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Clinical Trial Results:
Multicenter randomized open-label three-arms controlled 12 months clinical proof of concept study to evaluate efficacy and safety of Ranibizumab alone or in combination with laser photocoagulation vs. laser photocoagulation alone in Proliferative Diabetic Retinopathy 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.

Summary
EudraCT number	2011-005542-35
Trial protocol	DE
Global end of trial date	05 Dec 2017

Results information
Results version number	v1(current)
This version publication date	16 Dec 2018
First version publication date	16 Dec 2018
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

CRFB002DDE21

ISRCTN number

US NCT number

NCT01594281

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

05 Dec 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Dec 2017

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study was to assess the efficacy and safety of the anti-Vascular Endothelial Growth Factor (VEGF) agent ranibizumab (0.5 mg) with or without Panretinal laser photocoagulation (PRP) compared to PRP alone in patients with Proliferative Diabetic Retinopathy (PDR).

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

11 Dec 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 106

Worldwide total number of subjects

106

EEA total number of subjects

106

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

This study was conducted in Germany.

Screening details

Patients were screened for eligibility at 23 German study sites and randomized at 22 of the 23 sites.

Period 1 title

Interventional Core Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

An open-label design had been chosen in which the evaluation of the primary objective was performed by a reading center. The reading center that was evaluating the primary and several secondary and exploratory objectives was blinded to randomization and therefore assessed these objectives uninfluenced by treatment information. However, laser burns were visible on the images, and no full blinding regarding PRP was possible for the reading center.

Are arms mutually exclusive

Yes

Ranibizumab mono

Arm description

One intravitreal injection of ranibizumab 0.5 mg to the study eye monthly until stability regarding morphological parameters is confirmed (ie, no further improvement of morphology or no worsening of morphology for 3 consecutive months)

Arm type

Experimental

Investigational medicinal product name

ranibizumab 0.5 mg

Investigational medicinal product code

Other name

Lucentis RFB002

Pharmaceutical forms

Solution for injection in pre-filled syringe, Solution for injection

Routes of administration

Intravitreal use

Dosage and administration details

PRP mono

Arm description

Panretinal laser photocoagulation (PRP) treatment administered to the study eye in accordance with the modified diabetic retinopathy study (DRS) guidelines for panretinal laser photocoagulation procedures. If stability of morphological parameters could not be confirmed after 3 months, additional laser treatment was initiated.

Arm type

Panretinal laser photocoagulation

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Ranibizumab+PRP

Arm description

Ranibizumab 0.5 mg as described for the ranibizumab mono arm and PRP treatment as described for the PRP mono arm until stability regarding morphological parameters is confirmed

Arm type

Experimental

Investigational medicinal product name

ranibizumab 0.5 mg

Investigational medicinal product code

Other name

Lucentis RFB002

Pharmaceutical forms

Solution for injection, Solution for injection in pre-filled syringe

Routes of administration

Intravitreal use

Dosage and administration details

Number of subjects in period 1	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Started	35	35	36
Completed	29	26	28
Not completed	6	9	8
Adverse Event	4	4	4
Subject Withdrew Consent	-	1	1
Protocol Deviation	1	-	-
Death	1	1	2
Lost to follow-up	-	3	1

Period 2 title

Non-Interventional Follow Up Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Are arms mutually exclusive

Yes

Ranibizumab mono

Arm description

Treatment per physician´s routine standard of care until Month 24.

Arm type

Experimental

Investigational medicinal product name

ranibizumab 0.5 mg

Investigational medicinal product code

Other name

RFB002

Pharmaceutical forms

Solution for injection, Solution for injection in pre-filled syringe

Routes of administration

Intravitreal use

Dosage and administration details

Treatment per physician´s routine standard of care until Month 24.

PRP mono

Arm description

Treatment per physician´s routine standard of care until Month 24.

Arm type

Panretinal laser photocoagulation

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Ranibizumab+PRP

Arm description

Treatment per physician´s routine standard of care until Month 24.

Arm type

Experimental

Investigational medicinal product name

ranibizumab 0.5 mg

Investigational medicinal product code

Other name

RFB002

Pharmaceutical forms

Solution for injection, Solution for injection in pre-filled syringe

Routes of administration

Intravitreal use

Dosage and administration details

Treatment per physician´s routine standard of care until Month 24.

Number of subjects in period 2 ^[1]	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Started	28	21	25
Follow Up Set (FUS)	28	20	25
Completed	25	19	23
Not completed	3	2	2
Subject Withdrew Consent	1	-	1
Administrative Problems	-	-	1
Lost to follow-up	2	2	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Patients were invited to enter a twelve month Follow Up phase after completion of the core phase. A separate informed consent was signed for the Follow Up phase.

Baseline characteristics

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Reporting group title

Ranibizumab mono

Reporting group description

Reporting group title

PRP mono

Reporting group description

Reporting group title

Ranibizumab+PRP

Reporting group description

Ranibizumab 0.5 mg as described for the ranibizumab mono arm and PRP treatment as described for the PRP mono arm until stability regarding morphological parameters is confirmed

Reporting group values	Ranibizumab mono	PRP mono	Ranibizumab+PRP	Total
Number of subjects	35	35	36	106
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)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	30	30	26	86
From 65-84 years	5	5	10	20
85 years and over	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	52.5 ( 11.0 )	53.0 ( 12.1 )	55.0 ( 13.4 )	-
Sex: Female, Male
Units: Subjects
Female	14	11	8	33
Male	21	24	28	73

End points

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Reporting group title

Ranibizumab mono

Reporting group description

Reporting group title

PRP mono

Reporting group description

Reporting group title

Ranibizumab+PRP

Reporting group description

Ranibizumab 0.5 mg as described for the ranibizumab mono arm and PRP treatment as described for the PRP mono arm until stability regarding morphological parameters is confirmed

Reporting group title

Ranibizumab mono

Reporting group description

Treatment per physician´s routine standard of care until Month 24.

