non-fatal	-	-	-	-	1	-	-
Administrative Problems	2	2	1	-	-	-	-
Protocol deviation	1	-	-	-	-	-	-
Lack of efficacy	1	11	2	-	1	-	-

Period 2 title

Extension

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Cohort 4

Arm description

Extension- All patients are rollover patients from other cohorts. AIN457 10 mg/kg iv PRN no more than once per month. COHORT 4 not added to total mean as they are already included.

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

Extension- All patients are rollover patients from other cohorts. AIN457 10 mg/kg iv PRN no more than once per month. COHORT 4 not added to total mean as they are already included.

Number of subjects in period 2	Cohort 4
Started	28
Completed	21
Not completed	7
Consent withdrawn by subject	1
Adverse event, non-fatal	2
Administrative Issues	1
Protocol deviation	1
Lack of efficacy	2

Baseline characteristics

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Reporting group title

Cohort 1

Reporting group description

Cohort 1-300mg s.c. bi-weekly (q2wks)

Reporting group title

Cohort 2

Reporting group description

(300mg s.c. bi-weekly (q2wks)), 3 patients from cohort 1 rolled into this cohort

Reporting group title

Cohort 3

Reporting group description

10 mg/kg i.v. every 4 weeks (q4 wks)

Reporting group title

Cohort 5

Reporting group description

30 mg/kg AIN457 IV q4 weeks

Reporting group title

Cohort 6 Arm 1

Reporting group description

300mg sc q 2wks

Reporting group title

Cohort 6 Arm 2

Reporting group description

10mg/kg i.v. q2wks

Reporting group title

Cohort 6 Arm 3

Reporting group description

30mg/kg i.v. q4wks

Reporting group values	Cohort 1	Cohort 2	Cohort 3	Cohort 5	Cohort 6 Arm 1	Cohort 6 Arm 2	Cohort 6 Arm 3	Total
Number of subjects	16	17	5	4	12	13	12	79
Age categorical
Units: Subjects
18y < 65y	15	16	5	4	11	12	12	75
65y < 85y	1	1	0	0	1	1	0	4
Gender, Male/Female
Units: Participants
male	4	5	2	1	4	4	3	23
Female	12	12	3	3	8	9	9	56

Subject analysis set title

Adverse Events

Subject analysis set type

Safety analysis

Subject analysis set description

Found in Adverse Event Section

Subject analysis set title

Intermediate Uveitis

Subject analysis set type

Full analysis

Subject analysis set description

Intermediate uveitis is a form of uveitis localized to the vitreous and peripheral retina.

Subject analysis set title

Posterior uveitis

Subject analysis set type

Full analysis

Subject analysis set description

Inflammation in the back of the eye is commonly characterized by: Floaters,Blurred vision,Photopsia or seeing flashing lights

Subject analysis set title

Responders

Subject analysis set type

Full analysis

Subject analysis set description

Total number of responders

Subject analysis set title

Pan Uveitis

Subject analysis set type

Full analysis

Subject analysis set description

Panuveitis is a generalized inflammation of not only the whole of the uveal tract but also involves the retina and vitreous humor

Subject analysis set title

Anterior Uveitis

Subject analysis set type

Full analysis

Subject analysis set description

Anterior uveitis includes iridocyclitis and iritis. Iritis is the inflammation of the anterior chamber and iris. Iridocyclitis presents the same symptoms as iritis, but also includes inflammation in the vitreous cavity

Subject analysis set title

Birdshot

Subject analysis set type

Full analysis

Subject analysis set description

Birdshot chorioretinopathy is a rare form of bilateral posterior uveitis affecting the eye. It causes severe, progressive inflammation of both the choroid and retina

Subject analysis set title

Sympathetic Opthalmia

Subject analysis set type

Full analysis

Subject analysis set description

Sympathetic ophthalmia (SO) is a bilateral diffuse granulomatous uveitis (a kind of inflammation) of both eyes following trauma to one eye.

