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Clinical Trial Results:
RAINBOW extension study: an extension study to evaluate the long-term efficacy and safety of RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity

Summary
EudraCT number	2014-004048-36
Trial protocol	HU EE GB SK IT BE LT CZ DE AT SE GR DK FR HR PL
Global end of trial date	21 Apr 2022

Results information
Results version number	v1
This version publication date	05 Nov 2022
First version publication date	05 Nov 2022
Other versions	v2 , v3

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

CRFB002H2301E1

ISRCTN number

US NCT number

NCT02640664

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, Novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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

21 Apr 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Apr 2022

Was the trial ended prematurely?

Main objective of the trial

To evaluate the visual function of patients, by assessing the visual acuity (VA) in the better-seeing eye at the patients’ 5th birthday. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

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

16 Jun 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 4

Country: Number of subjects enrolled

Belgium: 10

Country: Number of subjects enrolled

Croatia: 5

Country: Number of subjects enrolled

Czechia: 9

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

Egypt: 1

Country: Number of subjects enrolled

Estonia: 2

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Greece: 10

Country: Number of subjects enrolled

Hungary: 2

Country: Number of subjects enrolled

India: 23

Country: Number of subjects enrolled

Italy: 12

Country: Number of subjects enrolled

Japan: 25

Country: Number of subjects enrolled

Lithuania: 1

Country: Number of subjects enrolled

Malaysia: 2

Country: Number of subjects enrolled

Romania: 13

Country: Number of subjects enrolled

Russian Federation: 18

Country: Number of subjects enrolled

Saudi Arabia: 1

Country: Number of subjects enrolled

Slovakia: 1

Country: Number of subjects enrolled

Taiwan: 7

Country: Number of subjects enrolled

Turkey: 10

Country: Number of subjects enrolled

United States: 15

Worldwide total number of subjects

180

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)

177

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

Study was carried out in Austria (2), Belgium (2), Croatia (1), Czech Republic (3), Denmark (1), Egypt (1), Estonia (1), France (2), Germany (1), Greece (3), Hungary (2), India (6), Italy (4), Japan (16), Lithuania (1), Malaysia (2), Romania (3), Russian Federation (5), Saudi Arabia (1), Slovakia (1), Taiwan (2), Turkey (3), UK (2), US (9)

Screening details

This study was not randomized. In the core study, participants were randomized to 1 of the 3 treatment arms (ranibizumab 0.2 mg, ranibizumab 0.1 mg, and laser). Treatment arm assignment and participant identifier in the extension study remained the same as in the core study.

Period 1 title

Core study: Epoch 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

This was an open-label study where the VA assessment at the child's 5th birthday visit was performed by an assessor who was masked to study treatment.

Are arms mutually exclusive

Yes

Ranibizumab 0.2 mg

Arm description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Arm type

Experimental

Investigational medicinal product name

Ranibizumab

Investigational medicinal product code

RFB002

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravitreal use

Dosage and administration details

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Ranibizumab 0.1 mg

Arm description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Arm type

Experimental

Investigational medicinal product name

Ranibizumab

Investigational medicinal product code

RFB002

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravitreal use

Dosage and administration details

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Laser therapy

Arm description

Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed

Arm type

laser ablation therapy

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Started	61	65	54
Completed	60	65	53
Not completed	1	0	1
Adverse event, serious fatal	-	-	1
Withdrawal of informed consent	1	-	-

Period 2 title

Extension study: Epoch 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

This was an open-label study where the VA assessment at the child's 5th birthday visit was performed by an assessor who was masked to study treatment.

Are arms mutually exclusive

Yes

Ranibizumab 0.2 mg

Arm description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Arm type

Experimental

Investigational medicinal product name

Ranibizumab

Investigational medicinal product code

RFB002

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravitreal use

Dosage and administration details

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Ranibizumab 0.1 mg

Arm description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Arm type

Experimental

Investigational medicinal product name

Ranibizumab

Investigational medicinal product code

RFB002

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravitreal use

Dosage and administration details

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Laser therapy

Arm description

Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed

Arm type

laser ablation therapy

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Started	60	65	53
Completed	54	55	47
Not completed	6	10	6
Adverse event, serious fatal	-	-	1
Withdrawal of informed consent	3	4	2
Lost to follow-up	3	4	1
Subject/guardian decision	-	2	2

Baseline characteristics

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Reporting group title

Ranibizumab 0.2 mg

Reporting group description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Reporting group title

Ranibizumab 0.1 mg

Reporting group description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Reporting group title

Laser therapy

Reporting group description

Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed

Reporting group values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy	Total
Number of subjects	61	65	54	180
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	1	1	1	3
Infants and toddlers (28 days-23 months)	60	64	53	177
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age Continuous
Age at core baseline visit
Units: Weeks
arithmetic mean (standard deviation)	11.32 ( 3.974 )	11.07 ( 3.515 )	9.89 ( 3.744 )	-
Sex: Female, Male
Units: Participants
Female	32	35	27	94
Male	29	30	27	86
Race/Ethnicity, Customized
Units: Subjects
Caucasian	38	40	32	110
Black	0	4	2	6
Asian	22	18	18	58
Native American	0	0	0	0
Pacific Islander	0	0	0	0
Unknown	0	0	0	0
Other	1	3	2	6