Reporting group title

PRP mono

Reporting group description

Treatment per physician´s routine standard of care until Month 24.

Reporting group title

Ranibizumab+PRP

Reporting group description

Treatment per physician´s routine standard of care until Month 24.

Subject analysis set title

Ranibizumab mono

Subject analysis set type

Full analysis

Subject analysis set description

Interventional Core Phase: All randomized patients with at least one study treatment and one post-baseline assessment.

Subject analysis set title

PRP mono

Subject analysis set type

Full analysis

Subject analysis set description

Interventional Core Phase: All randomized patients with at least one study treatment and one post-baseline assessment.

Subject analysis set title

Ranibizumab+PRP

Subject analysis set type

Full analysis

Subject analysis set description

Interventional Core Phase: All randomized patients with at least one study treatment and one post-baseline assessment.

Primary: Change from baseline in area of neovascularizations (NVs) at End of Core Study (EOCS)

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End point title

Change from baseline in area of neovascularizations (NVs) at End of Core Study (EOCS)

End point description

The area of neovascularizations (NV) was assessed by a central reading center via fluorescein angiography (FA) images. The area of NV was calculated as the sum of area of neovascularization of the disc (NVD) and neovascularization elsewhere (NVE) and was recorded in square millimeters. A higher positive change value may indicate a greater formation of new, abnormal blood vessels and thus disease progression. One eye (study eye) contributed to the analysis.

End point type

Primary

End point timeframe

Baseline, EOCS

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	33	33	33
Units: square millimeters
arithmetic mean (standard deviation)	-4.6 ( 11.3 )	-0.9 ( 3.9 )	-1.7 ( 3.0 )

Change from BL in area of NV at EOCS

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[1]

P-value

= 0.0344

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

-0.2

Notes
[1] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in area of NV at EOCS

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[2]

P-value

= 0.3809

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.8

upper limit

1.5

Notes
[2] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in area of NV at EOCS

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[3]

P-value

= 0.2113

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

4.3

Notes
[3] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Secondary: Change from baseline in area of neovascularizations (NVs) at Month 3

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End point title

Change from baseline in area of neovascularizations (NVs) at Month 3

End point description

End point type

Secondary

End point timeframe

Baseline, Month 3

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	33	32	33
Units: square millimeters
arithmetic mean (standard deviation)	-5.9 ( 12.7 )	-0.7 ( 2.8 )	-2.7 ( 3.9 )

Change from BL in area of NV at Month 3

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[4]

P-value

= 0.0081

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

-0.6

Notes
[4] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in area of NV at Month 3

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[5]

P-value

= 0.7494

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

1.5

Notes
[5] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in area of NV at Month 3

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[6]

P-value

= 0.0175

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

3.9

Notes
[6] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Secondary: Best Corrected Visual Acuity (BCVA) (ETDRS letters) at EOCS

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End point title

Best Corrected Visual Acuity (BCVA) (ETDRS letters) at EOCS

End point description

BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at a testing distance of 4 meters. A higher number of ETDRS letters may indicate better visual acuity. One eye (study eye) contributed to the analysis.

End point type

Secondary

End point timeframe

EOCS

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	35	35	36
Units: letters
arithmetic mean (standard deviation)	84.4 ( 8.6 )	76.8 ( 17.0 )	78.9 ( 12.2 )

BCVA (ETDRS letters) at EOCS

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[7]

P-value

= 0.0495

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

5.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[7] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

BCVA (ETDRS letters) at EOCS

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[8]

P-value

= 0.2767

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

8.5

Notes
[8] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

BCVA (ETDRS letters) at EOCS

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[9]

P-value

= 0.3641

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-7.9

upper limit

2.9

Notes
[9] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Secondary: Percentage of patients with change from baseline in BCVA (ETDRS letters) at EOCS

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End point title

Percentage of patients with change from baseline in BCVA (ETDRS letters) at EOCS

End point description

BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at a testing distance of 4 meters. No clinically relevant change was defined as <5 letters gain or loss. A higher positive change value may indicate a greater improvement in visual acuity. One eye (study eye) contributed to the analysis.

End point type

Secondary

End point timeframe

Baseline, EOCS

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	35	35	36
Units: percentage of participants
number (not applicable)
≥15 letters gain from Baseline at EOCS\|	0.0	2.9	0.0
≥10 letters gain from Baseline at EOCS\|	5.7	11.4	8.3
≥5 letters gain from Baseline at EOCS\|	31.4	20.0	13.9
No clinically relevant change from Baseline\|	51.4	42.9	61.1
≥5 letters loss from Baseline at EOCS\|	17.1	37.1	25.0
≥10 letters loss from Baseline at EOCS\|	11.4	11.4	8.3
≥15 letters loss from Baseline at EOCS\|	2.9	8.6	2.8

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥10 letters gain

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[10]

P-value

= 0.4019

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

2.749

Notes
[10] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥5 letters gain

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[11]

P-value

= 0.2772

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.833

Confidence interval

level

95%

sides

2-sided

lower limit

0.614

upper limit

5.471

Notes
[11] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

No clinically relevant change

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[12]