Subject analysis set title

Multi-focal Choroiditis

Subject analysis set type

Full analysis

Subject analysis set description

MCP is a condition characterized by intraocular inflammation and multifocal choroidal lesions occurring in the absence of any known ocular or systemic disease

Subject analysis sets values	Adverse Events	Intermediate Uveitis	Posterior uveitis	Responders	Pan Uveitis	Anterior Uveitis	Birdshot	Sympathetic Opthalmia	Multi-focal Choroiditis
Number of subjects	79	79	79	79	79	79	79	79	79
Age categorical
Units: Subjects
18y < 65y	75	75	75	75	75	75	75	75	75
65y < 85y	4	4	4	4	4	4	4	4	4
Age Continuous \|
Units: years
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )	( )	( )	( )
Gender, Male/Female
Units: Participants
male
Female

End points

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Reporting group title

Cohort 1

Reporting group description

Cohort 1-300mg s.c. bi-weekly (q2wks)

Reporting group title

Cohort 2

Reporting group description

(300mg s.c. bi-weekly (q2wks)), 3 patients from cohort 1 rolled into this cohort

Reporting group title

Cohort 3

Reporting group description

10 mg/kg i.v. every 4 weeks (q4 wks)

Reporting group title

Cohort 5

Reporting group description

30 mg/kg AIN457 IV q4 weeks

Reporting group title

Cohort 6 Arm 1

Reporting group description

300mg sc q 2wks

Reporting group title

Cohort 6 Arm 2

Reporting group description

10mg/kg i.v. q2wks

Reporting group title

Cohort 6 Arm 3

Reporting group description

30mg/kg i.v. q4wks

Reporting group title

Cohort 4

Reporting group description

Extension- All patients are rollover patients from other cohorts. AIN457 10 mg/kg iv PRN no more than once per month. COHORT 4 not added to total mean as they are already included.

Subject analysis set title

Adverse Events

Subject analysis set type

Safety analysis

Subject analysis set description

Found in Adverse Event Section

Subject analysis set title

Intermediate Uveitis

Subject analysis set type

Full analysis

Subject analysis set description

Intermediate uveitis is a form of uveitis localized to the vitreous and peripheral retina.

Subject analysis set title

Posterior uveitis

Subject analysis set type

Full analysis

Subject analysis set description

Inflammation in the back of the eye is commonly characterized by: Floaters,Blurred vision,Photopsia or seeing flashing lights

Subject analysis set title

Responders

Subject analysis set type

Full analysis

Subject analysis set description

Total number of responders

Subject analysis set title

Pan Uveitis

Subject analysis set type

Full analysis

Subject analysis set description

Panuveitis is a generalized inflammation of not only the whole of the uveal tract but also involves the retina and vitreous humor

Subject analysis set title

Anterior Uveitis

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Birdshot

Subject analysis set type

Full analysis

Subject analysis set description

Birdshot chorioretinopathy is a rare form of bilateral posterior uveitis affecting the eye. It causes severe, progressive inflammation of both the choroid and retina

Subject analysis set title

Sympathetic Opthalmia

Subject analysis set type

Full analysis

Subject analysis set description

Sympathetic ophthalmia (SO) is a bilateral diffuse granulomatous uveitis (a kind of inflammation) of both eyes following trauma to one eye.

Subject analysis set title

Multi-focal Choroiditis

Subject analysis set type

Full analysis

Subject analysis set description

MCP is a condition characterized by intraocular inflammation and multifocal choroidal lesions occurring in the absence of any known ocular or systemic disease

Primary: Number of participants with ocular examinations, physical examination, and adverse events

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End point title

Number of participants with ocular examinations, physical examination, and adverse events ^[1]

End point description

All safety measures are described in the adverse event section.

End point type

Primary

End point timeframe

Baseline day through end of study

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: insufficient number of participants with events and so there were no statistics performed

End point values	Adverse Events
Number of subjects analysed	0 ^[2]
Units: participants

Notes
[2] - See Safety

No statistical analyses for this end point

Secondary: Reduction in ocular inflammation Responders at day 57

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End point title

Reduction in ocular inflammation Responders at day 57

End point description

Patients from cohorts 1 and 3 participated in an open-label, single sequence, proof-of-concept study to evaluate the effects of 2 intravenous doses of 10 mg/kg of AIN457. Patients from cohort 2 participated in a randomized, double-masked study to evaluate the effects of a single initial dose of 10 mg/kg of Sp2/0-derived AIN457, 3 mg/kg CHO-derived AIN457, or 1 mg/kg of CHO-derived AIN457, followed, if deemed necessary, by a second dose at 10 mg/kg 2 or 3 weeks after the initial dose. Cohort 5 was an open-label single-dose safety study of 30 mg/kg AIN457 delivered in a single 2 hour i.v. infusion. Cohort 6 patients received both subcutaneous and intravenous study drug administration in a double-masked, double dummy design. Patients who responded to AIN457 therapy while in cohorts 1, 2, 3, 5 or 6 and who passed the end of study visit in these cohorts could be enrolled into cohort 4 in which they could continue to receive AIN457 as needed