End points

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Reporting group title

Ranibizumab 0.2 mg

Reporting group description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Reporting group title

Ranibizumab 0.1 mg

Reporting group description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Reporting group title

Laser therapy

Reporting group description

Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed

Reporting group title

Ranibizumab 0.2 mg

Reporting group description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Reporting group title

Ranibizumab 0.1 mg

Reporting group description

1 intravitreal injection in both eyes on Day 1 (Baseline), with up to 2 re-treatments allowed for each eye if required

Reporting group title

Laser therapy

Reporting group description

Laser treatment to each eye on Day 1 (Baseline), with supplementary treatments allowed

Primary: Visual acuity (letters) of the better-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

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End point title

Visual acuity (letters) of the better-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

End point description

The VA assessment at the child’s 5th birthday visit was performed using ETDRS methodology. VA measurements were taken in a sitting position at an initial test distance of 3 meters using Lea Symbols charts. Scoring was reported as a letter score representing the number of optotypes (Lea symbols) the participant identified. VA was tested in each eye, using the child’s current refractive index. If the child had a score of ‘0’ (could not identify any of the Lea symbols on the chart at 1 meter) on the VA assessment or the score was ‘missing’, they were tested with low VA testing. Low VA testing consisted of determining if the child could count the examiner’s fingers, see hand motion, or perceive light. The better-seeing eye was defined as the eye with the higher ETDRS score at the 5th birthday visit. If both eyes had the same ETDRS letter score, then the right eye was assigned as the better-seeing eye.

End point type

Primary

End point timeframe

at the participant’s fifth birthday visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	45	43	36
Units: Score
least squares mean (standard error)	66.8 ( 1.95 )	64.6 ( 2.00 )	62.1 ( 2.18 )

Ranibizumab 0.2 mg vs Laser

Comparison groups

Ranibizumab 0.2 mg v Laser therapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

4.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

10.5

Variability estimate

Standard error of the mean

Dispersion value

2.93

Ranibizumab 0.2 mg vs Ranibizumab 0.1 mg

Comparison groups

Ranibizumab 0.2 mg v Ranibizumab 0.1 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

7.8

Variability estimate

Standard error of the mean

Dispersion value

2.79

Ranibizumab 0.1 mg vs Laser

Comparison groups

Ranibizumab 0.1 mg v Laser therapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

8.3

Variability estimate

Standard error of the mean

Dispersion value

2.96

Secondary: Number of participants with ocular adverse events regardless of study treatment or procedure relationship by preferred term

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End point title

Number of participants with ocular adverse events regardless of study treatment or procedure relationship by preferred term

End point description

Number of participants with ocular AEs starting during the core study and ongoing at extension baseline, or starting on/after extension baseline were reported.

End point type

Secondary

End point timeframe

throughout the study, approximately 5 years

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	61	65	54
Units: Participants	19	26	22

No statistical analyses for this end point

Secondary: Visual acuity (VA) of the worse-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

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End point title

Visual acuity (VA) of the worse-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

End point description

The VA assessment at the child’s 5th birthday visit was performed using ETDRS methodology. VA measurements were taken in a sitting position at an initial test distance of 3 meters using Lea Symbols charts. Scoring was reported as a letter score representing the number of optotypes (Lea symbols) the patient identified. VA was tested in each eye, using the child’s current refractive index. If the child had a score of ‘0’ (could not identify any of the Lea symbols on the chart at 1 meter) on the VA assessment or the score was ‘missing’, they were tested with low VA testing. Low VA testing consisted of determining if the child could count the examiner’s fingers, see hand motion, or perceive light. The worse-seeing eye was the eye with a lower ETDRS letter score at the 5th birthday visit. If both eyes had the same ETDRS letter score, then the left eye is assigned as the worse-seeing eye.

End point type

Secondary

End point timeframe

at the participant’s fifth birthday visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	45	42	36
Units: Score
least squares mean (standard error)	60.2 ( 2.95 )	53.8 ( 3.05 )	52.2 ( 3.30 )

Ranibizumab 0.2 mg vs Laser

Comparison groups

Ranibizumab 0.2 mg v Laser therapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

16.7

Variability estimate

Standard error of the mean

Dispersion value

4.42

Ranibizumab 0.2 mg vs Ranibizumab 0.1 mg

Comparison groups

Ranibizumab 0.2 mg v Ranibizumab 0.1 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

6.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

14.8

Variability estimate

Standard error of the mean

Dispersion value

4.24

Ranibizumab 0.1 mg vs Laser

Comparison groups

Ranibizumab 0.1 mg v Laser therapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

ANOVA

Parameter type

Mean difference (net)

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-7.3

upper limit

10.5

Variability estimate

Standard error of the mean

Dispersion value

4.49

Secondary: Number of participants with non-ocular adverse events regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term

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End point title

Number of participants with non-ocular adverse events regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term

End point description

Number of participants with non-ocular adverse events regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term were reported.