P-value

= 0.4731

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.412

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

3.622

Notes
[12] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥5 letters loss

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[13]

P-value

= 0.065

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.155

upper limit

1.068

Notes
[13] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥10 letters loss

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[14]

P-value

= 1

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.229

upper limit

4.361

Notes
[14] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥15 letters loss

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[15]

P-value

= 0.3261

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.314

Confidence interval

level

95%

sides

2-sided

lower limit

0.031

upper limit

3.173

Notes
[15] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥10 letters gain

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[16]

P-value

= 0.668

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.667

Confidence interval

level

95%

sides

2-sided

lower limit

0.104

upper limit

4.253

Notes
[16] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥5 letters gain

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[17]

P-value

= 0.0838

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.842

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

9.283

Notes
[17] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

No clinically relevant change

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[18]

P-value

= 0.4116

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.674

Confidence interval

level

95%

sides

2-sided

lower limit

0.263

upper limit

1.729

Notes
[18] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥5 letters loss

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[19]

P-value

= 0.4197

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.621

Confidence interval

level

95%

sides

2-sided

lower limit

0.195

upper limit

1.977

Notes
[19] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥10 letters loss

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[20]

P-value

= 0.6632

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.419

Confidence interval

level

95%

sides

2-sided

lower limit

0.294

upper limit

6.856

Notes
[20] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥15 letters loss

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[21]

P-value

= 0.9839

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.029

Confidence interval

level

95%

sides

2-sided

lower limit

0.062

upper limit

17.127

Notes
[21] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥10 letters gain

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[22]

P-value

= 0.663

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.419

Confidence interval

level

95%

sides

2-sided

lower limit

0.294

upper limit

6.858

Notes
[22] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥5 letters gain

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[23]

P-value

= 0.4941 ^[24]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.441

upper limit

5.444

Notes
[23] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.
[24] - P-value was calculated as a point estimate.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

No clinically relevant change

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[25]

P-value

= 0.1259

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.477

Confidence interval

level

95%

sides

2-sided

lower limit

0.185

upper limit

1.231

Notes
[25] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥5 letters loss

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[26]

P-value

= 0.271

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.773

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

4.913

Notes
[26] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥10 letters loss

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[27]

P-value

= 0.6632

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.419

Confidence interval

level

95%

sides

2-sided

lower limit

0.294

upper limit

6.856

Notes
[27] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in BCVA (ETDRS letters) at EOCS

Statistical analysis description

≥15 letters loss

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[28]

P-value

= 0.314

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.282

Confidence interval

level

95%

sides

2-sided

lower limit

0.325

upper limit

33.171

Notes
[28] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Secondary: Number of patients with change from baseline in ETDRS severity grade of diabetic retinopathy (DR) at EOCS

Top of page

End point title

Number of patients with change from baseline in ETDRS severity grade of diabetic retinopathy (DR) at EOCS

End point description

The severity level of diabetic retinopathy was determined using the ETDRS severity scale. However, in contrast to the original ETDRS severity scale, wide field fluorescein angiography images were used in addition to color fundus photography for identification of NVs and prior PRP treatment was not considered for determining the severity level. Eyes could be graded in the following classes: “DR absent” (10), “questionable DR” (14,15), “NPDR” (20-53), “mild PDR” (60-61), “moderate PDR” (65), “high risk PDR” (71-75), “advanced PDR” (81-85) and “cannot grade” (90). One eye (study eye) contributed to the analysis. No statistical analysis was conducted for ≥ 1 class deterioration or ≥ 2 class deterioration from Baseline at EOCS because ratios could not be calculated in case of zero frequencies in at least one of the three treatment groups.

End point type

Secondary

End point timeframe

Baseline, EOCS

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	29	26	28
Units: participants
≥ 1 class improvement from Baseline at EOCS\|	10	9	13
≥ 2 class improvement from Baseline at EOCS\|	2	2	5
≥ 1 class deterioration from Baseline at EOCS\|	2	0	1
≥ 2 class deterioration from Baseline at EOCS\|	0	0	0

Change from BL in DR severity grade at EOCS

Statistical analysis description

≥ 1 class improvement from Baseline at EOCS

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[29]

P-value

= 0.9918

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.994

Confidence interval

level

95%

sides

2-sided

lower limit

0.327

upper limit

3.026

Notes
[29] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in DR severity grade at EOCS

Statistical analysis description

≥ 1 class improvement from Baseline at EOCS

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[30]

P-value

= 0.3595

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.607

Confidence interval

level

95%

sides

2-sided

lower limit

0.209

upper limit

1.765

Notes
[30] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in DR severity grade at EOCS

Statistical analysis description

≥ 1 class improvement from Baseline at EOCS

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[31]

P-value

= 0.3787

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.611

Confidence interval

level

95%

sides

2-sided

lower limit

0.204

upper limit

1.83

Notes
[31] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in DR severity grade at EOCS

Statistical analysis description

≥ 2 class improvement from Baseline at EOCS

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[32]

P-value

= 0.9097

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.889

Confidence interval

level

95%

sides

2-sided

lower limit

0.116

upper limit

6.806

Notes
[32] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in DR severity grade at EOCS

Statistical analysis description

≥ 2 class improvement from Baseline at EOCS

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[33]

P-value

= 0.223

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.341

Confidence interval

level

95%

sides

2-sided

lower limit

0.06

upper limit

1.925

Notes
[33] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in DR severity grade at EOCS

Statistical analysis description

≥ 2 class improvement from Baseline at EOCS

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[34]

P-value

= 0.2792

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.383

Confidence interval

level

95%

sides

2-sided

lower limit

0.068

upper limit

2.177

Notes
[34] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Secondary: Change from baseline in central subfield thickness at EOCS

Top of page

End point title

Change from baseline in central subfield thickness at EOCS

End point description

Central subfield retinal thickness (CST) was assessed by a central reading center using Optical Coherence Tomography images. A positive change value may indicate disease progression. One eye (study eye) contributed to the analysis.