End point type

Secondary

End point timeframe

One week through nine months

End point values	Responders	Intermediate Uveitis	Posterior uveitis	Pan Uveitis	Anterior Uveitis	Birdshot	Sympathetic Opthalmia	Multi-focal Choroiditis
Number of subjects analysed	79	79	79	79	79	79	79	79 ^[3]
Units: Participants
Cohort 1 10mg/Kg Sp2/0	11	0	3	5	3	0	0	0
Cohort 2 10mg/Kg Sp2/0	1	0	0	1	0	0	0	0
Cohort 2 10mg/Kg CHO	5	1	0	3	1	0	0	0
Cohort 2 3mg/Kg CHO	0	0	0	0	0	0	0	0
Cohort 2 1mg/Kg CHO	0	0	0	0	0	0	0	0
Cohort 3 10mg/Kg CHO	3	0	0	0	0	2	1	0

Notes
[3] - insufficient number of participants with events

No statistical analyses for this end point

Secondary: Reduction in ocular inflammation Complete Responders at day 57

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End point title

Reduction in ocular inflammation Complete Responders at day 57

End point description

End point type

Secondary

End point timeframe

One week through nine months

End point values	Responders	Intermediate Uveitis	Posterior uveitis	Pan Uveitis	Anterior Uveitis	Birdshot	Sympathetic Opthalmia	Multi-focal Choroiditis
Number of subjects analysed	79	79	79	79	79	79	79	79
Units: Participants
Cohort 2 10mg/Kg Sp2/0	0	0	0	0	0	0	0	0
Cohort 2 10mg/Kg CHO	2	0	0	1	1	0	0	0
Cohort 2 3mg/Kg CHO	0	0	0	0	0	0	0	0
Cohort 2 1mg/Kg CHO	0	0	0	0	0	0	0	0
Cohort 3 10mg/Kg CHO	3	0	0	0	0	2	1	0
Cohort 6 300 mg SC	2	0	1	1	0	0	0	0
Cohort 6 10 mg/Kg iv	5	1	2	2	0	0	0	0
Cohort 6 30 mg/Kg iv	3	1	0	2	0	0	0	0

No statistical analyses for this end point

Secondary: Number of participants with ability to induce a remission in uveitis

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End point title

Number of participants with ability to induce a remission in uveitis

End point description

Not enough patients for analysis...only a few that are detailed by narrative in study report

End point type

Secondary

End point timeframe

one week through nine months

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 5	Cohort 6 Arm 1	Cohort 6 Arm 2	Cohort 6 Arm 3
Number of subjects analysed	0 ^[4]	0 ^[5]	0 ^[6]	0 ^[7]	0 ^[8]	0 ^[9]	0 ^[10]
Units: Participants

Notes
[4] - insufficient number of participants with events
[5] - insufficient number of participants with events
[6] - insufficient number of participants with events
[7] - insufficient number of participants with events
[8] - insufficient number of participants with events
[9] - insufficient number of participants with events
[10] - insufficient number of participants with events

No statistical analyses for this end point

Secondary: Number of participants with Reduction in other immunosuppressant drugs

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End point title

Number of participants with Reduction in other immunosuppressant drugs

End point description

End point type

Secondary

End point timeframe

One week through nine months

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 5	Cohort 6 Arm 1	Cohort 6 Arm 2	Cohort 6 Arm 3
Number of subjects analysed	0 ^[11]	0 ^[12]	0 ^[13]	0 ^[14]	0 ^[15]	0 ^[16]	0 ^[17]
Units: participants

Notes
[11] - insufficient number of participants with events
[12] - insufficient number of participants with events
[13] - insufficient number of participants with events
[14] - insufficient number of participants with events
[15] - insufficient number of participants with events
[16] - insufficient number of participants with events
[17] - insufficient number of participants with events

No statistical analyses for this end point

Secondary: Number of participants with remission in uveitis

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End point title

Number of participants with remission in uveitis

End point description

Not enough patients for analysis...only a few that are detailed by narrative in study report