End point type

Secondary

End point timeframe

throughout the study, approximately 5 years

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	61	65	54
Units: Participants	46	53	46

No statistical analyses for this end point

Secondary: Number of participants with absence of active Retinopathy of Prematurity (ROP) at 40 weeks post core baseline visit

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End point title

Number of participants with absence of active Retinopathy of Prematurity (ROP) at 40 weeks post core baseline visit

End point description

The absence of active ROP in both eyes is defined by the absence of all of the following features: (1) Vessel dilatation of plus disease in at least 2 quardrants (some persisting tortuosity is allowed), (2) Extra-retina vessels extending from the retina into the vitreous and judged to be a sign of active ROP disease.

End point type

Secondary

End point timeframe

at 40 weeks post core baseline visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	55	58	46
Units: Participants
Absence of active ROP	55	58	46

No statistical analyses for this end point

Secondary: Number of participants with absence of active Retinopathy of Prematurity (ROP) at 52 weeks post core baseline visit

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End point title

Number of participants with absence of active Retinopathy of Prematurity (ROP) at 52 weeks post core baseline visit

End point description

End point type

Secondary

End point timeframe

at 52 weeks post core baseline visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	58	63	50
Units: Participants	58	63	49

No statistical analyses for this end point

Secondary: Number of participants with absence of all ocular structural abnormalities at or before 40 weeks post baseline visit

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End point title

Number of participants with absence of all ocular structural abnormalities at or before 40 weeks post baseline visit

End point description

The absence of ocular structural abnormalities is defined by the absence of all of the following fundus features in both eyes at or before the given time point: (1) Substantial temporal retinal vessel dragging causing abnormal structural features/macular Ectopia, (2) Retrolental membrane obscuring the view of the posterior pole, (3) Posterior retinal fold involving the macula, (4) Retinal detachment involving the macula

End point type

Secondary

End point timeframe

at or before 40 weeks post baseline visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	60	65	53
Units: Participants	59	61	47

No statistical analyses for this end point

Secondary: Number of participants with absence of all ocular structural abnormalities at or before the participant’s fifth birthday visit

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End point title

Number of participants with absence of all ocular structural abnormalities at or before the participant’s fifth birthday visit

End point description

End point type

Secondary

End point timeframe

at or before the participant’s fifth birthday visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	60	65	53
Units: Participants	59	61	47

No statistical analyses for this end point

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before 40 weeks post baseline visit

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End point title

Number of participants with absence of individual ocular structural abnormalities at or before 40 weeks post baseline visit

End point description

End point type

Secondary

End point timeframe

at or before 40 weeks post baseline visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	60	65	53
Units: Participants
Absence of substantial temporal retinal vessel	59	63	49
Absence of Retrolental membrane	60	65	53
Absence of posterior retinal fold	59	65	51
Absence of retinal detachment	60	63	51
Abs of retinal detachment not involving the macula	60	62	50
Absence of pre-retinal fibrosis	58	60	49

No statistical analyses for this end point

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before the participant’s fifth birthday visit

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End point title

Number of participants with absence of individual ocular structural abnormalities at or before the participant’s fifth birthday visit

End point description

End point type

Secondary

End point timeframe

at or before the participant’s fifth birthday visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	60	65	53
Units: Participants
Absence of temporal retinal vessel dragging	59	63	49
Absence of Retrolental membrane	60	65	52
Absence of posterior retinal fold	59	65	51
Absence of retinal detachment	60	63	50
Abs of retinal detachment not involving macula	60	62	50
Absence of pre-retinal fibrosis	58	59	48
Absence of optic disc pallor	60	65	52
Absence of optic disc swelling	60	65	53
Absence of pigmentary disturbance in the macula	60	64	52
Absence of atrophic changes in macula	60	65	51

No statistical analyses for this end point

Secondary: Number of participants with absence of all ocular structural abnormalities at or before participant’s 2 years corrected age visit

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End point title

Number of participants with absence of all ocular structural abnormalities at or before participant’s 2 years corrected age visit

End point description

End point type

Secondary

End point timeframe

at or before participant’s 2 years corrected age visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	60	65	53
Units: Participants	59	61	47

No statistical analyses for this end point

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before participant’s 2 years corrected age visit

Top of page

End point title

Number of participants with absence of individual ocular structural abnormalities at or before participant’s 2 years corrected age visit

End point description

End point type

Secondary

End point timeframe

at or before participant’s 2 years corrected age visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	60	65	53
Units: Participants
Abs of temporal retinal vessel dragging	59	63	49
Absence of Retrolental membrane	60	65	52
Absence of posterior retinal fold	59	65	51
Abs of retinal detachment involving the macula	60	63	50
Abs of retinal detachment not involving the macula	60	62	50
Absence of pre-retinal fibrosis	58	59	48
Absence of optic disc pallor	60	65	53
Absence of optic disc swelling	60	65	53
Absence of pigmentary disturbance in the macula	60	64	52
Absence of atrophic changes in macula	60	65	52

No statistical analyses for this end point

Secondary: Number of participants with recurrence of ROP up to 40 weeks post baseline visit in the core study

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End point title

Number of participants with recurrence of ROP up to 40 weeks post baseline visit in the core study

End point description

Recurrence of ROP was defined as ROP receiving any post-baseline intervention after the 1st study treatment in the core study. In the ranibizumab arms, post-baseline interventions were ranibizumab retreatment or switch to laser. In the laser arm, post-baseline interventions were supplementary laser treatments after 11 days post-baseline, or switch to ranibizumab; supplementary laser treatment within 11 days post-baseline was not counted as recurrence.