End point type

Secondary

End point timeframe

Baseline, EOCS

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	32	31	31
Units: micrometer
arithmetic mean (standard deviation)	-6.0 ( 15.1 )	36.2 ( 55.9 )	17.6 ( 46.7 )

Change from BL in CST at EOCS

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[35]

P-value

= 0.0003

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-40.7

Confidence interval

level

95%

sides

2-sided

lower limit

-62.1

upper limit

-19.3

Notes
[35] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in CST at EOCS

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[36]

P-value

= 0.0357

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-22.9

Confidence interval

level

95%

sides

2-sided

lower limit

-44.2

upper limit

-1.6

Notes
[36] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in CST at EOCS

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[37]

P-value

= 0.1034

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

17.8

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

39.3

Notes
[37] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Secondary: Change from baseline in foveal center point retinal thickness at EOCS

Top of page

End point title

Change from baseline in foveal center point retinal thickness at EOCS

End point description

Foveal center point retinal thickness (FCPT) was assessed by a central reading center using Optical Coherence Tomography images. A positive change value may indicate disease progression. One eye (study eye) contributed to the analysis.

End point type

Secondary

End point timeframe

Baseline, EOCS

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	32	31	31
Units: micrometer
arithmetic mean (standard deviation)	-4.7 ( 21.2 )	48.1 ( 83.7 )	25.5 ( 53.5 )

Change from BL in FCPT at EOCS

Comparison groups

Ranibizumab mono v PRP mono

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[38]

P-value

= 0.0007

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-51.7

Confidence interval

level

95%

sides

2-sided

lower limit

-81.1

upper limit

-22.3

Notes
[38] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in FCPT at EOCS

Comparison groups

Ranibizumab mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[39]

P-value

= 0.0542

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

-28.9

Confidence interval

level

95%

sides

2-sided

lower limit

-58.4

upper limit

0.5

Notes
[39] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Change from BL in FCPT at EOCS

Comparison groups

PRP mono v Ranibizumab+PRP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[40]

P-value

= 0.1288

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

22.8

Confidence interval

level

95%

sides

2-sided

lower limit

-6.7

upper limit

52.3

Notes
[40] - The focus of this PoC study was not on hypothesis testing but on a rough estimation of differences between treatments. The usual p-values are provided as a descriptive tool.

Secondary: Number of ranibizumab injections until EOCS

Top of page

End point title

Number of ranibizumab injections until EOCS

End point description

The total number of ranibizumab injections until EOCS was calculated. One eye (study eye) contributed to the analysis. No statistical analysis was conducted.

End point type

Secondary

End point timeframe

Baseline to EOCS

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	35	35	36
Units: injections
arithmetic mean (standard deviation)	5.2 ( 2.3 )	999 ( 999 )	5.0 ( 2.2 )

No statistical analyses for this end point

Secondary: Number of PRP laser spots until EOCS

Top of page

End point title

Number of PRP laser spots until EOCS

End point description

The total number of PRP laser spots from baseline until EOCS was calculated. One eye (study eye) contributed to the analysis. No statistical analysis was conducted.

End point type

Secondary

End point timeframe

Baseline to EOCS

End point values	Ranibizumab mono	PRP mono	Ranibizumab+PRP
Number of subjects analysed	35	35	36
Units: PRP laser spots
arithmetic mean (standard deviation)	999 ( 999 )	1919.4 ( 673.1 )	1670.0 ( 568.4 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Timeframe for AE

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Baseline to Month 12 phase Ranibizumab

Reporting group description

Baseline to Month 12 phase Ranibizumab

Reporting group title

Baseline to Month 12 phase Panretinal laser

Reporting group description

Baseline to Month 12 phase Panretinal laser

Reporting group title

Baseline to Month 12 phase Combination

Reporting group description

Baseline to Month 12 phase Combination

Reporting group title

Follow-up phase Ranibizumab

Reporting group description

Follow-up phase Ranibizumab

Reporting group title

Follow-up phase Panretinal laser

Reporting group description

Follow-up phase Panretinal laser

Reporting group title

Follow-up phase Combination

Reporting group description

Follow-up phase Combination

Serious adverse events	Baseline to Month 12 phase Ranibizumab	Baseline to Month 12 phase Panretinal laser	Baseline to Month 12 phase Combination	Follow-up phase Ranibizumab	Follow-up phase Panretinal laser	Follow-up phase Combination
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 35 (22.86%)	11 / 35 (31.43%)	16 / 36 (44.44%)	5 / 28 (17.86%)	5 / 20 (25.00%)	11 / 25 (44.00%)
number of deaths (all causes)	1	1	2	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CHRONIC LYMPHOCYTIC LEUKAEMIA (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC CANCER (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
DIABETIC MICROANGIOPATHY (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERTENSION (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL ARTERY OCCLUSION (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL VENOUS DISEASE (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
PREGNANCY (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
CHEST PAIN (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NON-CARDIAC CHEST PAIN (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL SWELLING (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
COUGH (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPNOEA (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
PSYCHIATRIC DECOMPENSATION (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	1 / 20 (5.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
BLOOD GLUCOSE FLUCTUATION (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	1 / 20 (5.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
FRACTURED COCCYX (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HUMERUS FRACTURE (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPHAEMA (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
KIDNEY CONTUSION (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MENISCUS INJURY (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RIB FRACTURE (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SPINAL FRACTURE (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TENDON RUPTURE (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	1 / 20 (5.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIAL FIBRILLATION (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONGESTIVE CARDIOMYOPATHY (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CORONARY ARTERY DISEASE (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEART VALVE STENOSIS (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	1 / 20 (5.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
CEREBROVASCULAR ACCIDENT (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIZZINESS (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
SUDDEN HEARING LOSS (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
ANTERIOR CHAMBER DISORDER (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CATARACT (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CATARACT (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETIC RETINAL OEDEMA (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETIC RETINAL OEDEMA (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETIC RETINOPATHY (Left eye)
subjects affected / exposed	1 / 35 (2.86%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	2 / 20 (10.00%)	2 / 25 (8.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETIC RETINOPATHY (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	2 / 36 (5.56%)	0 / 28 (0.00%)	1 / 20 (5.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GLAUCOMA (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MACULAR FIBROSIS (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MACULAR FIBROSIS (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MACULAR OEDEMA (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OPEN ANGLE GLAUCOMA (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RETINAL DETACHMENT (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RETINAL HAEMORRHAGE (Both eyes)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RETINAL HAEMORRHAGE (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RETINAL NEOVASCULARISATION (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VISUAL ACUITY REDUCED (Left eye)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VITREOUS ADHESIONS (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VITREOUS HAEMORRHAGE (Left eye)
subjects affected / exposed	1 / 35 (2.86%)	1 / 35 (2.86%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VITREOUS HAEMORRHAGE (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	2 / 35 (5.71%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	2 / 25 (8.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHRONIC GASTRITIS (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DENTAL CYST (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIARRHOEA (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UMBILICAL HERNIA (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
COLD SWEAT (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETIC FOOT (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	3 / 36 (8.33%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
CHRONIC KIDNEY DISEASE (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC PROTRUSION (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OSTEITIS (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
GASTROENTERITIS (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTED SKIN ULCER (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LOCALISED INFECTION (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MENINGITIS (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OSTEOMYELITIS (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OSTEOMYELITIS CHRONIC (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
POSTOPERATIVE WOUND INFECTION (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
DEHYDRATION (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETES MELLITUS (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERGLYCAEMIA (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOGLYCAEMIA (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OBESITY (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Baseline to Month 12 phase Ranibizumab	Baseline to Month 12 phase Panretinal laser	Baseline to Month 12 phase Combination	Follow-up phase Ranibizumab	Follow-up phase Panretinal laser	Follow-up phase Combination
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 35 (97.14%)	29 / 35 (82.86%)	34 / 36 (94.44%)	21 / 28 (75.00%)	12 / 20 (60.00%)	21 / 25 (84.00%)
Investigations
BLOOD CHOLESTEROL INCREASED (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 36 (2.78%)	3 / 28 (10.71%)	1 / 20 (5.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	3	1	0
BLOOD PRESSURE INCREASED (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 36 (0.00%)	2 / 28 (7.14%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	2	0	0
BLOOD TRIGLYCERIDES INCREASED (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	2 / 28 (7.14%)	2 / 20 (10.00%)	1 / 25 (4.00%)
occurrences all number	1	0	0	2	2	1
GLYCOSYLATED HAEMOGLOBIN INCREASED (Non-ocular)
subjects affected / exposed	4 / 35 (11.43%)	0 / 35 (0.00%)	6 / 36 (16.67%)	3 / 28 (10.71%)	2 / 20 (10.00%)	1 / 25 (4.00%)
occurrences all number	5	0	6	3	2	1
INTRAOCULAR PRESSURE INCREASED (Left eye)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	3 / 36 (8.33%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	4	0	0	0
INTRAOCULAR PRESSURE INCREASED (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	3	0	0	0
Injury, poisoning and procedural complications
CONTUSION (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	2 / 36 (5.56%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	2	1	0	0
FALL (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	3 / 35 (8.57%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	3	0	0	0	0
FOOT FRACTURE (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	0	0	0	0
PROCEDURAL PAIN (Both eyes)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	3 / 36 (8.33%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	3	0	0	0
PROCEDURAL PAIN (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	4 / 36 (11.11%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	11	11	0	0	0
RIB FRACTURE (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	0	0	0	2
ROAD TRAFFIC ACCIDENT (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	0	0	0	2
SCRATCH (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	0	0	0	0
Vascular disorders
HYPERTENSION (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	1 / 35 (2.86%)	0 / 36 (0.00%)	1 / 28 (3.57%)	1 / 20 (5.00%)	1 / 25 (4.00%)
occurrences all number	2	1	0	1	1	1
Nervous system disorders
HEADACHE (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	4 / 35 (11.43%)	5 / 36 (13.89%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	2	4	6	0	0	1
Eye disorders
ABNORMAL SENSATION IN EYE (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	2	0	0	0	0
BLEPHARITIS (Both eyes)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	2	0	0	0
CATARACT (Both eyes)
subjects affected / exposed	3 / 35 (8.57%)	1 / 35 (2.86%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	3	1	1	0	0	1
CATARACT (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	1 / 35 (2.86%)	0 / 36 (0.00%)	2 / 28 (7.14%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	1	0	2	0	1
CONJUNCTIVAL HAEMORRHAGE (Left eye)
subjects affected / exposed	3 / 35 (8.57%)	0 / 35 (0.00%)	3 / 36 (8.33%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	4	0	6	1	0	0
CONJUNCTIVAL HAEMORRHAGE (Right eye)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	2 / 36 (5.56%)	1 / 28 (3.57%)	1 / 20 (5.00%)	0 / 25 (0.00%)
occurrences all number	2	0	2	1	1	0
CONJUNCTIVITIS ALLERGIC (Both eyes)
subjects affected / exposed	3 / 35 (8.57%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	3	0	1	0	0	0
CORNEAL EROSION (Left eye)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	6 / 36 (16.67%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	9	0	0	0
CORNEAL EROSION (Right eye)
subjects affected / exposed	3 / 35 (8.57%)	5 / 35 (14.29%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	4	6	1	0	0	0
CYSTOID MACULAR OEDEMA (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	2	3	0	0	0
DIABETIC RETINAL OEDEMA (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	1	3	0	0	1
DIABETIC RETINAL OEDEMA (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	6 / 36 (16.67%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	7	0	0	0
DIABETIC RETINOPATHY (Both eyes)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	2 / 36 (5.56%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	2	1	0	0
DIABETIC RETINOPATHY (Left eye)
subjects affected / exposed	7 / 35 (20.00%)	1 / 35 (2.86%)	7 / 36 (19.44%)	2 / 28 (7.14%)	0 / 20 (0.00%)	4 / 25 (16.00%)
occurrences all number	7	1	7	2	0	4
DIABETIC RETINOPATHY (Right eye)
subjects affected / exposed	4 / 35 (11.43%)	2 / 35 (5.71%)	3 / 36 (8.33%)	2 / 28 (7.14%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	4	4	3	2	0	0
DRY EYE (Both eyes)
subjects affected / exposed	3 / 35 (8.57%)	2 / 35 (5.71%)	2 / 36 (5.56%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	3	2	2	1	0	1
EYE IRRITATION (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	4 / 36 (11.11%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	5	0	0	0
EYE IRRITATION (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	3 / 36 (8.33%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	4	0	0	0
EYE PAIN (Left eye)
subjects affected / exposed	2 / 35 (5.71%)	3 / 35 (8.57%)	5 / 36 (13.89%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	4	6	0	0	0
EYE PAIN (Right eye)
subjects affected / exposed	3 / 35 (8.57%)	1 / 35 (2.86%)	6 / 36 (16.67%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	3	1	7	3	0	0
FOREIGN BODY SENSATION IN EYES (Left eye)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	6	0	0	0	0	0
FOREIGN BODY SENSATION IN EYES (Right eye)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	2	0	0	0
GLARE (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	2	0	1	0	0
IRIS NEOVASCULARISATION (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	2	0	0	0
IRIS NEOVASCULARISATION (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	1 / 35 (2.86%)	3 / 36 (8.33%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	1	3	0	0	1
LACRIMATION INCREASED (Left eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	3 / 36 (8.33%)	0 / 28 (0.00%)	1 / 20 (5.00%)	0 / 25 (0.00%)
occurrences all number	0	0	3	0	1	0
LACRIMATION INCREASED (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	1 / 35 (2.86%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	1	4	0	0	0
MACULAR FIBROSIS (Left eye)
subjects affected / exposed	3 / 35 (8.57%)	1 / 35 (2.86%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	3	1	0	1	0	0
MACULAR FIBROSIS (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	2 / 35 (5.71%)	3 / 36 (8.33%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	2	3	0	0	0
MACULAR OEDEMA (Both eyes)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	2 / 36 (5.56%)	2 / 28 (7.14%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	2	2	2	0	1
MACULAR OEDEMA (Left eye)
subjects affected / exposed	5 / 35 (14.29%)	4 / 35 (11.43%)	4 / 36 (11.11%)	2 / 28 (7.14%)	4 / 20 (20.00%)	3 / 25 (12.00%)
occurrences all number	6	5	4	2	4	3
MACULAR OEDEMA (Right eye)
subjects affected / exposed	3 / 35 (8.57%)	8 / 35 (22.86%)	4 / 36 (11.11%)	5 / 28 (17.86%)	1 / 20 (5.00%)	4 / 25 (16.00%)
occurrences all number	4	12	6	8	1	6
OCULAR DISCOMFORT (Left eye)
subjects affected / exposed	3 / 35 (8.57%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	5	0	0	0	0	0
OCULAR HYPERAEMIA (Left eye)
subjects affected / exposed	4 / 35 (11.43%)	0 / 35 (0.00%)	4 / 36 (11.11%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	5	0	4	0	0	0
OCULAR HYPERAEMIA (Right eye)
subjects affected / exposed	3 / 35 (8.57%)	0 / 35 (0.00%)	4 / 36 (11.11%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	4	0	6	0	0	0
PUNCTATE KERATITIS (Both eyes)
subjects affected / exposed	0 / 35 (0.00%)	3 / 35 (8.57%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	3	0	0	0	0
RETINAL CYST (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	3 / 35 (8.57%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	3	0	0	0	1
RETINAL EXUDATES (Left eye)
subjects affected / exposed	2 / 35 (5.71%)	2 / 35 (5.71%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	2	0	0	0	0
RETINAL HAEMORRHAGE (Left eye)
subjects affected / exposed	5 / 35 (14.29%)	0 / 35 (0.00%)	3 / 36 (8.33%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	5	0	3	1	0	1
RETINAL HAEMORRHAGE (Right eye)
subjects affected / exposed	3 / 35 (8.57%)	1 / 35 (2.86%)	3 / 36 (8.33%)	1 / 28 (3.57%)	0 / 20 (0.00%)	2 / 25 (8.00%)
occurrences all number	3	1	3	1	0	2
RETINAL ISCHAEMIA (Left eye)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	2 / 36 (5.56%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	0	4	1	0	1
RETINAL NEOVASCULARISATION (Both eyes)
subjects affected / exposed	1 / 35 (2.86%)	1 / 35 (2.86%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	5 / 25 (20.00%)
occurrences all number	1	1	2	0	0	5
RETINAL NEOVASCULARISATION (Left eye)
subjects affected / exposed	5 / 35 (14.29%)	4 / 35 (11.43%)	9 / 36 (25.00%)	8 / 28 (28.57%)	0 / 20 (0.00%)	4 / 25 (16.00%)
occurrences all number	6	4	10	9	0	4
RETINAL NEOVASCULARISATION (Right eye)
subjects affected / exposed	12 / 35 (34.29%)	3 / 35 (8.57%)	10 / 36 (27.78%)	5 / 28 (17.86%)	2 / 20 (10.00%)	4 / 25 (16.00%)
occurrences all number	13	4	11	5	2	4
VISION BLURRED (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	4 / 36 (11.11%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	2	4	0	0	0
VISUAL ACUITY REDUCED (Both eyes)
subjects affected / exposed	2 / 35 (5.71%)	1 / 35 (2.86%)	2 / 36 (5.56%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	2	1	2	1	0	1
VISUAL ACUITY REDUCED (Left eye)
subjects affected / exposed	5 / 35 (14.29%)	3 / 35 (8.57%)	12 / 36 (33.33%)	2 / 28 (7.14%)	1 / 20 (5.00%)	1 / 25 (4.00%)
occurrences all number	5	3	16	2	1	1
VISUAL ACUITY REDUCED (Right eye)
subjects affected / exposed	7 / 35 (20.00%)	9 / 35 (25.71%)	5 / 36 (13.89%)	3 / 28 (10.71%)	3 / 20 (15.00%)	1 / 25 (4.00%)
occurrences all number	9	13	7	3	3	1
VISUAL IMPAIRMENT (Left eye)
subjects affected / exposed	1 / 35 (2.86%)	1 / 35 (2.86%)	2 / 36 (5.56%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	1	2	1	0	1
VITREOUS ADHESIONS (Right eye)
subjects affected / exposed	2 / 35 (5.71%)	2 / 35 (5.71%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	3	0	1	0	0
VITREOUS DETACHMENT (Both eyes)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	2	0	0	0	0
VITREOUS FLOATERS (Left eye)
subjects affected / exposed	3 / 35 (8.57%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	3	1	0	0	0	1
VITREOUS FLOATERS (Right eye)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	2	0	0	0
VITREOUS HAEMORRHAGE (Left eye)
subjects affected / exposed	6 / 35 (17.14%)	6 / 35 (17.14%)	5 / 36 (13.89%)	4 / 28 (14.29%)	2 / 20 (10.00%)	4 / 25 (16.00%)
occurrences all number	6	8	7	5	2	6
VITREOUS HAEMORRHAGE (Right eye)
subjects affected / exposed	4 / 35 (11.43%)	7 / 35 (20.00%)	5 / 36 (13.89%)	3 / 28 (10.71%)	1 / 20 (5.00%)	7 / 25 (28.00%)
occurrences all number	4	10	6	3	2	9
RETINAL ISCHAEMIA (Right eye)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	2 / 36 (5.56%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	0	2	1	0	1
Gastrointestinal disorders
DIARRHOEA (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	1 / 35 (2.86%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	1	1	0	0	0
NAUSEA (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	2	0	0	2	0	1
TOOTHACHE (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	1	0	0	0
VOMITING (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	1 / 35 (2.86%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	2	1	0	0	0	1
Respiratory, thoracic and mediastinal disorders
COUGH (Non-ocular)
subjects affected / exposed	4 / 35 (11.43%)	1 / 35 (2.86%)	3 / 36 (8.33%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	4	2	3	0	0	0
Skin and subcutaneous tissue disorders
DIABETIC FOOT (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	2	0	0	0
Endocrine disorders
HYPOTHYROIDISM (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	2 / 20 (10.00%)	0 / 25 (0.00%)
occurrences all number	0	0	0	0	2	0
Musculoskeletal and connective tissue disorders
ARTHRITIS (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	2	0	0	0
PAIN IN EXTREMITY (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	3 / 36 (8.33%)	1 / 28 (3.57%)	0 / 20 (0.00%)	2 / 25 (8.00%)
occurrences all number	1	0	3	1	0	2
BACK PAIN (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	2 / 35 (5.71%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	2	2	0	1	0	1
Infections and infestations
BRONCHITIS (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	2 / 25 (8.00%)
occurrences all number	1	0	0	0	0	2
GASTROENTERITIS (Non-ocular)
subjects affected / exposed	1 / 35 (2.86%)	0 / 35 (0.00%)	4 / 36 (11.11%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	5	0	0	0
HORDEOLUM (Left eye)
subjects affected / exposed	2 / 35 (5.71%)	2 / 35 (5.71%)	0 / 36 (0.00%)	1 / 28 (3.57%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	2	0	1	0	0
INFLUENZA (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	4	3	0	0	0
NASOPHARYNGITIS (Non-ocular)
subjects affected / exposed	7 / 35 (20.00%)	12 / 35 (34.29%)	9 / 36 (25.00%)	2 / 28 (7.14%)	2 / 20 (10.00%)	3 / 25 (12.00%)
occurrences all number	10	15	13	3	2	3
RHINITIS (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	1 / 35 (2.86%)	1 / 36 (2.78%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	2	1	0	0	0
SINUSITIS (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	2 / 35 (5.71%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	2	2	0	0	2
Metabolism and nutrition disorders
HYPERCHOLESTEROLAEMIA (Non-ocular)
subjects affected / exposed	0 / 35 (0.00%)	0 / 35 (0.00%)	2 / 36 (5.56%)	0 / 28 (0.00%)	0 / 20 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	2	0	0	1
VITAMIN D DEFICIENCY (Non-ocular)
subjects affected / exposed	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 36 (0.00%)	0 / 28 (0.00%)	0 / 20 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

14 May 2012

Amendment 1 was issued before inclusion of the first patient and introduced the following changes: • Exploratory objectives were added. Serum biomarker samples were planned to be taken therefore. • The screening period was extended to 28 days to allow for sufficient time to obtain grade-able FA/FP images (Visit 1.1 was added). • Exclusion criteria were stated more precisely, i.e. if these were related to the study eye or either eye. • Specification of exclusion criteria #15 (previous treatment with PRP) • Specification of exclusion criteria #30 (permit for re-randomization/rescreening) • A paragraph was added clarifying rescreening conditions (5.2. Rescreening of patients). • Specification of the randomization process (eCRF) • More detailed definition of treatment/re-treatment. • Imaging procedures were clarified. • Visit 14.1 was added in order to obtain FA/FP images that can be graded by Central reading center at end of study. • OCT image of Visit 1 was to be checked by Reading Center for CSME. • The number of blood samples was increased (HbA1c, Serum Lipids, Biomarkers). • Gonioscopy was added for V1 and V14 (exclusion of Rubeosis iridis). • Visit schedule was updated. • Appendix 2 of the protocol was updated.

11 Apr 2014

Amendment 2 was issued when 73 patients were screened, 48 were randomized, and 8 completed core study and introduced the following changes: • 2 observational Follow-Up Visits were added (6 and 12 months after Month 12 visit). As a consequence exploratory objectives, study design, schedules etc. were updated. It was clarified that in the Follow-Up phase randomization and forbidden treatments were no longer to be followed, no study medication was to be dispensed and treatment was to be done as in physician’s routine. • Exclusion criteria regarding size of neovascularization, vitreous hemorrhage, history of vitrectomy for study and fellow eye and pretreatment with steroid implants were defined more precisely. • Recommendations for use of PRP therapy were moved to Appendix 3 Section 5 and updated to give more precise guidance on treatment and retreatment. Furthermore, it was clarified that if investigator center was of the opinion that PRP treatment was insufficient, PRP treatment should start immediately independent of 3 months interval to last laser treatment. • Minor updates and precisions were made in several chapters. • Use of study bulk ware in chapter 6.6.1. was deleted. • Kryocoagulation therapy as rescue therapy was added in section 6.6.4. • Use of antimicrobials before and after injection were deleted/updated to “at investigator’s discretion” to align protocol with current summary of product characteristic of ranibizumab and guidance from scientific societies. • Use of concomitant anti-VEGF agents for systemic use, study and fellow eye and use of steroids (esp. when applied long term in study eye/systemically) were defined more precisely. Newly started fingolimod during core study was now prohibited. A course of action was added to give guidance if vitrectomy could not be delayed. • Specific biomarkers were added. It was clarified that if further biomarkers were of interest, they had to be defined during/at end of study with amendments.

12 Nov 2015

Amendment 3 was issued when 148 patients were screened and 101 patients were randomized and introduced the following changes: • Purpose to terminate the enrolment to the trial. • Sample size calculation was adapted to show reduced recruitment and site numbers. • Clarification that the primary outcome and further objectives was to be evaluated as soon as respective timepoints were completed.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in area of neovascularizations (NVs) at End of Core Study (EOCS)

Primary: Change from baseline in area of neovascularizations (NVs) at End of Core Study (EOCS)

Secondary: Change from baseline in area of neovascularizations (NVs) at Month 3

Secondary: Change from baseline in area of neovascularizations (NVs) at Month 3

Secondary: Best Corrected Visual Acuity (BCVA) (ETDRS letters) at EOCS

Secondary: Best Corrected Visual Acuity (BCVA) (ETDRS letters) at EOCS

Secondary: Percentage of patients with change from baseline in BCVA (ETDRS letters) at EOCS

Secondary: Percentage of patients with change from baseline in BCVA (ETDRS letters) at EOCS

Secondary: Number of patients with change from baseline in ETDRS severity grade of diabetic retinopathy (DR) at EOCS

Secondary: Number of patients with change from baseline in ETDRS severity grade of diabetic retinopathy (DR) at EOCS

Secondary: Change from baseline in central subfield thickness at EOCS

Secondary: Change from baseline in central subfield thickness at EOCS

Secondary: Change from baseline in foveal center point retinal thickness at EOCS

Secondary: Change from baseline in foveal center point retinal thickness at EOCS

Secondary: Number of ranibizumab injections until EOCS

Secondary: Number of ranibizumab injections until EOCS

Secondary: Number of PRP laser spots until EOCS

Secondary: Number of PRP laser spots until EOCS

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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