End point type

Secondary

End point timeframe

one week through nine months

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 5	Cohort 6 Arm 1	Cohort 6 Arm 2	Cohort 6 Arm 3
Number of subjects analysed	0 ^[18]	0 ^[19]	0 ^[20]	0 ^[21]	0 ^[22]	0 ^[23]	0 ^[24]
Units: Participants

Notes
[18] - insufficient number of participants with events
[19] - insufficient number of participants with events
[20] - insufficient number of participants with events
[21] - insufficient number of participants with events
[22] - insufficient number of participants with events
[23] - insufficient number of participants with events
[24] - insufficient number of participants with events

No statistical analyses for this end point

Secondary: Number of participants able to re-induce a remission if a flare-up occurs

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End point title

Number of participants able to re-induce a remission if a flare-up occurs

End point description

Not enough patients for analysis...only a few that are detailed by narrative in study report

End point type

Secondary

End point timeframe

One week through nine months

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 5	Cohort 6 Arm 1	Cohort 6 Arm 2	Cohort 6 Arm 3
Number of subjects analysed	0 ^[25]	0 ^[26]	0 ^[27]	0 ^[28]	0 ^[29]	0 ^[30]	0 ^[31]
Units: Participants

Notes
[25] - Not enough patients for analysis
[26] - Not enough patients for analysis
[27] - Not enough patients for analysis
[28] - Not enough patients for analysis
[29] - Not enough patients for analysis
[30] - Not enough patients for analysis
[31] - Not enough patients for analysis

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious Adverse Events are monitored from date of First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All other adverse events are monitored from First Patient First Treatment until Last Patient Last Visit.

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Cohort 1 - AIN457 10mg/kg SP2/0 10mg/kg SP2/0

Reporting group description

Cohort 1 - AIN457 10mg/kg SP2/0 10mg/kg SP2/0

Reporting group title

Cohort 2 - AIN457 10mg/kg SP2/0 10mg/kg SP2/0

Reporting group description

Cohort 2 - AIN457 10mg/kg SP2/0 10mg/kg SP2/0

Reporting group title

Cohort 2 - AIN457 10mg/kg CHO 10mg/kg CHO

Reporting group description

Cohort 2 - AIN457 10mg/kg CHO 10mg/kg CHO

Reporting group title

Cohort 2 - AIN457 3mg/kg CHO 10mg/kg CHO

Reporting group description

Cohort 2 - AIN457 3mg/kg CHO 10mg/kg CHO

Reporting group title

Cohort 2 - AIN457 1mg/kg CHO None

Reporting group description

Cohort 2 - AIN457 1mg/kg CHO None

Reporting group title

Cohort 2 - AIN457 1mg/kg CHO 10mg/kg CHO

Reporting group description

Cohort 2 - AIN457 1mg/kg CHO 10mg/kg CHO

Reporting group title

Cohort 3 - AIN457 10mg/kg CHO 10mg/kg CHO

Reporting group description

Cohort 3 - AIN457 10mg/kg CHO 10mg/kg CHO

Reporting group title

Cohort 5 - AIN457 30mg/kg i.v. q4wks

Reporting group description

Cohort 5 - AIN457 30mg/kg i.v. q4wks

Reporting group title

Cohort 6 - AIN457 300mg sc q2wks

Reporting group description

Cohort 6 - AIN457 300mg sc q2wks

Reporting group title

Cohort 6 - AIN457 10mg/kg i.v. q2wks

Reporting group description

Cohort 6 - AIN457 10mg/kg i.v. q2wks

Reporting group title

Cohort 6 - AIN457 30mg/kg i.v. q4wks

Reporting group description

Cohort 6 - AIN457 30mg/kg i.v. q4wks

Reporting group title

Cohort 4 (extension) - AIN457

Reporting group description

Cohort 4 (extension) - AIN457

Cohort 1 - AIN457 10mg/kg SP2/0 10mg/kg SP2/0

Cohort 2 - AIN457 10mg/kg SP2/0 10mg/kg SP2/0

Cohort 2 - AIN457 10mg/kg CHO 10mg/kg CHO

Cohort 2 - AIN457 3mg/kg CHO 10mg/kg CHO

Cohort 2 - AIN457 1mg/kg CHO None

Cohort 2 - AIN457 1mg/kg CHO 10mg/kg CHO

Cohort 3 - AIN457 10mg/kg CHO 10mg/kg CHO

Cohort 5 - AIN457 30mg/kg i.v. q4wks

Cohort 6 - AIN457 300mg sc q2wks

Cohort 6 - AIN457 10mg/kg i.v. q2wks

Cohort 6 - AIN457 30mg/kg i.v. q4wks

Cohort 4 (extension) - AIN457

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 15 (0.00%)