End point type

Secondary

End point timeframe

up to 40 weeks post baseline visit in the core study

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	61	65	54
Units: Participants	19	22	11

No statistical analyses for this end point

Secondary: Number of participants with recurrence of ROP up to 52 weeks post baseline visit in the core study

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End point title

Number of participants with recurrence of ROP up to 52 weeks post baseline visit in the core study

End point description

End point type

Secondary

End point timeframe

up to 52 weeks post baseline visit in the core study

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	61 ^[1]	65 ^[2]	54 ^[3]
Units: Participants	999	999	999

Notes
[1] - analysis identical to ‘recurrence of ROP upto 40 wks post-baseline’ as recurrence remained unchanged
[2] - analysis identical to ‘recurrence of ROP upto 40 wks post-baseline’ as recurrence remained unchanged
[3] - analysis identical to ‘recurrence of ROP upto 40 wks post-baseline’ as recurrence remained unchanged

No statistical analyses for this end point

Secondary: Number of ranibizumab injections received per participant over the whole safety observation period

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End point title

Number of ranibizumab injections received per participant over the whole safety observation period

End point description

Number of ranibizumab injections received in the treatment of participants with ROP up to and including 40 weeks post baseline visit in the core study were reported.

End point type

Secondary

End point timeframe

up to and including 40 weeks post baseline visit in the core study

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	61	65	11
Units: Number of injections
arithmetic mean (standard deviation)	2.5 ( 0.96 )	2.5 ( 1.06 )	2.4 ( 0.92 )

No statistical analyses for this end point

Secondary: Refraction status: Summary of participants at participant’s 2 years corrected age

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End point title

Refraction status: Summary of participants at participant’s 2 years corrected age

End point description

Summary of participants was reported to evaluate the refraction in each eye at the participant’s 2 years corrected age

End point type

Secondary

End point timeframe

at participant’s 2 years corrected age

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	57	54	47
Units: diopters
arithmetic mean (standard deviation)
Best eye	-0.697 ( 2.7032 )	-0.713 ( 2.6100 )	-1.793 ( 4.1570 )
Worst eye	-0.825 ( 2.6575 )	-0.829 ( 2.8346 )	-1.516 ( 3.5652 )

No statistical analyses for this end point

Secondary: Refraction status: Summary of participants at the participant’s fifth birthday visit - Best eye

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End point title

Refraction status: Summary of participants at the participant’s fifth birthday visit - Best eye

End point description

Summary of participants was reported to evaluate the refraction in each eye at the participant’s fifth birthday visit

End point type

Secondary

End point timeframe

at the participant’s fifth birthday visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	52	55	45
Units: diopters
arithmetic mean (standard deviation)
Best eye	-0.601 ( 2.8107 )	-0.859 ( 2.7406 )	-1.883 ( 4.4970 )

No statistical analyses for this end point

Secondary: Refraction status: Summary of participants at the participant’s fifth birthday visit - Worst eye

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End point title

Refraction status: Summary of participants at the participant’s fifth birthday visit - Worst eye

End point description

Summary of participants was reported to evaluate the refraction in each eye at the participant’s fifth birthday visit

End point type

Secondary

End point timeframe

at the participant’s fifth birthday visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	52	54	45
Units: diopters
arithmetic mean (standard deviation)	-0.904 ( 2.8501 )	-1.074 ( 3.0405 )	-1.706 ( 3.5740 )

No statistical analyses for this end point

Secondary: Change from baseline in weight at the participant’s 2 years’ corrected age

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End point title

Change from baseline in weight at the participant’s 2 years’ corrected age

End point description

Subject´s weight was reported to evaluate the physical development.

End point type

Secondary

End point timeframe

Baseline, at the participant’s 2 years’ corrected age

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	56	58	46
Units: grams
arithmetic mean (standard deviation)
Year 2	8695.9 ( 1406.58 )	8461.7 ( 1375.95 )	8840.6 ( 1643.80 )

No statistical analyses for this end point

Secondary: Change from baseline in weight at the participant’s fifth birthday

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End point title

Change from baseline in weight at the participant’s fifth birthday

End point description

Subject´s weight was reported to evaluate the physical development.

End point type

Secondary

End point timeframe

Baseline, at the participant’s fifth birthday

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	52	54	45
Units: grams
arithmetic mean (standard deviation)	14611.9 ( 3018.65 )	14324.7 ( 2616.96 )	14689.4 ( 3300.05 )

No statistical analyses for this end point

Secondary: Change from baseline in Head Circumference

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End point title

Change from baseline in Head Circumference

End point description

Subject´s head circumference was reported to evaluate the physical development.

End point type

Secondary

End point timeframe

Baseline and at the subject’s 2 years’ corrected age

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	55	56	44
Units: cm
arithmetic mean (standard deviation)	16.5 ( 2.60 )	16.2 ( 2.78 )	17.2 ( 2.81 )

No statistical analyses for this end point

Secondary: Change from baseline in Sitting Diastolic Blood Pressure

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End point title

Change from baseline in Sitting Diastolic Blood Pressure

End point description

Subject´s Sitting Diastolic Blood Pressure was reported to evaluate the physical development.

End point type

Secondary

End point timeframe

Baseline and at the subject’s 2 years’ corrected age

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	38	33	31
Units: mmHg
arithmetic mean (standard deviation)	16.7 ( 14.92 )	13.6 ( 14.10 )	16.5 ( 12.14 )

No statistical analyses for this end point

Secondary: Change from baseline in Sitting Systolic Blood Pressure

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End point title

Change from baseline in Sitting Systolic Blood Pressure

End point description

Subject´s Sitting Systolic Blood Pressure was reported to evaluate the physical development.

End point type

Secondary

End point timeframe

Baseline and at the subject’s 2 years’ corrected age

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	38	32	31
Units: mmHg
arithmetic mean (standard deviation)	20.6 ( 16.13 )	16.2 ( 15.95 )	17.6 ( 12.75 )

No statistical analyses for this end point

Secondary: Number of participants with the summary of respiratory function status

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End point title

Number of participants with the summary of respiratory function status

End point description

Number of participants with respiratory function status was reported

End point type

Secondary

End point timeframe

at the participants’ fifth birthday visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	61	65	54
Units: Participants
participants with Wheezing/whistling status	6	4	2
participants with attacks of wheezing	47	50	45
participants with frequency of sleep disturbance	47	52	47
participants with wheezing limiting speech ability	1	0	0
participants with dry cough status at night	5	2	1
participants with presence of smoker at home	15	8	4

No statistical analyses for this end point

Secondary: Number of participants with hearing impairment of any type

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End point title

Number of participants with hearing impairment of any type

End point description

Number of participants with hearing function status was reported

End point type

Secondary

End point timeframe

at the subjects’ fifth birthday visit

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	61	65	54
Units: Participants
participants with hearing impairment of any type	2	2	4
participants with use of hearing aid(s)	1	2	3
participants with usual hearing	49	51	41

No statistical analyses for this end point

Secondary: Weight at the time of first hospital discharge

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End point title

Weight at the time of first hospital discharge

End point description

Weight (gram) at the time of first hospital discharge was reported to evaluate the health status of the subject

End point type

Secondary

End point timeframe

from birth to first hospital discharge home, up to 5 years

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	56	62	51
Units: gram
arithmetic mean (standard deviation)	2910.9 ( 1359.34 )	2966.5 ( 1198.60 )	2658.7 ( 926.92 )

No statistical analyses for this end point

Secondary: Duration of hospitalization

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End point title

Duration of hospitalization

End point description

Duration of hospitalization was reported to evaluate the health status of the subject

End point type

Secondary

End point timeframe

from birth to first hospital discharge home, up to 5 years

End point values	Ranibizumab 0.2 mg	Ranibizumab 0.1 mg	Laser therapy
Number of subjects analysed	61	65	54
Units: days
arithmetic mean (standard deviation)	111.1 ( 62.27 )	116.2 ( 78.10 )	95.7 ( 57.07 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Timeframe for AE