0 / 1 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 13 (0.00%)

0 / 12 (0.00%)

1 / 28 (3.57%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uterine cancer

subjects affected / exposed

0 / 15 (0.00%)

0 / 1 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 12 (0.00%)

0 / 28 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Tibia fracture

subjects affected / exposed

0 / 15 (0.00%)

0 / 1 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 12 (0.00%)

1 / 28 (3.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Infections and infestations

Pyelonephritis

subjects affected / exposed

0 / 15 (0.00%)

0 / 1 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 13 (0.00%)

0 / 12 (0.00%)

0 / 28 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 15 (0.00%)

0 / 1 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 13 (0.00%)

0 / 12 (0.00%)

0 / 28 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Hypokalaemia

subjects affected / exposed

0 / 15 (0.00%)

0 / 1 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 12 (8.33%)

0 / 13 (0.00%)

0 / 12 (0.00%)

0 / 28 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort 1 - AIN457 10mg/kg SP2/0 10mg/kg SP2/0	Cohort 2 - AIN457 10mg/kg SP2/0 10mg/kg SP2/0	Cohort 2 - AIN457 10mg/kg CHO 10mg/kg CHO	Cohort 2 - AIN457 3mg/kg CHO 10mg/kg CHO	Cohort 2 - AIN457 1mg/kg CHO None	Cohort 2 - AIN457 1mg/kg CHO 10mg/kg CHO	Cohort 3 - AIN457 10mg/kg CHO 10mg/kg CHO	Cohort 5 - AIN457 30mg/kg i.v. q4wks	Cohort 6 - AIN457 300mg sc q2wks	Cohort 6 - AIN457 10mg/kg i.v. q2wks	Cohort 6 - AIN457 30mg/kg i.v. q4wks	Cohort 4 (extension) - AIN457
Total subjects affected by non serious adverse events
subjects affected / exposed	15 / 15 (100.00%)	1 / 1 (100.00%)	4 / 5 (80.00%)	2 / 5 (40.00%)	2 / 2 (100.00%)	3 / 4 (75.00%)	5 / 5 (100.00%)	3 / 4 (75.00%)	9 / 12 (75.00%)	10 / 13 (76.92%)	12 / 12 (100.00%)	20 / 28 (71.43%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibroadenoma of breast
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Vascular disorders
Hot flush
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	2 / 13 (15.38%)	2 / 12 (16.67%)	1 / 28 (3.57%)
occurrences all number	2	0	0	0	0	0	0	0	2	2	2	1
Infusion site extravasation
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0
Irritability
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Oedema peripheral
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	1	0	0
Pain
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	1 / 28 (3.57%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1	1
Pyrexia
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	0	2
Reproductive system and breast disorders
Uterine haemorrhage
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Uterine spasm
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	1	0	0
Nasal congestion
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	1
Rhinorrhoea
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Sinus congestion
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Vocal cord disorder
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	2 / 13 (15.38%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	3	0	0
Anxiety disorder
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Depression
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Insomnia
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0
Nervousness
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Blood pressure increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Blood triglycerides increased
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	0	0
Blood urine present
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Intraocular pressure increased
subjects affected / exposed	5 / 15 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	5	0	0	0	0	0	0	0	0	1	0	4
Lipase increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Lymphocyte percentage decreased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Neutrophil percentage increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Protein urine
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	1	0	0
Weight decreased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Injury, poisoning and procedural complications
Back injury
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Joint injury
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Laceration
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Muscle strain
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0
Post procedural complication
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Radius fracture
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Nervous system disorders
Aphonia
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Dizziness
subjects affected / exposed	3 / 15 (20.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	0	0	0	0	0	0	0	0	1	0	0
Headache
subjects affected / exposed	10 / 15 (66.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	3 / 4 (75.00%)	3 / 5 (60.00%)	2 / 4 (50.00%)	5 / 12 (41.67%)	3 / 13 (23.08%)	4 / 12 (33.33%)	1 / 28 (3.57%)
occurrences all number	30	0	0	1	0	4	4	3	12	5	7	1
Hyperaesthesia
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Migraine
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	2
Presyncope
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Sinus headache
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0	0	0	1	0	0	0	0	0
Somnolence
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0
Syncope
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Tension headache
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 12 (8.33%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Eye disorders
Abnormal sensation in eye
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Anterior chamber flare
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Cataract
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Chalazion
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Colour blindness acquired
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Conjunctival hyperaemia
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	1	0	0
Conjunctivitis allergic
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3
Corneal disorder
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Dry eye
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	2 / 13 (15.38%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	2
Eye irritation
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Eye pain
subjects affected / exposed	3 / 15 (20.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	1 / 12 (8.33%)	3 / 28 (10.71%)