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Ranibizumab 0.2 mg

Reporting group description

Ranibizumab 0.2 mg

Reporting group title

Laser

Reporting group description

Laser

Reporting group title

Total

Reporting group description

Total

Reporting group title

Ranibizumab 0.1 mg

Reporting group description

Ranibizumab 0.1 mg

Serious adverse events	Ranibizumab 0.2 mg	Laser	Total	Ranibizumab 0.1 mg
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 61 (34.43%)	26 / 54 (48.15%)	74 / 180 (41.11%)	27 / 65 (41.54%)
number of deaths (all causes)	0	2	2	0
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	2 / 180 (1.11%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Perinatal brain damage
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	3 / 61 (4.92%)	2 / 54 (3.70%)	6 / 180 (3.33%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Developmental delay
subjects affected / exposed	2 / 61 (3.28%)	0 / 54 (0.00%)	2 / 180 (1.11%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	2 / 180 (1.11%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 61 (1.64%)	2 / 54 (3.70%)	6 / 180 (3.33%)	3 / 65 (4.62%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 9	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial obstruction
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopulmonary dysplasia
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercapnia
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	2 / 180 (1.11%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal discharge discolouration
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngospasm
subjects affected / exposed	2 / 61 (3.28%)	0 / 54 (0.00%)	2 / 180 (1.11%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Increased bronchial secretion
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary vein stenosis
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	2 / 180 (1.11%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	2 / 180 (1.11%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillar hypertrophy
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Psychomotor retardation
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Oxygen saturation decreased
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	2 / 180 (1.11%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Head injury
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body in respiratory tract
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endotracheal intubation complication
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital haematoma
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Cerebral palsy
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coarctation of the aorta
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cryptorchism
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Bradycardia
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	2 / 180 (1.11%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebellar haemorrhage
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile convulsion
subjects affected / exposed	2 / 61 (3.28%)	0 / 54 (0.00%)	5 / 180 (2.78%)	3 / 65 (4.62%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 61 (1.64%)	1 / 54 (1.85%)	2 / 180 (1.11%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nystagmus
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myoclonus
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Motor dysfunction
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Quadriparesis
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periventricular leukomalacia
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorder
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal haemorrhage
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	2 / 180 (1.11%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinopathy of prematurity
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	2 / 180 (1.11%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acetonaemic vomiting
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 61 (3.28%)	1 / 54 (1.85%)	4 / 180 (2.22%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Flatulence
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Necrotising colitis
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mechanical ileus
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 61 (1.64%)	2 / 54 (3.70%)	6 / 180 (3.33%)	3 / 65 (4.62%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 8	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Portal hypertension
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erythema multiforme
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash papular
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urticarial vasculitis
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Diabetes insipidus
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteopenia
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Adenovirus infection
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial food poisoning
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	4 / 61 (6.56%)	0 / 54 (0.00%)	7 / 180 (3.89%)	3 / 65 (4.62%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	3 / 61 (4.92%)	5 / 54 (9.26%)	11 / 180 (6.11%)	3 / 65 (4.62%)
occurrences causally related to treatment / all	0 / 3	0 / 12	0 / 18	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear infection
subjects affected / exposed	1 / 61 (1.64%)	1 / 54 (1.85%)	2 / 180 (1.11%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis adenovirus
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 61 (1.64%)	2 / 54 (3.70%)	3 / 180 (1.67%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epstein-Barr virus infection
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	2 / 180 (1.11%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpangina
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hand-foot-and-mouth disease
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leptospirosis
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	1 / 61 (1.64%)	1 / 54 (1.85%)	2 / 180 (1.11%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parainfluenzae viral bronchitis
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 61 (3.28%)	4 / 54 (7.41%)	10 / 180 (5.56%)	4 / 65 (6.15%)
occurrences causally related to treatment / all	0 / 2	0 / 7	0 / 15	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	1 / 61 (1.64%)	1 / 54 (1.85%)	4 / 180 (2.22%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis streptococcal
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	2 / 180 (1.11%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	1 / 61 (1.64%)	1 / 54 (1.85%)	2 / 180 (1.11%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchitis
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	2 / 180 (1.11%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	1 / 61 (1.64%)	2 / 54 (3.70%)	4 / 180 (2.22%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Streptococcal infection
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 61 (3.28%)	1 / 54 (1.85%)	3 / 180 (1.67%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral tonsillitis
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral pharyngitis
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	3 / 61 (4.92%)	1 / 54 (1.85%)	4 / 180 (2.22%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	1 / 180 (0.56%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperphosphatasaemia
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	1 / 180 (0.56%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 4%