occurrences all number	8	0	1	1	0	0	1	0	1	1	1	6
Eye pruritus
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	1	0
Eye swelling
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Eyelid oedema
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	2 / 28 (7.14%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	1	2
Foreign body sensation in eyes
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0
Iridocyclitis
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0
Iris adhesions
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Iris bombe
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Keratoconjunctivitis sicca
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Lacrimation increased
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Macular fibrosis
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Macular oedema
subjects affected / exposed	1 / 15 (6.67%)	1 / 1 (100.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	1	1	0	0	0	0	1	0	0	0	1
Ocular hyperaemia
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 12 (0.00%)	3 / 28 (10.71%)
occurrences all number	2	0	0	0	0	0	0	0	1	0	0	4
Papilloedema
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Photophobia
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	2
Photopsia
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1
Pupillary reflex impaired
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Retinal detachment
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Retinal tear
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Scleritis
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Uveitis
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	0	0	0	0	0	2	0	0	1
Vision blurred
subjects affected / exposed	3 / 15 (20.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	3 / 12 (25.00%)	1 / 28 (3.57%)
occurrences all number	3	0	1	0	0	0	1	0	0	0	3	1
Visual acuity reduced
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	0	0	0	1	0	0	0	0	0	0	1
Vitreous detachment
subjects affected / exposed	0 / 15 (0.00%)	1 / 1 (100.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	2
Vitreous floaters
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	4 / 28 (14.29%)
occurrences all number	3	0	1	0	0	0	3	0	0	0	1	4
Vitreous haemorrhage
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	3	0	0	0	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0
Abdominal pain lower
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	3 / 15 (20.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	4	0	0	0	0	1	0	0	0	0	0	0
Constipation
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Diarrhoea
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	1	0	0	0
Inguinal hernia
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	1	0
Tooth disorder
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	5	0	0	1	0	0	0	0	0	0	0	0
Hepatobiliary disorders
Non-alcoholic steatohepatitis
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0
Alopecia
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Dermatitis acneiform
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Dermatitis contact
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Eczema
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Madarosis
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 12 (8.33%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	1	0	0	0	3	1	2
Pruritus generalised
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0
Psoriasis
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Rash
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 12 (8.33%)	1 / 28 (3.57%)
occurrences all number	3	0	1	0	0	1	3	0	0	1	1	3
Rash pruritic
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Skin odour abnormal
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	1	0	0	0	1	0	0	1	0	0
Back pain
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	1	0	0	0	3	0	0	0	0	0
Exostosis
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Flank pain
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	3	0	0	0	0	0	0	0	0	0	0	1
Joint swelling
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Limb discomfort
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Muscle spasms
subjects affected / exposed	2 / 15 (13.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	0	0	0	0	0	0	0	0	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Myalgia
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	0	0	0	2	0	0	0	0	1
Pain in extremity
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0
Spondylitis
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Ear infection
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	2
Gastroenteritis
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Hordeolum
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Lice infestation
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	3 / 12 (25.00%)	6 / 28 (21.43%)
occurrences all number	1	0	0	1	0	0	1	0	1	2	3	14
Oral herpes
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Pharyngitis streptococcal
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Respiratory tract infection
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Sinusitis
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2
Urinary tract infection
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 12 (16.67%)	1 / 28 (3.57%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	2	1
Vaginitis bacterial
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 12 (8.33%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	1	0
Metabolism and nutrition disorders
Gout
subjects affected / exposed	1 / 15 (6.67%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Increased appetite
subjects affected / exposed	0 / 15 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 12 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

12 Jun 2008

Patients were randomized prior to this date. Amendment 1 modified key secondary efficacy outcomes and key efficacy variables, to use a 15-letter change in BCVA rather than a 10-letter change, as one of the criteria for declaring a patient as responding to therapy with AIN457, to use a 2- grade improvement in vitreous haze as an outcome criterion, and to delete the secondary efficacy variable “change in macular edema”. The exclusion criteria were modified to add aqueous tap to ocular surgeries allowed in the study eye, to allow “up to every hour while awake” use of topical corticosteroids, and to allow patients to be on any dose of prednisone before baseline day. Additionally, it modified the section on Rescue medication so that clinical assessments continued after rescue.)