Non-serious adverse events	Ranibizumab 0.2 mg	Laser	Total	Ranibizumab 0.1 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	41 / 61 (67.21%)	40 / 54 (74.07%)	127 / 180 (70.56%)	46 / 65 (70.77%)
Nervous system disorders
Febrile convulsion
subjects affected / exposed	3 / 61 (4.92%)	3 / 54 (5.56%)	8 / 180 (4.44%)	2 / 65 (3.08%)
occurrences all number	3	4	10	3
Nystagmus
subjects affected / exposed	1 / 61 (1.64%)	1 / 54 (1.85%)	5 / 180 (2.78%)	3 / 65 (4.62%)
occurrences all number	1	1	6	4
Seizure
subjects affected / exposed	3 / 61 (4.92%)	2 / 54 (3.70%)	5 / 180 (2.78%)	0 / 65 (0.00%)
occurrences all number	4	2	6	0
General disorders and administration site conditions
Developmental delay
subjects affected / exposed	5 / 61 (8.20%)	3 / 54 (5.56%)	9 / 180 (5.00%)	1 / 65 (1.54%)
occurrences all number	5	3	9	1
Pyrexia
subjects affected / exposed	6 / 61 (9.84%)	10 / 54 (18.52%)	27 / 180 (15.00%)	11 / 65 (16.92%)
occurrences all number	6	23	59	30
Immune system disorders
Seasonal allergy
subjects affected / exposed	3 / 61 (4.92%)	1 / 54 (1.85%)	6 / 180 (3.33%)	2 / 65 (3.08%)
occurrences all number	3	1	6	2
Eye disorders
Astigmatism
subjects affected / exposed	3 / 61 (4.92%)	2 / 54 (3.70%)	7 / 180 (3.89%)	2 / 65 (3.08%)
occurrences all number	3	2	7	2
Myopia
subjects affected / exposed	6 / 61 (9.84%)	5 / 54 (9.26%)	14 / 180 (7.78%)	3 / 65 (4.62%)
occurrences all number	6	6	15	3
Strabismus
subjects affected / exposed	10 / 61 (16.39%)	12 / 54 (22.22%)	34 / 180 (18.89%)	12 / 65 (18.46%)
occurrences all number	11	12	38	15
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 61 (0.00%)	2 / 54 (3.70%)	5 / 180 (2.78%)	3 / 65 (4.62%)
occurrences all number	0	2	13	11
Gastrooesophageal reflux disease
subjects affected / exposed	4 / 61 (6.56%)	5 / 54 (9.26%)	13 / 180 (7.22%)	4 / 65 (6.15%)
occurrences all number	4	5	13	4
Diarrhoea
subjects affected / exposed	3 / 61 (4.92%)	5 / 54 (9.26%)	13 / 180 (7.22%)	5 / 65 (7.69%)
occurrences all number	4	6	17	7
Constipation
subjects affected / exposed	4 / 61 (6.56%)	2 / 54 (3.70%)	14 / 180 (7.78%)	8 / 65 (12.31%)
occurrences all number	4	2	17	11
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary dysplasia
subjects affected / exposed	2 / 61 (3.28%)	4 / 54 (7.41%)	9 / 180 (5.00%)	3 / 65 (4.62%)
occurrences all number	2	5	10	3
Cough
subjects affected / exposed	5 / 61 (8.20%)	3 / 54 (5.56%)	14 / 180 (7.78%)	6 / 65 (9.23%)
occurrences all number	7	6	25	12
Dyspnoea
subjects affected / exposed	1 / 61 (1.64%)	0 / 54 (0.00%)	4 / 180 (2.22%)	3 / 65 (4.62%)
occurrences all number	1	0	10	9
Rhinorrhoea
subjects affected / exposed	2 / 61 (3.28%)	1 / 54 (1.85%)	6 / 180 (3.33%)	3 / 65 (4.62%)
occurrences all number	2	2	10	6
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	3 / 180 (1.67%)	3 / 65 (4.62%)
occurrences all number	0	0	3	3
Dry skin
subjects affected / exposed	2 / 61 (3.28%)	3 / 54 (5.56%)	5 / 180 (2.78%)	0 / 65 (0.00%)
occurrences all number	2	3	5	0
Rash
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	3 / 180 (1.67%)	3 / 65 (4.62%)
occurrences all number	0	0	3	3
Psychiatric disorders
Autism spectrum disorder
subjects affected / exposed	3 / 61 (4.92%)	1 / 54 (1.85%)	5 / 180 (2.78%)	1 / 65 (1.54%)
occurrences all number	3	1	5	1
Musculoskeletal and connective tissue disorders
Rickets
subjects affected / exposed	0 / 61 (0.00%)	3 / 54 (5.56%)	3 / 180 (1.67%)	0 / 65 (0.00%)
occurrences all number	0	3	3	0
Infections and infestations
Bronchiolitis
subjects affected / exposed	2 / 61 (3.28%)	0 / 54 (0.00%)	5 / 180 (2.78%)	3 / 65 (4.62%)
occurrences all number	4	0	7	3
Bronchitis
subjects affected / exposed	4 / 61 (6.56%)	6 / 54 (11.11%)	14 / 180 (7.78%)	4 / 65 (6.15%)
occurrences all number	11	9	24	4
COVID-19
subjects affected / exposed	1 / 61 (1.64%)	3 / 54 (5.56%)	5 / 180 (2.78%)	1 / 65 (1.54%)
occurrences all number	1	3	6	2
Conjunctivitis
subjects affected / exposed	2 / 61 (3.28%)	4 / 54 (7.41%)	10 / 180 (5.56%)	4 / 65 (6.15%)
occurrences all number	2	4	10	4
Ear infection
subjects affected / exposed	4 / 61 (6.56%)	0 / 54 (0.00%)	7 / 180 (3.89%)	3 / 65 (4.62%)
occurrences all number	5	0	10	5
Nasopharyngitis
subjects affected / exposed	11 / 61 (18.03%)	9 / 54 (16.67%)	31 / 180 (17.22%)	11 / 65 (16.92%)
occurrences all number	25	13	59	21
Influenza
subjects affected / exposed	4 / 61 (6.56%)	1 / 54 (1.85%)	7 / 180 (3.89%)	2 / 65 (3.08%)
occurrences all number	4	1	9	4
Gastroenteritis viral
subjects affected / exposed	1 / 61 (1.64%)	3 / 54 (5.56%)	5 / 180 (2.78%)	1 / 65 (1.54%)
occurrences all number	1	3	5	1
Exanthema subitum
subjects affected / exposed	3 / 61 (4.92%)	1 / 54 (1.85%)	6 / 180 (3.33%)	2 / 65 (3.08%)
occurrences all number	3	1	6	2
Otitis media
subjects affected / exposed	7 / 61 (11.48%)	3 / 54 (5.56%)	12 / 180 (6.67%)	2 / 65 (3.08%)
occurrences all number	9	3	14	2
Respiratory tract infection viral
subjects affected / exposed	3 / 61 (4.92%)	1 / 54 (1.85%)	8 / 180 (4.44%)	4 / 65 (6.15%)
occurrences all number	5	3	16	8
Pneumonia
subjects affected / exposed	5 / 61 (8.20%)	0 / 54 (0.00%)	6 / 180 (3.33%)	1 / 65 (1.54%)
occurrences all number	6	0	7	1
Pharyngitis
subjects affected / exposed	2 / 61 (3.28%)	5 / 54 (9.26%)	10 / 180 (5.56%)	3 / 65 (4.62%)
occurrences all number	2	9	15	4
Upper respiratory tract infection
subjects affected / exposed	3 / 61 (4.92%)	5 / 54 (9.26%)	11 / 180 (6.11%)	3 / 65 (4.62%)
occurrences all number	3	6	14	5
Viral upper respiratory tract infection
subjects affected / exposed	0 / 61 (0.00%)	0 / 54 (0.00%)	3 / 180 (1.67%)	3 / 65 (4.62%)
occurrences all number	0	0	5	5
Metabolism and nutrition disorders
Iron deficiency
subjects affected / exposed	4 / 61 (6.56%)	4 / 54 (7.41%)	8 / 180 (4.44%)	0 / 65 (0.00%)
occurrences all number	5	4	9	0
Malnutrition
subjects affected / exposed	0 / 61 (0.00%)	1 / 54 (1.85%)	4 / 180 (2.22%)	3 / 65 (4.62%)
occurrences all number	0	1	4	3

More information

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Were there any global substantial amendments to the protocol? Yes

31 Jul 2018

Introduced the collection of additional visual function data following EU national scientific advice meeting

10 Jul 2019

Included the requirement of masked VA assessments to be performed at the 5th birthday visit, following a request from the EMA.