01 Aug 2008

This amendment was issued when 4 patients had been randomized, introduced the following change: removal of the weight inclusion criterion that specified a range of masses (45 –100 kg, or 99 to 220 pounds).

17 Feb 2009

This amendment introduced the following changes: Addition of two new cohorts of patients, designated cohort 2 and cohort 3. The study of cohort 2 had the following objectives: - determine if a single dose of AIN457 was sufficient to induce a remission of uveitis within 3 weeks, -determine if AIN457 produced from Sp2/0 cells was similar in efficacy to AIN457produced from CHO cells, -determine the time to flare-up once a remission was achieved, -determine if remission can be re-induced with AIN457 once a flare-up occurred, -determine if continued periodic doses of AIN457 maintain a remission. Cohort 3 was to determine whether AIN457 was efficacious in treating forms of uveitis that often progress to blindness with all currently available immunosuppressive therapies. The amendment also revised certain inclusion and exclusion criteria. For example, the 3-week washout period for oral low-molecular weight immunosuppressant drugs was eliminated. Patients with active uveitis were allowed to continue their oral immunosuppressant drugs throughout the interval between the screening visit and the baseline visit when the first dose of AIN457 was given, thereby improving the safety of enrolled patients as it minimized the deleterious effects of up to 3 weeks of untreated uveitis or the need to start corticosteroids during this interval. Another inclusion criterion that was revised was the requirement for visual acuity of 20/40 or less. Many eyes with active uveitis have visual acuity better than 20/40, and it was reasonable to determine how well AIN457 suppressed uveitis in these eyes. Finally, an exclusion criterion was added for patients whose disease had resolved between screening and baseline visits.

06 Apr 2009

This amendment was to clarify and emphasize that the patients and all assessing personnel (e.g., the investigators and clinical coordinators) would be masked to the treatment arm assigned to patients randomized to Cohort 2. Additionally, patients from Cohort 1 who proceeded to participate in Cohort 2 were randomized to only the 3 mg/kg and 1 mg/kg initial doses, not the 10 mg/kg dose that was given to cohort 1. The following changes were also introduced -physical examinations at screening and at various time points during the trial,-clarification on testing for tuberculosis required for patients, AIN457 doses of 10 mg/kg would not be given more frequently than every 4 weeks (lower doses of 3 mg/kg or 1 mg/kg could be given as frequently as every 3 weeks), mentions in the synopsis that AIN457 comes in 150-mg vials as well as 50-mg vials, reduction in the exclusion period after ocular surgery before enrollment to 4 months from 6 months , elimination of the contingency of dosing patients in cohort 2 with the Sp2/0-derived AIN457 in an unblinded manner prior to the availability of CHO-derived AIN457, and provides for emergency unblinding of treatment assignment in cohort 2.

18 May 2009

This amendment was made to add exploratory pharmacogenetic studies with the objective of identifying genetic variants that may be associated with the etiology of uveitis that may predict the response to therapy with AIN457,susceptibility to interactions between AIN457 and other therapies and the risk for side effects. The logistics and consent processes of pharacogenetic data collection were detailed. These pharmacogenetic analyses are not part of this study report because they are planned to be combined with other studies of AIN457 to increase the number of patients and thereby the power of the analyses. The synopsis and assessment schedule were revised as well to change the current serum pregnancy test, conducted at study completion, to a urine pregnancy test. In addition, exclusion criteria were revised to increase the washout period to 12 months for two immunosuppressive agents, Raptiva and Rituxan, and to correct some minor clerical errors in language.

13 Jul 2009

This amendment introduced the following: AIN457 could be used as a rescue medication in patients whose uveitis responded after receiving two doses of 10 mg/kg while enrolled in Cohort 1 but whose uveitis did not subside for up to 8 weeks after a single dose of 1 or 3 mg/kg while enrolled in Cohort 2. Such patients, if their uveitis was active within 8-16 weeks after that single dose while in cohort 2, would be given one or two doses of 10 mg/kg iv. If their uveitis responded to these doses, then the patient would be provided periodic doses of AIN457 as specified in the protocol. Observing the efficacy of 10 mg/kg in comparison with 1 and 3 mg/kg AIN457 in the same patient would allow the selection of the optimal dose for the treatment of uveitis.

23 Feb 2010

This amendment allowed the continued treatment of study patients from Cohorts 1-3 who responded well with AIN457 and who preferred this therapy to any other uveitis therapy. These patients were enrolled into Cohort 4.

01 Dec 2010

This amendment was made to test for the first time in humans,a higher dose of AIN457, 30 mg/kg, given intravenously, and tested a subcutaneous route at adose of AIN457 (300 mg), and updated inclusion/exclusion criteria to be consistent with other uveitis studies.

13 May 2011

This amendment explained the retreatment sequence for patients in Safety Cohort 5. Although the critical data for patients in this cohort is the safety of a single 30 mg/kg iv infusion of AIN457, the protocol provided the opportunity for continued AIN457 treatment for these patients following confirmation of safety of this dose. Criteria for continued treatment were intended to be identical to those used for patients in Cohort 6. However, it was clearly stated in the protocol that no patient in this cohort was to receive a second dose of AIN457 30 mg/kg until all 4 patients in Cohort 5 had demonstrated that the dose was safe for a minimum of 29 days. As an unintended consequence of this stipulation, for all patients of this cohort, the second dose of study medication was delayed beyond Day 29. This amendment addressed the resultant changes in the visit and assessment schedule, as well as clarifying the institution of therapeutic intervention to maintain the patient’s response until they could be re-treated. Cohort 4 was comprised of patients from all other cohorts of this study whose uveitis was in remission at the end of study observation. These patients are offered open-label access to AIN457 on a PRN basis. In this amendment Cohort 4 was extended to include open-label treatment for complete responders in Cohort 5 and Cohort 6 as well as to stipulate a firm end date for this open-label extension cohort as 1 year following last patient last visit date of Cohort 6. Cohort 4 efficacy assessment collections will be discontinued with safety being the key variable, after finalization of the current amendment. These amendments were not considered to have affected the interpretation of study results as they were minor and occurred prior to study unblinding.

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 trials

Clinical Trial Results:
An open-label proof-of-concept study with a double-masked, dose-ranging component to assess the effects of AIN457 in patients with noninfectious uveitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants with ocular examinations, physical examination, and adverse events

Primary: Number of participants with ocular examinations, physical examination, and adverse events

Secondary: Reduction in ocular inflammation Responders at day 57

Secondary: Reduction in ocular inflammation Responders at day 57

Secondary: Reduction in ocular inflammation Complete Responders at day 57

Secondary: Reduction in ocular inflammation Complete Responders at day 57

Secondary: Number of participants with ability to induce a remission in uveitis

Secondary: Number of participants with ability to induce a remission in uveitis

Secondary: Number of participants with Reduction in other immunosuppressant drugs

Secondary: Number of participants with Reduction in other immunosuppressant drugs

Secondary: Number of participants with remission in uveitis

Secondary: Number of participants with remission in uveitis

Secondary: Number of participants able to re-induce a remission if a flare-up occurs

Secondary: Number of participants able to re-induce a remission if a flare-up occurs

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: An open-label proof-of-concept study with a double-masked, dose-ranging component to assess the effects of AIN457 in patients with noninfectious uveitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants with ocular examinations, physical examination, and adverse events

Primary: Number of participants with ocular examinations, physical examination, and adverse events

Secondary: Reduction in ocular inflammation Responders at day 57

Secondary: Reduction in ocular inflammation Responders at day 57

Secondary: Reduction in ocular inflammation Complete Responders at day 57

Secondary: Reduction in ocular inflammation Complete Responders at day 57

Secondary: Number of participants with ability to induce a remission in uveitis

Secondary: Number of participants with ability to induce a remission in uveitis

Secondary: Number of participants with Reduction in other immunosuppressant drugs

Secondary: Number of participants with Reduction in other immunosuppressant drugs

Secondary: Number of participants with remission in uveitis

Secondary: Number of participants with remission in uveitis

Secondary: Number of participants able to re-induce a remission if a flare-up occurs

Secondary: Number of participants able to re-induce a remission if a flare-up occurs

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An open-label proof-of-concept study with a double-masked, dose-ranging component to assess the effects of AIN457 in patients with noninfectious uveitis