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.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

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Clinical trials

Clinical Trial Results: RAINBOW extension study: an extension study to evaluate the long-term efficacy and safety of RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Visual acuity (letters) of the better-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

Primary: Visual acuity (letters) of the better-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

Secondary: Number of participants with ocular adverse events regardless of study treatment or procedure relationship by preferred term

Secondary: Number of participants with ocular adverse events regardless of study treatment or procedure relationship by preferred term

Secondary: Visual acuity (VA) of the worse-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

Secondary: Visual acuity (VA) of the worse-seeing eye at the participant’s fifth birthday visit – comparison between treatment arms

Secondary: Number of participants with non-ocular adverse events regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term

Secondary: Number of participants with non-ocular adverse events regardless of study treatment or procedure relationship (greater than or equal to 3% in any arm) by preferred term

Secondary: Number of participants with absence of active Retinopathy of Prematurity (ROP) at 40 weeks post core baseline visit

Secondary: Number of participants with absence of active Retinopathy of Prematurity (ROP) at 40 weeks post core baseline visit

Secondary: Number of participants with absence of active Retinopathy of Prematurity (ROP) at 52 weeks post core baseline visit

Secondary: Number of participants with absence of active Retinopathy of Prematurity (ROP) at 52 weeks post core baseline visit

Secondary: Number of participants with absence of all ocular structural abnormalities at or before 40 weeks post baseline visit

Secondary: Number of participants with absence of all ocular structural abnormalities at or before 40 weeks post baseline visit

Secondary: Number of participants with absence of all ocular structural abnormalities at or before the participant’s fifth birthday visit

Secondary: Number of participants with absence of all ocular structural abnormalities at or before the participant’s fifth birthday visit

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before 40 weeks post baseline visit

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before 40 weeks post baseline visit

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before the participant’s fifth birthday visit

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before the participant’s fifth birthday visit

Secondary: Number of participants with absence of all ocular structural abnormalities at or before participant’s 2 years corrected age visit

Secondary: Number of participants with absence of all ocular structural abnormalities at or before participant’s 2 years corrected age visit

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before participant’s 2 years corrected age visit

Secondary: Number of participants with absence of individual ocular structural abnormalities at or before participant’s 2 years corrected age visit

Secondary: Number of participants with recurrence of ROP up to 40 weeks post baseline visit in the core study

Secondary: Number of participants with recurrence of ROP up to 40 weeks post baseline visit in the core study

Secondary: Number of participants with recurrence of ROP up to 52 weeks post baseline visit in the core study

Secondary: Number of participants with recurrence of ROP up to 52 weeks post baseline visit in the core study

Secondary: Number of ranibizumab injections received per participant over the whole safety observation period

Secondary: Number of ranibizumab injections received per participant over the whole safety observation period

Secondary: Refraction status: Summary of participants at participant’s 2 years corrected age

Secondary: Refraction status: Summary of participants at participant’s 2 years corrected age

Secondary: Refraction status: Summary of participants at the participant’s fifth birthday visit - Best eye

Secondary: Refraction status: Summary of participants at the participant’s fifth birthday visit - Best eye

Secondary: Refraction status: Summary of participants at the participant’s fifth birthday visit - Worst eye

Secondary: Refraction status: Summary of participants at the participant’s fifth birthday visit - Worst eye

Secondary: Change from baseline in weight at the participant’s 2 years’ corrected age

Secondary: Change from baseline in weight at the participant’s 2 years’ corrected age

Secondary: Change from baseline in weight at the participant’s fifth birthday

Secondary: Change from baseline in weight at the participant’s fifth birthday

Secondary: Change from baseline in Head Circumference

Secondary: Change from baseline in Head Circumference

Secondary: Change from baseline in Sitting Diastolic Blood Pressure

Secondary: Change from baseline in Sitting Diastolic Blood Pressure

Secondary: Change from baseline in Sitting Systolic Blood Pressure

Secondary: Change from baseline in Sitting Systolic Blood Pressure

Secondary: Number of participants with the summary of respiratory function status

Secondary: Number of participants with the summary of respiratory function status

Secondary: Number of participants with hearing impairment of any type

Secondary: Number of participants with hearing impairment of any type

Secondary: Weight at the time of first hospital discharge

Secondary: Weight at the time of first hospital discharge

Secondary: Duration of hospitalization

Secondary: Duration of hospitalization

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
RAINBOW extension study: an extension study to evaluate the long-term efficacy and safety of RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity