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Clinical Trial Results:
A Two-Year, Two-Arm, Randomized, Double Masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in Adult Patients with Visual Impairment due to Diabetic Macular Edema

Summary
EudraCT number	2017-003960-11
Trial protocol	DE LV LT SK SE BE DK HU CZ BG PL
Global end of trial date	08 Jun 2021

Results information
Results version number	v1(current)
This version publication date	17 Jun 2022
First version publication date	17 Jun 2022
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

CRTH258B2302

ISRCTN number

US NCT number

NCT03481660

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis Campus, 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

08 Jun 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jun 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to demonstrate that brolucizumab was non-inferior to aflibercept with respect to the visual outcome after the first year of treatment

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

27 Jul 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Bulgaria: 8

Country: Number of subjects enrolled

Czechia: 22

Country: Number of subjects enrolled

Denmark: 3

Country: Number of subjects enrolled

Estonia: 3

Country: Number of subjects enrolled

France: 56

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Hungary: 47

Country: Number of subjects enrolled

India: 24

Country: Number of subjects enrolled

Korea, Republic of: 19

Country: Number of subjects enrolled

Latvia: 4

Country: Number of subjects enrolled

Lebanon: 4

Country: Number of subjects enrolled

Lithuania: 7

Country: Number of subjects enrolled

Malaysia: 15

Country: Number of subjects enrolled

Norway: 4

Country: Number of subjects enrolled

Poland: 13

Country: Number of subjects enrolled

Russian Federation: 17

Country: Number of subjects enrolled

Singapore: 7

Country: Number of subjects enrolled

Slovakia: 32

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

Switzerland: 7

Country: Number of subjects enrolled

Taiwan: 24

Country: Number of subjects enrolled

Turkey: 23

Worldwide total number of subjects

360

EEA total number of subjects

220

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)

202

From 65 to 84 years

156

85 years and over

Subject disposition

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Recruitment details

This study was conducted in 79 centers in 23 countries worldwide.

Screening details

360 subjects were randomized in a 1:1 ratio to brolucizumab 6 mg arm (n=179) or aflibercept 2 mg arm (n=181).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Brolucizumab 6 mg

Arm description

Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule

Arm type

Experimental

Investigational medicinal product name

Brolucizumab

Investigational medicinal product code

Other name

RTH258, ESBA1008

Pharmaceutical forms

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

Routes of administration

Intravitreal use

Dosage and administration details

Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule

Aflibercept 2 mg

Arm description

Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks

Arm type

Active comparator

Investigational medicinal product name

Aflibercept

Investigational medicinal product code

Other name

Eylea

Pharmaceutical forms

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

Routes of administration

Intravitreal use

Dosage and administration details

Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks

Number of subjects in period 1	Brolucizumab 6 mg	Aflibercept 2 mg
Started	179	181
Completed	143	156
Not completed	36	25
Adverse event, serious fatal	13	9
Physician decision	2	3
Consent withdrawn by subject	14	7
Adverse event, non-fatal	5	4
Lost to follow-up	2	2

Baseline characteristics

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Reporting group title

Brolucizumab 6 mg

Reporting group description

Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule

Reporting group title

Aflibercept 2 mg

Reporting group description

Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks

Reporting group values	Brolucizumab 6 mg	Aflibercept 2 mg	Total
Number of subjects	179	181	360
Age Categorical
Units: Participants
< 65 years	100	102	202
>= 65 years	79	79	158
Age Continuous
Units: Years
arithmetic mean (standard deviation)	62.3 ( 10.55 )	62.2 ( 9.48 )	-
Sex: Female, Male
Units: Participants
Female	59	66	125
Male	120	115	235
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	43	48	91
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	3	1	4
White	133	132	265
More than one race	0	0	0
Unknown or Not Reported	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	3	4	7
Not Hispanic or Latino	163	170	333
Unknown or Not Reported	13	7	20

End points

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Reporting group title

Brolucizumab 6 mg

Reporting group description

Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule

Reporting group title

Aflibercept 2 mg

Reporting group description

Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks

Primary: Mean change from Baseline in best-corrected visual acuity (BCVA) at Week 52 for the study eye

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End point title

Mean change from Baseline in best-corrected visual acuity (BCVA) at Week 52 for the study eye

End point description

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Primary

End point timeframe

Baseline, Week 52

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Scores on a scale
least squares mean (confidence interval 95%)	10.6 (9.3 to 11.9)	9.4 (8.1 to 10.7)

BCVA at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

< 0.001

Method

ANOVA

Parameter type

LS mean difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

3.1

Variability estimate

Standard error of the mean

Dispersion value

0.94

Notes
[1] - (4-letter margin) (1-sided)

Secondary: Average mean change from Baseline in BCVA over the period Week 40 through Week 52 for the study eye

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End point title

Average mean change from Baseline in BCVA over the period Week 40 through Week 52 for the study eye

End point description

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. For each participants, this endpoint was defined as the mean change from baseline to the average value over the period Week 40 through Week 52. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

Baseline, period Week 40 through Week 52

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Scores on a scale
least squares mean (confidence interval 95%)	10.3 (9.1 to 11.5)	9.4 (8.2 to 10.6)

BCVA over period Week 40 through Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.164

Method

ANOVA

Confidence interval

BCVA over period Week 40 through Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

< 0.001

Method

ANOVA

Parameter type

LS mean difference

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

0.88

Notes
[2] - (4-letter margin) (1-sided)

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w up to Week 52 and up to q12w/q16w up to Week 100.

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End point title

(Brolucizumab treatment arm only): Percentage of participants maintained at q12w up to Week 52 and up to q12w/q16w up to Week 100.

End point description

The number of participants maintaining every 12 weeks (q12w) treatment status in the Brolucizumab arm was derived based on Kaplan-Meier estimates time-to-first q8w treatment need. Positive treatment status was defined as intravitreal treatment (IVT) injections per planned dosing regimen [every 12 weeks (q12w)].

End point type

Secondary

End point timeframe

Week 52, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	0 ^[3]
Units: Percentage of participants
number (confidence interval 95%)
Week 48	50.3 (42.5 to 57.7)	( to )
Week 96	36.8 (29.1 to 45.5)	( to )

Notes
[3] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w up to Week 52 within those patients that qualified for q12w at Week 36

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End point title

(Brolucizumab treatment arm only): Percentage of participants maintained at q12w up to Week 52 within those patients that qualified for q12w at Week 36

End point description

End point type

Secondary

End point timeframe

Week 36, Week 52

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	87	0 ^[4]
Units: Percentage of participants
number (confidence interval 95%)	95.1 (87.4 to 98.1)	( to )

Notes
[4] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w/q16w up to Week 100, within those patients that qualified for q12w at Week 36

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End point title

(Brolucizumab treatment arm only): Percentage of participants maintained at q12w/q16w up to Week 100, within those patients that qualified for q12w at Week 36

End point description

Disease activity assessments (DAAs) were performed to identify q8w-need at pre-specified visits (Weeks 32, 36, 48, 60, 72 and every visit from Week 72 through Week 96). Weeks 32 and 36 were the two DAA visits of the initial q12w cycle after the loading phase of the brolucizumab arm. At Week 72 or Week 76 (if DAA/disease stability assessment was missed at Week 72), participants in the brolucizumab were evaluated for an additional 4-week dose regimen extension. The number of participants maintaining every 12 weeks (q12w) treatment status in the Brolucizumab arm was derived based on Kaplan-Meier estimates time-to-first q8w treatment need. Positive treatment status was defined as intravitreal treatment (IVT) injections per planned dosing regimen [every 12 weeks (q12w)].

End point type

Secondary

End point timeframe

Week 36, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	87	0 ^[5]
Units: Percentage of participants
number (confidence interval 95%)	69.6 (57.4 to 78.9)	( to )

Notes
[5] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained on q16w up to Week 100 within the patients on q12w at Week 68 and on q16w at Week 76

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End point title

(Brolucizumab treatment arm only): Percentage of participants maintained on q16w up to Week 100 within the patients on q12w at Week 68 and on q16w at Week 76

End point description

End point type

Secondary

End point timeframe

Week 68, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	44	0 ^[6]
Units: Percentage of participants
number (confidence interval 95%)	87.9 (73.3 to 94.8)	( to )

Notes
[6] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: (Brolucizumab treatment arm only): Percentage of participants re-assigned and maintained on q12w up to Week 100 within the patients on q8w at Week 68 and on q12w at Week 80

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End point title

(Brolucizumab treatment arm only): Percentage of participants re-assigned and maintained on q12w up to Week 100 within the patients on q8w at Week 68 and on q12w at Week 80

End point description

End point type

Secondary

End point timeframe

Week 68, Week 80, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	34	0 ^[7]
Units: Percentage of participants
number (confidence interval 95%)	73.1 (54.5 to 85.0)	( to )

Notes
[7] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: (Brolucizumab treatment arm only): Number of participants with injections per planned dosing regimen (every 8, 12 or 16 weeks)

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End point title

(Brolucizumab treatment arm only): Number of participants with injections per planned dosing regimen (every 8, 12 or 16 weeks)

End point description

Reported categorically for the subjects who completed the study treatment period: every 8 weeks (q8w), Every 12 weeks (q12w), Every 16 weeks (q16w)

End point type

Secondary

End point timeframe

Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	141	0 ^[8]
Units: Participants
q8w	74
q12w	32
q16w	35

Notes
[8] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: Mean change from Baseline in Best Corrected Visual Acuity (BCVA) at each visit up to Week 100 for the study eye

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End point title

Mean change from Baseline in Best Corrected Visual Acuity (BCVA) at each visit up to Week 100 for the study eye

End point description

End point type

Secondary

End point timeframe

Baseline, Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Scores on a scale
least squares mean (confidence interval 95%)
Week 4	5.1 (4.3 to 6.0)	4.2 (3.4 to 5.1)
Week 6	6.8 (5.9 to 7.6)	5.9 (5.0 to 6.7)
Week 8	7.8 (6.9 to 8.7)	6.7 (5.8 to 7.5)
Week 12	8.6 (7.6 to 9.5)	7.7 (6.7 to 8.6)
Week 16	9.0 (7.9 to 10.1)	8.3 (7.2 to 9.5)
Week 18	9.2 (8.0 to 10.3)	9.2 (8.0 to 10.3)
Week 20	9.6 (8.4 to 10.8)	9.4 (8.2 to 10.6)
Week 24	10.0 (8.8 to 11.2)	8.7 (7.5 to 9.9)
Week 28	9.8 (8.6 to 11.1)	9.4 (8.2 to 10.6)
Week 32	10.3 (9.1 to 11.5)	8.9 (7.7 to 10.1)
Week 36	9.6 (8.4 to 10.9)	9.4 (8.2 to 10.7)
Week 40	9.9 (8.7 to 11.2)	9.2 (7.9 to 10.4)
Week 44	10.6 (9.3 to 11.8)	9.5 (8.3 to 10.8)
Week 48	10.1 (8.8 to 11.3)	9.6 (8.3 to 10.9)
Week 52	10.6 (9.3 to 11.9)	9.4 (8.1 to 10.7)
Week 56	10.7 (9.3 to 12.0)	9.5 (8.2 to 10.9)
Week 60	10.5 (9.1 to 11.9)	9.3 (8.0 to 10.7)
Week 64	11.0 (9.7 to 12.3)	9.5 (8.2 to 10.8)
Week 68	11.0 (9.6 to 12.3)	9.5 (8.2 to 10.8)
Week 72	11.0 (9.6 to 12.3)	9.4 (8.1 to 10.8)
Week 76	10.5 (9.2 to 11.8)	9.8 (8.4 to 11.1)
Week 80	10.2 (8.9 to 11.6)	9.4 (8.1 to 10.8)
Week 84	10.9 (9.4 to 12.4)	8.9 (7.4 to 10.4)
Week 88	10.7 (9.1 to 12.4)	8.6 (7.0 to 10.2)
Week 92	10.7 (9.1 to 12.2)	9.3 (7.7 to 10.8)
Week 96	10.7 (9.1 to 12.3)	8.5 (6.8 to 10.1)
Week 100	10.9 (9.3 to 12.6)	8.4 (6.7 to 10.1)

BCVA at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[9]

Method

Parameter type

LS mean difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

3.1

Variability estimate

Standard error of the mean

Dispersion value

0.94

Notes
[9] - Treatment Difference

BCVA at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[10]

Method

Parameter type

LS mean difference

Point estimate

2.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

4.9

Variability estimate

Standard error of the mean

Dispersion value

1.21

Notes
[10] - Treatment Difference

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 4 to Week 52/100 for the study eye

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End point title

Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 4 to Week 52/100 for the study eye

End point description

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. For each participants, this endpoint was defined as the mean change from baseline to the average value over the periods: Week 4 through Week 52, Week 4 through Week 100. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

Baseline, period Week 4 through Week 52, period Week 4 through Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Scores on a scale
least squares mean (confidence interval 95%)
period Week 4 through Week 52	9.1 (8.2 to 10.1)	8.4 (7.4 to 9.3)
period Week 4 through Week 100	9.8 (8.8 to 10.9)	8.7 (7.7 to 9.8)

BCVA over period Week 4 through Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[11]

Method

Parameter type

LS mean difference

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

0.78

Notes
[11] - Treatment difference

BCVA over period Week 4 through Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[12]

Method

Parameter type

LS mean difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

2.1

Variability estimate

Standard error of the mean

Dispersion value

0.7

Notes
[12] - Treatment difference

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 20 to Week 52/100 and Week 28 to Week 52/100 for the study eye

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End point title

Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 20 to Week 52/100 and Week 28 to Week 52/100 for the study eye

End point description

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. For each participants, this endpoint was defined as the mean change from baseline to the average value over the periods: Week 20 through Week 52, Week 20 through Week 100, Week 28 through Week 52, Week 28 through Week 100. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

Baseline, period Week 20 through Week 52, period Week 20 through Week 100, period Week 28 through Week 52, period Week 28 through Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Scores on a scale
least squares mean (confidence interval 95%)
period Week 20 through Week 52	10.1 (8.9 to 11.2)	9.3 (8.1 to 10.4)
period Week 20 through Week 100	10.4 (9.2 to 11.7)	9.2 (8.0 to 10.4)
period Week 28 through Week 52	10.1 (9.0 to 11.3)	9.4 (8.2 to 10.5)
period Week 28 through Week 100	10.5 (9.3 to 11.7)	9.2 (8.0 to 10.5)

BCVA over period Week 20 through Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[13]

Method

Parameter type

LS mean difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

2.4

Variability estimate

Standard error of the mean

Dispersion value

0.83

Notes
[13] - Treatment difference

BCVA over period Week 28 through Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[14]

Method

Parameter type

LS mean difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

2.5

Variability estimate

Standard error of the mean

Dispersion value

0.85

Notes
[14] - Treatment difference

BCVA over period Week 20 through Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[15]

Method

Parameter type

LS mean difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

2.9

Variability estimate

Standard error of the mean

Dispersion value

0.87

Notes
[15] - Treatment difference

BCVA over period Week 28 through Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[16]

Method

Parameter type

LS mean difference

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.89

Notes
[16] - Treatment difference

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 88 to 100 for the study eye

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End point title

Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 88 to 100 for the study eye

End point description

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. For each participants, this endpoint was defined as the mean change from baseline to the average value over the period Week 88 through Week 100. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

Baseline, period Week 88 through Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Scores on a scale
least squares mean (confidence interval 95%)	10.8 (9.2 to 12.3)	8.7 (7.1 to 10.2)

BCVA over period Week 88 through Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[17]

Method

Parameter type

LS mean difference

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

4.3

Variability estimate

Standard error of the mean

Dispersion value

1.12

Notes
[17] - Treatment difference

Secondary: Percentage of participants who gained >= 5 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

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End point title

Percentage of participants who gained >= 5 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

End point description

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	49.2 (41.6 to 56.7)	46.4 (39.0 to 54.0)
Week 6	62.0 (54.5 to 69.1)	62.4 (54.9 to 69.5)
Week 8	67.6 (60.2 to 74.4)	63.5 (56.1 to 70.5)
Week 12	70.9 (63.7 to 77.5)	73.5 (66.4 to 79.8)
Week 16	71.5 (64.3 to 78.0)	73.5 (66.4 to 79.8)
Week 18	77.7 (70.8 to 83.5)	77.9 (71.1 to 83.7)
Week 20	79.3 (72.7 to 85.0)	76.2 (69.4 to 82.2)
Week 24	79.9 (73.3 to 85.5)	77.9 (71.1 to 83.7)
Week 28	75.4 (68.4 to 81.5)	77.9 (71.1 to 83.7)
Week 32	77.1 (70.2 to 83.0)	80.7 (74.1 to 86.1)
Week 36	74.3 (67.2 to 80.5)	80.7 (74.1 to 86.1)
Week 40	74.9 (67.8 to 81.0)	79.6 (72.9 to 85.2)
Week 44	74.3 (67.2 to 80.5)	80.7 (74.1 to 86.1)
Week 48	76.0 (69.0 to 82.0)	79.0 (72.3 to 84.7)
Week 52	77.7 (70.8 to 83.5)	79.0 (72.3 to 84.7)
Week 56	77.7 (70.8 to 83.5)	80.7 (74.1 to 86.1)
Week 60	76.0 (69.0 to 82.0)	79.0 (72.3 to 84.7)
Week 64	78.2 (71.4 to 84.0)	79.0 (72.3 to 84.7)
Week 68	77.7 (70.8 to 83.5)	76.8 (70.0 to 82.7)
Week 72	79.9 (73.3 to 85.5)	77.3 (70.6 to 83.2)
Week 76	74.3 (67.2 to 80.5)	77.3 (70.6 to 83.2)
Week 80	74.3 (67.2 to 80.5)	75.7 (68.8 to 81.7)
Week 84	78.2 (71.4 to 84.0)	73.5 (66.4 to 79.8)
Week 88	77.7 (70.8 to 83.5)	75.7 (68.8 to 81.7)
Week 92	79.3 (72.7 to 85.0)	74.0 (67.0 to 80.3)
Week 96	78.8 (72.0 to 84.5)	73.5 (66.4 to 79.8)
Week 100	77.1 (70.2 to 83.0)	73.5 (66.4 to 79.8)

Gain of >= 5 letters in BCVA at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[18]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

14.5

Notes
[18] - Treatment difference

Gain of >= 5 letters in BCVA at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[19]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-7.6

upper limit

8.9

Notes
[19] - Treatment difference

Secondary: Percentage of participants who gained >= 10 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

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End point title

Percentage of participants who gained >= 10 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

End point description

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	22.9 (17.0 to 29.8)	23.8 (17.8 to 30.6)
Week 6	34.6 (27.7 to 42.1)	31.5 (24.8 to 38.8)
Week 8	39.7 (32.4 to 47.2)	36.5 (29.5 to 43.9)
Week 12	43.0 (35.7 to 50.6)	45.9 (39.4 to 53.4)
Week 16	44.1 (36.7 to 51.7)	49.7 (42.2 to 57.2)
Week 18	47.5 (40.0 to 55.1)	53.0 (45.5 to 60.5)
Week 20	53.1 (45.5 to 60.6)	56.9 (49.4 to 64.2)
Week 24	56.4 (48.8 to 63.8)	53.6 (46.0 to 61.0)
Week 28	55.3 (47.7 to 62.7)	55.2 (47.7 to 62.6)
Week 32	58.7 (51.1 to 66.0)	51.9 (44.4 to 59.4)
Week 36	57.5 (49.9 to 64.9)	55.2 (47.7 to 62.6)
Week 40	58.1 (50.5 to 65.4)	52.5 (44.9 to 59.9)
Week 44	61.5 (53.9 to 68.6)	56.9 (49.4 to 64.2)
Week 48	60.9 (53.3 to 68.1)	53.0 (45.5 to 60.5)
Week 52	61.5 (53.9 to 68.6)	58.6 (51.0 to 65.8)
Week 56	62.0 (54.5 to 69.1)	54.1 (46.6 to 61.6)
Week 60	61.5 (53.9 to 68.6)	54.7 (47.1 to 62.1)
Week 64	63.7 (56.2 to 70.7)	56.9 (49.4 to 64.2)
Week 68	62.0 (54.5 to 69.1)	57.5 (49.9 to 64.8)
Week 72	63.7 (56.2 to 70.7)	56.4 (48.8 to 63.7)
Week 76	60.9 (53.3 to 68.1)	56.9 (49.4 to 64.2)
Week 80	57.5 (49.9 to 64.9)	55.8 (48.2 to 63.2)
Week 84	63.7 (56.2 to 70.7)	58.6 (51.0 to 65.8)
Week 88	61.5 (53.9 to 68.6)	58.0 (50.5 to 65.3)
Week 92	63.7 (56.2 to 70.7)	58.6 (51.0 to 65.8)
Week 96	62.6 (55.0 to 69.7)	56.9 (49.4 to 64.2)
Week 100	61.5 (53.9 to 68.6)	54.1 (46.6 to 61.6)

Gain of >= 10 letters in BCVA at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[20]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

9.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

19.4

Notes
[20] - Treatment difference

Gain of >= 10 letters in BCVA at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[21]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

14.7

Notes
[21] - Treatment difference

Secondary: Percentage of participants who gained >= 15 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

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End point title

Percentage of participants who gained >= 15 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

End point description

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	12.3 (7.9 to 18.0)	9.4 (5.6 to 14.6)
Week 6	13.4 (8.8 to 19.3)	13.8 (9.1 to 19.7)
Week 8	25.1 (19.0 to 32.2)	16.0 (11.0 to 22.2)
Week 12	25.1 (19.0 to 32.2)	22.1 (16.3 to 28.9)
Week 16	33.5 (26.7 to 40.9)	25.4 (19.2 to 32.4)
Week 18	31.8 (25.1 to 39.2)	33.1 (26.3 to 40.5)
Week 20	34.6 (27.7 to 42.1)	32.6 (25.8 to 39.9)
Week 24	41.9 (34.6 to 49.5)	30.9 (24.3 to 38.2)
Week 28	40.2 (33.0 to 47.8)	37.0 (30.0 to 44.5)
Week 32	44.1 (36.7 to 51.7)	30.4 (23.8 to 37.6)
Week 36	45.3 (37.8 to 52.8)	32.6 (25.8 to 39.9)
Week 40	44.7 (37.3 to 52.3)	31.5 (24.8 to 38.8)
Week 44	50.3 (42.7 to 57.8)	35.4 (28.4 to 42.8)
Week 48	41.9 (34.6 to 49.5)	37.0 (30.0 to 44.5)
Week 52	46.4 (38.9 to 54.0)	37.6 (30.5 to 45.1)
Week 56	46.4 (38.9 to 54.0)	35.9 (28.9 to 43.4)
Week 60	46.9 (39.4 to 54.5)	38.7 (31.5 to 46.2)
Week 64	50.3 (42.7 to 57.8)	36.5 (29.5 to 43.9)
Week 68	48.6 (41.1 to 56.2)	35.9 (28.9 to 43.4)
Week 72	48.0 (40.5 to 55.6)	35.4 (28.4 to 42.8)
Week 76	46.4 (38.9 to 54.0)	40.9 (33.6 to 48.4)
Week 80	43.6 (36.2 to 51.2)	37.6 (30.5 to 45.1)
Week 84	46.4 (38.9 to 54.0)	37.0 (30.0 to 44.5)
Week 88	47.5 (40.0 to 55.1)	40.9 (33.6 to 48.4)
Week 92	44.7 (37.3 to 52.3)	40.3 (33.1 to 47.9)
Week 96	46.9 (39.4 to 54.5)	38.1 (31.0 to 45.6)
Week 100	49.7 (42.2 to 57.3)	37.6 (30.5 to 45.1)

Gain of >= 15 letters in BCVA at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[22]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

9.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

20.2

Notes
[22] - Treatment difference

Gain of >= 15 letters in BCVA at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[23]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

13.6

Confidence interval

level

95%

sides

2-sided

lower limit

3.3

upper limit

23.5

Notes
[23] - Treatment difference

Secondary: Percentage of participants who lost >= 5 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

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End point title

Percentage of participants who lost >= 5 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

End point description

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	3.4 (1.2 to 7.2)	4.4 (1.9 to 8.5)
Week 6	1.7 (0.3 to 4.8)	3.3 (1.2 to 7.1)
Week 8	1.1 (0.1 to 4.0)	2.8 (0.9 to 6.3)
Week 12	1.1 (0.1 to 4.0)	2.2 (0.6 to 5.6)
Week 16	0.6 (0.0 to 3.1)	2.2 (0.6 to 5.6)
Week 18	1.1 (0.1 to 4.0)	1.1 (0.1 to 3.9)
Week 20	2.2 (0.6 to 5.6)	2.8 (0.9 to 6.3)
Week 24	1.7 (0.3 to 4.8)	3.3 (1.2 to 7.1)
Week 28	1.7 (0.3 to 4.8)	2.2 (0.6 to 5.6)
Week 32	2.2 (0.6 to 5.6)	2.2 (0.6 to 5.6)
Week 36	4.5 (1.9 to 8.6)	1.1 (0.1 to 3.9)
Week 40	3.9 (1.6 to 7.9)	2.2 (0.6 to 5.6)
Week 44	2.8 (0.9 to 6.4)	2.2 (0.6 to 5.6)
Week 48	2.8 (0.9 to 6.4)	2.8 (0.9 to 6.3)
Week 52	3.4 (1.2 to 7.2)	3.3 (1.2 to 7.1)
Week 56	5.0 (2.3 to 9.3)	3.3 (1.2 to 7.1)
Week 60	3.9 (1.6 to 7.9)	4.4 (1.9 to 8.5)
Week 64	2.8 (0.9 to 6.4)	3.3 (1.2 to 7.1)
Week 68	3.9 (1.6 to 7.9)	2.8 (0.9 to 6.3)
Week 72	4.5 (1.9 to 8.6)	5.0 (2.3 to 9.2)
Week 76	3.4 (1.2 to 7.2)	4.4 (1.9 to 8.5)
Week 80	2.8 (0.9 to 6.4)	6.1 (3.1 to 10.6)
Week 84	3.4 (1.2 to 7.2)	7.7 (4.3 to 12.6)
Week 88	3.9 (1.6 to 7.9)	7.2 (3.9 to 12.0)
Week 92	3.4 (1.2 to 7.2)	6.6 (3.5 to 11.3)
Week 96	3.9 (1.6 to 7.9)	7.2 (3.9 to 12.0)
Week 100	2.8 (0.9 to 6.4)	8.3 (4.7 to 13.3)

Loss of >= 5 letters in BCVA at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[24]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

2.9

Notes
[24] - Treatment difference

Loss of >= 5 letters in BCVA at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[25]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.8

upper limit

-1.7

Notes
[25] - Treatment difference

Secondary: Percentage of participants who lost >= 10 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

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End point title

Percentage of participants who lost >= 10 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

End point description

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	999 (999 to 999)	1.1 (0.1 to 3.9)
Week 6	1.1 (0.1 to 4.0)	0.6 (0.0 to 3.0)
Week 8	1.1 (0.1 to 4.0)	999 (999 to 999)
Week 12	999 (999 to 999)	0.6 (0.0 to 3.0)
Week 16	0.6 (0.0 to 3.1)	999 (999 to 999)
Week 18	1.1 (0.1 to 4.0)	999 (999 to 999)
Week 20	1.7 (0.3 to 4.8)	999 (999 to 999)
Week 24	1.7 (0.3 to 4.8)	1.1 (0.1 to 3.9)
Week 28	1.7 (0.3 to 4.8)	999 (999 to 999)
Week 32	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 36	3.4 (1.2 to 7.2)	999 (999 to 999)
Week 40	2.8 (0.9 to 6.4)	999 (999 to 999)
Week 44	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 48	2.2 (0.6 to 5.6)	0.6 (0.0 to 3.0)
Week 52	2.2 (0.6 to 5.6)	2.2 (0.6 to 5.6)
Week 56	2.2 (0.6 to 5.6)	1.1 (0.1 to 3.9)
Week 60	1.7 (0.3 to 4.8)	1.7 (0.3 to 4.8)
Week 64	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 68	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 72	2.2 (0.6 to 5.6)	1.7 (0.3 to 4.8)
Week 76	2.2 (0.6 to 5.6)	0.6 (0.0 to 3.0)
Week 80	1.7 (0.3 to 4.8)	1.7 (0.3 to 4.8)
Week 84	2.2 (0.6 to 5.6)	4.4 (1.9 to 8.5)
Week 88	2.8 (0.9 to 6.4)	3.9 (1.6 to 7.8)
Week 92	2.8 (0.9 to 6.3)	2.8 (0.9 to 6.3)
Week 96	2.2 (0.6 to 5.6)	3.9 (1.6 to 7.8)
Week 100	2.2 (0.6 to 5.6)	6.1 (3.1 to 10.6)

Loss of >= 10 letters in BCVA at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[26]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

2.4

Notes
[26] - Treatment difference

Loss of >= 10 letters in BCVA at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[27]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-8.4

upper limit

-0.1

Notes
[27] - Treatment difference

Secondary: Percentage of participants who lost >= 15 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

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End point title

Percentage of participants who lost >= 15 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

End point description

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	999 (999 to 999)	0.6 (0.0 to 3.0)
Week 6	1.1 (0.1 to 4.0)	999 (999 to 999)
Week 8	0.6 (0.0 to 3.1)	999 (999 to 999)
Week 12	999 (999 to 999)	0.6 (0.0 to 3.0)
Week 16	0.6 (0.0 to 3.1)	999 (999 to 999)
Week 18	1.1 (0.1 to 4.0)	999 (999 to 999)
Week 20	1.7 (0.3 to 4.8)	999 (999 to 999)
Week 24	1.1 (0.1 to 4.0)	0.6 (0.0 to 3.0)
Week 28	1.7 (0.3 to 4.8)	999 (999 to 999)
Week 32	1.7 (0.3 to 4.8)	999 (999 to 999)
Week 36	2.8 (0.9 to 6.4)	999 (999 to 999)
Week 40	2.2 (0.6 to 5.6)	999 (999 to 999)
Week 44	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 48	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 52	1.1 (0.1 to 4.0)	1.7 (0.3 to 4.8)
Week 56	1.7 (0.3 to 4.8)	1.1 (0.1 to 3.9)
Week 60	1.7 (0.3 to 4.8)	1.7 (0.3 to 4.8)
Week 64	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 68	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 72	2.2 (0.6 to 5.6)	1.1 (0.1 to 3.9)
Week 76	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 80	1.7 (0.3 to 4.8)	0.6 (0.0 to 3.0)
Week 84	1.7 (0.3 to 4.8)	2.2 (0.6 to 5.6)
Week 88	1.7 (0.3 to 4.8)	2.2 (0.6 to 5.6)
Week 92	2.2 (0.6 to 5.6)	2.2 (0.6 to 5.6)
Week 96	2.2 (0.6 to 5.6)	2.2 (0.6 to 5.6)
Week 100	2.2 (0.6 to 5.6)	3.3 (1.2 to 7.1)

Loss of >= 15 letters in BCVA at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[28]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

1.6

Notes
[28] - Treatment difference

Loss of >= 15 letters in BCVA at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[29]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

Notes
[29] - Treatment difference

Secondary: Percentage of participants with an Absolute Best Corrected Visual Acuity (BCVA) >= 73 ETDRS letters at each post-baseline visit for the study eye

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End point title

Percentage of participants with an Absolute Best Corrected Visual Acuity (BCVA) >= 73 ETDRS letters at each post-baseline visit for the study eye

End point description

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	55.3 (47.7 to 62.7)	42.5 (35.2 to 50.1)
Week 6	64.8 (57.3 to 71.8)	49.7 (42.2 to 57.2)
Week 8	66.5 (59.1 to 73.3)	50.8 (43.3 to 58.3)
Week 12	66.5 (59.1 to 73.3)	59.7 (52.1 to 66.9)
Week 16	69.8 (62.5 to 76.5)	60.8 (53.3 to 67.9)
Week 18	71.5 (64.3 to 78.0)	64.6 (57.2 to 71.6)
Week 20	71.5 (64.3 to 78.0)	61.3 (53.8 to 68.5)
Week 24	73.2 (66.1 to 79.5)	60.2 (52.7 to 67.4)
Week 28	72.6 (65.5 to 79.0)	61.9 (54.4 to 69.0)
Week 32	73.7 (66.7 to 80.0)	59.1 (51.6 to 66.4)
Week 36	70.4 (63.1 to 77.0)	65.2 (57.8 to 72.1)
Week 40	69.8 (62.5 to 76.5)	60.2 (52.7 to 67.4)
Week 44	73.7 (66.7 to 80.0)	63.5 (56.1 to 70.5)
Week 48	70.9 (63.7 to 77.5)	61.3 (53.8 to 68.5)
Week 52	73.7 (66.7 to 80.0)	64.6 (57.2 to 71.6)
Week 56	72.6 (65.5 to 79.0)	66.9 (59.5 to 73.7)
Week 60	70.9 (63.7 to 77.5)	66.9 (59.5 to 73.7)
Week 64	74.3 (67.2 to 80.5)	68.5 (61.2 to 75.2)
Week 68	71.5 (64.3 to 78.0)	66.3 (58.9 to 73.1)
Week 72	73.7 (66.7 to 80.0)	65.2 (57.8 to 72.1)
Week 76	72.6 (65.5 to 79.0)	66.9 (59.5 to 73.7)
Week 80	70.9 (63.7 to 77.5)	64.1 (56.6 to 71.1)
Week 84	70.9 (63.7 to 77.5)	65.2 (57.8 to 72.1)
Week 88	72.6 (65.5 to 79.0)	63.5 (56.1 to 70.5)
Week 92	71.5 (64.3 to 78.0)	63.5 (56.1 to 70.5)
Week 96	70.4 (63.1 to 77.0)	62.4 (54.9 to 69.5)
Week 100	70.9 (63.7 to 77.5)	62.4 (54.9 to 69.5)

Absolute BCVA >= 73 letters at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[30]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

12.6

Notes
[30] - Treatment difference

Absolute BCVA >= 73 letters at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[31]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-4.9

upper limit

Notes
[31] - Treatment difference

Secondary: Mean change from Baseline in Central Subfield Thickness (CSFT) at each post-baseline visit for the study eye

Top of page

End point title

Mean change from Baseline in Central Subfield Thickness (CSFT) at each post-baseline visit for the study eye

End point description

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Micrometers
arithmetic mean (standard deviation)
Week 4	-128.2 ( 131.47 )	-113.9 ( 123.20 )
Week 6	-136.9 ( 135.57 )	-126.0 ( 124.82 )
Week 8	-155.4 ( 139.09 )	-130.8 ( 124.71 )
Week 12	-160.8 ( 137.23 )	-137.9 ( 132.30 )
Week 16	-179.1 ( 137.26 )	-145.3 ( 132.63 )
Week 18	-175.8 ( 139.10 )	-149.0 ( 132.28 )
Week 20	-183.7 ( 139.76 )	-151.0 ( 130.98 )
Week 24	-183.3 ( 143.14 )	-134.0 ( 136.67 )
Week 28	-192.0 ( 145.85 )	-161.4 ( 131.27 )
Week 32	-178.6 ( 138.5 )	-144.9 ( 135.93 )
Week 36	-163.5 ( 144.34 )	-162.9 ( 135.19 )
Week 40	-183.3 ( 139.84 )	-149.9 ( 132.66 )
Week 44	-193.3 ( 144.12 )	-163.5 ( 133.01 )
Week 48	-172.8 ( 141.83 )	-154.6 ( 130.54 )
Week 52	-196.5 ( 144.44 )	-165.0 ( 134.77 )
Week 56	-191.08 ( 148.02 )	-162.4 ( 132.53 )
Week 60	-189.8 ( 147.93 )	-166.2 ( 132.61 )
Week 64	-193.2 ( 143.36 )	-160.2 ( 137.83 )
Week 68	-194.5 ( 141.47 )	-169.8 ( 143.97 )
Week 72	-190.4 ( 142.25 )	-165.1 ( 141.38 )
Week 76	-185.6 ( 143.68 )	-174.7 ( 138.70 )
Week 80	-185.7 ( 145.52 )	-171.1 ( 138.53 )
Week 84	-193.5 ( 142.53 )	-175.1 ( 139.76 )
Week 88	-191.0 ( 141.29 )	-172.2 ( 138.08 )
Week 92	-193.8 ( 142.07 )	-180.1 ( 138.88 )
Week 96	-197.2 ( 144.29 )	-170.2 ( 154.37 )
Week 100	-201.4 ( 142.90 )	-173.9 ( 152.03 )

No statistical analyses for this end point

Secondary: Average mean change from Baseline in Central Subfield Thickness (CSFT) over the period Week 40 through Week 52 / Week 88 through Week 100 for the study eye

Top of page

End point title

Average mean change from Baseline in Central Subfield Thickness (CSFT) over the period Week 40 through Week 52 / Week 88 through Week 100 for the study eye

End point description

The thickness of the retina was measured using Spectral Domain (SD) optical coherence tomography (OCT) equipment (SD-OCT) and reported as a difference, in micrometers. a negative change from baseline indicates a reduction in thickness, whereas a positive change from baseline indicates an increase. An increase in thickness may indicate a progression of the underlying disease. CSFT assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment. For each participants, this endpoint was derived as the average of the changes from Baseline to Weeks 40, 44, 48, 52. Then the same was derived over the period Week 88 through Week 100, considering the average of the changes from Baseline to Weeks 88, 92, 96, 100. This endpoint was only assessed in the year-2 analysis (Week 100).

End point type

Secondary

End point timeframe

Baseline, period Week 40 through Week 52, period Week 88 through Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Micrometers
least squares mean (confidence interval 95%)
period Week 40 through Week 52	-187.1 (-200.7 to -173.5)	-157.7 (-171.2 to -144.1)
period Week 88 through Week 100	-196.6 (-210.9 to -182.3)	-173.4 (-187.6 to -159.1)

CSFT over period Week 40 through Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

< 0.003

Method

ANOVA

Parameter type

LS mean difference

Point estimate

-29.4

Confidence interval

level

95%

sides

2-sided

lower limit

-48.6

upper limit

-10.2

Variability estimate

Standard error of the mean

Dispersion value

9.76

Notes
[32] - Treatment difference

CSFT over period Week 40 through Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

ANOVA

Confidence interval

CSFT over period Week 88 through Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[33]

Method

Parameter type

LS mean difference

Point estimate

-23.2

Confidence interval

level

95%

sides

2-sided

lower limit

-43.5

upper limit

-3

Variability estimate

Standard error of the mean

Dispersion value

10.28

Notes
[33] - Treatment difference

Secondary: Average mean change from baseline in CSFT over the period Week 4 to Week 52 / 100 for the study eye

Top of page

End point title

Average mean change from baseline in CSFT over the period Week 4 to Week 52 / 100 for the study eye

End point description

End point type

Secondary

End point timeframe

Baseline, period Week 4 through Week 52, period Week 4 through Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Micrometers
least squares mean (confidence interval 95%)
period Week 4 through Week 52	-172.8 (-185.8 to -159.8)	-145.4 (-158.4 to -132.4)
period Week 4 through Week 100	-181.8 (-194.7 to -168.9)	-156.1 (-169.0 to -143.2)

CSFT over period Week 4 through Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[34]

Method

Parameter type

LS mean difference

Point estimate

-27.4

Confidence interval

level

95%

sides

2-sided

lower limit

-45.8

upper limit

-9

Variability estimate

Standard error of the mean

Dispersion value

9.35

Notes
[34] - Treatment difference

CSFT over period Week 4 through Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[35]

Method

Parameter type

LS mean difference

Point estimate

-25.8

Confidence interval

level

95%

sides

2-sided

lower limit

-44

upper limit

-7.5

Variability estimate

Standard error of the mean

Dispersion value

9.29

Notes
[35] - Treatment difference

Secondary: Percentage of participants with normal CSFT thickness (<280 micrometers) at each post-baseline visit for the study eye

Top of page

End point title

Percentage of participants with normal CSFT thickness (<280 micrometers) at each post-baseline visit for the study eye

End point description

The thickness of the retina was measured using Spectral Domain (SD) optical coherence tomography (OCT) equipment (SD-OCT) and reported as a difference, in micrometers. CSFT assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	12.8 (8.3 to 18.7)	13.3 (8.7 to 19.2)
Week 6	16.8 (11.6 to 23.1)	14.4 (9.7 to 20.4)
Week 8	22.9 (17.0 to 29.8)	16.7 (11.5 to 22.9)
Week 12	30.2 (23.5 to 37.5)	24.4 (18.4 to 31.4)
Week 16	36.9 (29.8 to 44.4)	29.4 (22.9 to 36.7)
Week 18	39.1 (31.9 to 46.7)	30.0 (23.4 to 37.3)
Week 20	42.5 (35.1 to 50.1)	31.1 (24.4 to 38.4)
Week 24	48.6 (41.1 to 56.2)	29.4 (22.9 to 36.7)
Week 28	50.3 (42.7 to 57.8)	33.9 (27.0 to 41.3)
Week 32	48.0 (40.5 to 55.6)	30.6 (23.9 to 37.8)
Week 36	38.5 (31.4 to 46.1)	38.9 (31.7 to 46.4)
Week 40	51.4 (43.8 to 58.9)	37.2 (30.1 to 44.7)
Week 44	51.4 (43.8 to 58.9)	38.9 (31.7 to 46.4)
Week 48	49.7 (42.2 to 57.3)	37.2 (30.1 to 44.7)
Week 52	57.5 (49.9 to 64.9)	41.4 (34.2 to 49.0)
Week 56	57.5 (49.9 to 64.9)	40.3 (33.1 to 47.9)
Week 60	53.1 (45.5 to 60.6)	40.3 (33.1 to 47.9)
Week 64	54.2 (46.6 to 61.6)	38.1 (31.0 to 45.6)
Week 68	53.6 (46.0 to 61.1)	41.4 (34.2 to 49.0)
Week 72	56.4 (48.8 to 63.8)	38.7 (31.5 to 46.2)
Week 76	55.3 (47.7 to 62.7)	42.5 (35.2 to 50.1)
Week 80	57.0 (49.4 to 64.3)	39.8 (32.6 to 47.3)
Week 84	57.0 (49.4 to 64.3)	43.1 (35.8 to 50.6)
Week 88	56.4 (48.8 to 63.8)	41.4 (34.2 to 49.0)
Week 92	57.0 (49.4 to 64.3)	45.9 (38.4 to 53.4)
Week 96	59.8 (52.2 to 67.0)	43.6 (36.3 to 51.2)
Week 100	62.0 (54.5 to 69.1)	47.0 (39.5 to 54.5)

CSFT thickness (<280 micrometers) at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[36]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

14.7

Confidence interval

level

95%

sides

2-sided

lower limit

4.2

upper limit

24.9

Notes
[36] - Treatment difference

CSFT thickness (<280 micrometers) at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[37]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

16.3

Confidence interval

level

95%

sides

2-sided

lower limit

5.7

upper limit

25.9

Notes
[37] - Treatment difference

Secondary: Percentage of patients with presence of Subretinal Fluid (SRF) in the study eye at each post-baseline visit

Top of page

End point title

Percentage of patients with presence of Subretinal Fluid (SRF) in the study eye at each post-baseline visit

End point description

Presence of Subretinal Fluid (SRF) in the study eye was assessed by spectral domain optical coherence tomography (SD-OCT), angiography, and/or color fundus photography. Subretinal fluid status assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

Week 4, Week 6, Week 8, Week 12, Week 16, Week 18, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, Week 52, Week 56, Week 60, Week 64, Week 68, Week 72, Week 76, Week 80, Week 84, Week 88, Week 92, Week 96, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	12.3 (7.9 to 18.0)	19.3 (13.9 to 25.9)
Week 6	10.1 (6.1 to 15.4)	13.8 (9.1 to 19.7)
Week 8	5.6 (2.7 to 10.0)	12.2 (7.8 to 17.8)
Week 12	3.9 (1.6 to 7.9)	7.7 (4.3 to 12.6)
Week 16	1.7 (0.3 to 4.8)	3.9 (1.6 to 7.8)
Week 18	2.2 (0.6 to 5.6)	2.2 (0.6 to 5.6)
Week 20	1.7 (0.3 to 4.8)	3.3 (1.2 to 7.1)
Week 24	2.2 (0.6 to 5.6)	6.6 (3.5 to 11.3)
Week 28	2.2 (0.6 to 5.6)	2.8 (0.9 to 6.3)
Week 32	5.0 (2.3 to 9.3)	3.9 (1.6 to 7.8)
Week 36	6.7 (3.5 to 11.4)	1.7 (0.3 to 4.8)
Week 40	4.5 (1.9 to 8.6)	2.8 (0.9 to 6.3)
Week 44	2.2 (0.6 to 5.6)	2.8 (0.9 to 6.3)
Week 48	6.1 (3.1 to 10.7)	5.0 (2.3 to 9.2)
Week 52	1.7 (0.3 to 4.8)	3.3 (1.2 to 7.1)
Week 56	2.8 (0.9 to 6.4)	2.2 (0.6 to 5.6)
Week 60	2.8 (0.9 to 6.4)	2.2 (0.6 to 5.6)
Week 64	2.2 (0.6 to 5.6)	3.9 (1.6 to 7.8)
Week 68	3.4 (1.2 to 7.2)	4.4 (1.9 to 8.5)
Week 72	3.4 (1.2 to 7.2)	2.8 (0.9 to 6.3)
Week 76	3.9 (1.6 to 7.9)	2.2 (0.6 to 5.6)
Week 80	4.5 (1.9 to 8.6)	2.2 (0.6 to 5.6)
Week 84	2.2 (0.6 to 5.6)	2.2 (0.6 to 5.6)
Week 88	3.4 (1.2 to 7.2)	2.2 (0.6 to 5.6)
Week 92	1.7 (0.3 to 4.8)	1.1 (0.1 to 3.9)
Week 96	2.2 (0.6 to 5.6)	2.8 (0.9 to 6.3)
Week 100	2.2 (0.6 to 5.6)	2.8 (0.9 to 6.3)

Subretinal Fluid (SRF) at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[38]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

2.1

Notes
[38] - Treatment Difference

Subretinal Fluid (SRF) at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[39]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

3.4

Notes
[39] - Treatment Difference

Secondary: Percentage of patients with presence of Intraretinal Fluid (IRF) in the study eye at each post-baseline visit

Top of page

End point title

Percentage of patients with presence of Intraretinal Fluid (IRF) in the study eye at each post-baseline visit

End point description

Presence of Intraretinal Fluid (IRF) in the study eye was assessed by spectral domain optical coherence tomography (SD-OCT), angiography, and/or color fundus photography. Intraretinal fluid status assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	88.3 (82.6 to 92.6)	89.0 (83.5 to 93.1)
Week 6	85.5 (79.4 to 90.3)	86.2 (80.3 to 90.9)
Week 8	87.2 (81.3 to 91.7)	84.5 (78.4 to 89.5)
Week 12	83.8 (77.6 to 88.9)	85.6 (79.7 to 90.4)
Week 16	76.0 (69.0 to 82.0)	84.0 (77.8 to 89.0)
Week 18	77.7 (70.8 to 83.5)	81.2 (74.8 to 86.6)
Week 20	72.6 (65.5 to 79.0)	79.6 (72.9 to 85.2)
Week 24	69.8 (62.5 to 76.5)	82.3 (76.0 to 87.6)
Week 28	67.6 (60.2 to 74.4)	75.1 (68.2 to 81.3)
Week 32	67.6 (60.2 to 74.4)	76.8 (70.0 to 82.7)
Week 36	73.2 (66.1 to 79.5)	72.4 (65.3 to 78.7)
Week 40	57.5 (49.9 to 64.9)	74.0 (67.0 to 80.3)
Week 44	56.4 (48.8 to 63.8)	71.3 (64.1 to 77.7)
Week 48	60.9 (53.3 to 68.1)	75.7 (68.8 to 81.7)
Week 52	53.6 (46.0 to 61.1)	72.9 (65.8 to 79.3)
Week 56	51.4 (43.8 to 58.9)	70.2 (62.9 to 76.7)
Week 60	55.3 (47.7 to 62.7)	69.1 (61.8 to 75.7)
Week 64	48.6 (41.1 to 56.2)	69.6 (62.4 to 76.2)
Week 68	47.5 (40.0 to 55.1)	66.9 (59.5 to 73.7)
Week 72	45.8 (38.4 to 53.4)	66.9 (59.5 to 73.7)
Week 76	50.3 (42.7 to 57.8)	63.0 (55.5 to 70.0)
Week 80	45.8 (38.4 to 53.4)	65.7 (58.3 to 72.6)
Week 84	40.2 (33.0 to 47.8)	63.0 (55.5 to 70.0)
Week 88	48.0 (40.5 to 55.6)	64.1 (56.6 to 71.1)
Week 92	44.7 (37.3 to 52.3)	59.1 (51.6 to 66.4)
Week 96	41.3 (34.0 to 48.9)	61.9 (54.4 to 69.0)
Week 100	40.8 (33.5 to 48.4)	56.9 (49.4 to 64.2)

Intraretinal Fluid (IRF) at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[40]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-16.1

Confidence interval

level

95%

sides

2-sided

lower limit

-26.3

upper limit

-5.7

Notes
[40] - Treatment Difference

Intraretinal Fluid (IRF) at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[41]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-19.1

Confidence interval

level

95%

sides

2-sided

lower limit

-28.9

upper limit

-9.2

Notes
[41] - Treatment Difference

Secondary: Percentage of patients with presence of Subretinal Fluid (SRF) and/or Intraretinal Fluid (IRF) in the study eye at each post-baseline visit

Top of page

End point title

Percentage of patients with presence of Subretinal Fluid (SRF) and/or Intraretinal Fluid (IRF) in the study eye at each post-baseline visit

End point description

Presence of Subretinal Fluid (SRF) and/or Intraretinal Fluid (IRF) in the study eye was assessed by spectral domain optical coherence tomography (SD-OCT), angiography, and/or color fundus photography. Fluid status (SRF and/or IRF) assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 4	90.5 (85.2 to 94.4)	90.6 (85.4 to 94.4)
Week 6	86.6 (80.7 to 91.2)	88.4 (82.8 to 92.7)
Week 8	87.2 (81.3 to 91.7)	85.6 (79.7 to 90.4)
Week 12	83.8 (77.6 to 88.9)	86.2 (80.3 to 90.9)
Week 16	76.0 (69.0 to 82.0)	84.0 (77.8 to 89.0)
Week 18	78.2 (71.4 to 84.0)	81.2 (74.8 to 86.6)
Week 20	73.2 (66.1 to 79.5)	79.6 (72.9 to 85.2)
Week 24	70.4 (63.1 to 77.0)	82.3 (76.0 to 87.6)
Week 28	68.7 (61.4 to 75.4)	75.1 (68.2 to 81.3)
Week 32	68.7 (61.4 to 75.4)	76.8 (70.0 to 82.7)
Week 36	73.7 (66.7 to 80.0)	72.4 (65.3 to 78.7)
Week 40	58.1 (50.5 to 65.4)	74.0 (67.0 to 80.3)
Week 44	57.0 (49.4 to 64.3)	71.3 (64.1 to 77.7)
Week 48	61.5 (53.9 to 68.6)	75.7 (68.8 to 81.7)
Week 52	54.2 (46.6 to 61.6)	72.9 (65.8 to 79.3)
Week 56	52.0 (44.4 to 59.5)	70.2 (62.9 to 76.7)
Week 60	55.3 (47.7 to 62.7)	69.1 (61.8 to 75.7)
Week 64	49.2 (41.6 to 56.7)	69.6 (62.4 to 76.2)
Week 68	48.0 (40.5 to 55.6)	68.0 (60.6 to 74.7)
Week 72	46.9 (39.4 to 54.5)	66.9 (59.5 to 73.7)
Week 76	50.8 (43.3 to 58.4)	63.0 (55.5 to 70.0)
Week 80	46.4 (38.9 to 54.0)	65.7 (58.3 to 72.6)
Week 84	40.8 (33.5 to 48.4)	63.0 (55.5 to 70.0)
Week 88	48.6 (41.1 to 56.2)	64.1 (56.6 to 71.1)
Week 92	45.3 (37.8 to 52.8)	59.1 (51.6 to 66.4)
Week 96	41.3 (34.0 to 48.9)	61.9 (54.4 to 69.0)
Week 100	40.8 (33.5 to 48.4)	56.9 (49.4 to 64.2)

SRF and/or IRF at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[42]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-18.4

Confidence interval

level

95%

sides

2-sided

lower limit

-28.5

upper limit

-8.3

Notes
[42] - Treatment Difference

SRF and/or IRF at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[43]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-16.2

Confidence interval

level

95%

sides

2-sided

lower limit

-26.4

upper limit

-5.9

Notes
[43] - Treatment difference

Secondary: Percentage of participants with presence of leakage on Fluorescein Angiography (FA) at Weeks 52 and 100

Top of page

End point title

Percentage of participants with presence of leakage on Fluorescein Angiography (FA) at Weeks 52 and 100

End point description

Presence of leakage on Fluorescein Angiography as assessed by fluorescein angiography. Leakage on FA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

Week 52, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 52	54.7 (47.2 to 62.2)	79.4 (72.8 to 85.1)
Week 100	46.9 (39.4 to 54.5)	65.6 (58.1 to 72.5)

Fluorescein Angiography (FA) at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[44]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-19.1

Confidence interval

level

95%

sides

2-sided

lower limit

-29.1

upper limit

-8.2

Notes
[44] - Treatment difference

Fluorescein Angiography (FA) at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[45]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-25.4

Confidence interval

level

95%

sides

2-sided

lower limit

-34.4

upper limit

-16.3

Notes
[45] - Treatment difference

Secondary: Percentage of Participants with with >=2-step improvement from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Top of page

End point title

Percentage of Participants with with >=2-step improvement from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

End point description

The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. DRSS assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 28	25.0 (18.8 to 32.1)	20.9 (15.2 to 27.6)
Week 52	29.0 (22.4 to 36.3)	27.7 (21.2 to 34.9)
Week 76	30.1 (23.4 to 37.5)	30.5 (23.8 to 37.9)
Week 100	35.8 (28.7 to 43.4)	31.1 (24.3 to 38.5)

>=2-step improvement in ETDRS-DRSS at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[46]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

10.8

Notes
[46] - Treatment difference

>=2-step improvement in ETDRS-DRSS at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[47]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.6

upper limit

7.8

Notes
[47] - Treatment difference

Secondary: Percentage of Participants with with >=3-step improvement from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Top of page

End point title

Percentage of Participants with with >=3-step improvement from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 28	13.1 (8.5 to 19.0)	11.3 (7.0 to 16.9)
Week 52	14.8 (9.9 to 20.9)	15.3 (10.3 to 21.4)
Week 76	18.8 (13.3 to 25.3)	15.3 (10.3 to 21.4)
Week 100	21.0 (15.3 to 27.8)	16.9 (11.7 to 23.3)

>=3-step improvement in ETDRS-DRSS at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[48]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

Notes
[48] - Treatment difference

>=3-step improvement in ETDRS-DRSS at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[49]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-7.1

upper limit

5.7

Notes
[49] - Treatment difference

Secondary: Percentage of Participants with with >=2-step worsening from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Top of page

End point title

Percentage of Participants with with >=2-step worsening from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

End point description

The Diabetic Retinopathy Disease Severity Scale was based on 7-field stereo color fundus photography and measured 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. DRSS assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 28	2.3 (0.6 to 5.7)	0.6 (0.0 to 3.1)
Week 52	1.7 (0.4 to 4.9)	0.6 (0.0 to 3.1)
Week 76	3.4 (1.3 to 7.3)	0.6 (0.0 to 3.1)
Week 100	4.5 (2.0 to 8.8)	1.7 (0.4 to 4.9)

>=2-step worsening in ETDRS-DRSS at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[50]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

6.9

Notes
[50] - Treatment difference

>=2-step worsening in ETDRS-DRSS at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[51]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

3.6

Notes
[51] - Treatment difference

Secondary: Percentage of Participants with with >=3-step worsening from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Top of page

End point title

Percentage of Participants with with >=3-step worsening from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)
Week 28	0.6 (0.0 to 3.1)	999 (999 to 999)
Week 52	0.6 (0.0 to 3.1)	999 (999 to 999)
Week 76	0.6 (0.0 to 3.1)	999 (999 to 999)
Week 100	0.6 (0.0 to 3.1)	1.1 (0.1 to 4.0)

>=3-step worsening in ETDRS-DRSS at Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[52]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.6

upper limit

1.3

Notes
[52] - Treatment difference

>=3-step worsening in ETDRS-DRSS at Week 52

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[53]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

2.1

Notes
[53] - Treatment difference

Secondary: Percentage of participants with progression to proliferative diabetic retinopathy (PDR) as assessed by ETDRS-DRSS Score of at least 61 by Week 100

Top of page

End point title

Percentage of participants with progression to proliferative diabetic retinopathy (PDR) as assessed by ETDRS-DRSS Score of at least 61 by Week 100

End point description

End point type

Secondary

End point timeframe

Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Percentage of Participants
number (confidence interval 95%)	0.6 (0.0 to 3.4)	0.6 (0.0 to 3.4)

PDR of at least 61 by Week 100

Comparison groups

Brolucizumab 6 mg v Aflibercept 2 mg

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

other ^[54]

Method

Parameter type

Clopper-Pearson exact method

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

1.9

Notes
[54] - Treatment difference

Secondary: Number of Participants with Ocular and Non-ocular Adverse Events (AEs)

Top of page

End point title

Number of Participants with Ocular and Non-ocular Adverse Events (AEs)

End point description

The number of participants with ocular and non-ocular adverse events was was assessed by CTCAE and reported categorically: Mild, Moderate, Severe.

End point type

Secondary

End point timeframe

From randomization till 30 days safety follow-up, assessed up to 35 months.

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Participants
Ocular adverse events\|Mild	52	47
Non-ocular adverse events\|Mild	52	51
Ocular adverse events\|Moderate	15	23
Non-ocular adverse events\|Moderate	51	50
Ocular adverse events\|Severe	6	4
Non-ocular adverse events\|Severe	33	40

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): composite score

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): composite score

End point description

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	5.7 ( 11.91 )	6.3 ( 10.19 )
Week 52	8.9 ( 11.67 )	6.7 ( 12.12 )
Week 76	9.8 ( 12.22 )	7.6 ( 11.81 )
Week 100	9.0 ( 12.94 )	6.2 ( 14.13 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - General Vision

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - General Vision

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	9.0 ( 16.11 )	10.2 ( 15.63 )
Week 52	11.2 ( 17.05 )	10.5 ( 17.14 )
Week 76	12.4 ( 16.49 )	12.0 ( 16.40 )
Week 100	12.0 ( 16.25 )	10.1 ( 18.73 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Ocular Pain

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Ocular Pain

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	4.1 ( 19.52 )	4.6 ( 18.48 )
Week 52	4.6 ( 18.75 )	4.4 ( 17.92 )
Week 76	6.2 ( 16.95 )	4.6 ( 18.68 )
Week 100	4.3 ( 16.60 )	5.4 ( 20.77 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Near Activities

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Near Activities

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	6.4 ( 20.83 )	6.3 ( 18.42 )
Week 52	10.5 ( 20.30 )	9.3 ( 19.57 )
Week 76	11.0 ( 21.91 )	9.2 ( 18.76 )
Week 100	13.0 ( 20.21 )	7.3 ( 21.71 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Distance Activities

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Distance Activities

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	6.2 ( 18.87 )	5.6 ( 15.78 )
Week 52	11.7 ( 17.62 )	8.2 ( 17.12 )
Week 76	12.1 ( 18.32 )	8.1 ( 16.71 )
Week 100	11.4 ( 18.94 )	6.6 ( 19.07 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Social Functioning

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Social Functioning

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	3.3 ( 15.82 )	4.4 ( 16.48 )
Week 52	7.1 ( 16.22 )	4.9 ( 15.59 )
Week 76	6.3 ( 16.65 )	5.0 ( 15.34 )
Week 100	6.1 ( 16.78 )	4.1 ( 17.55 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Mental Health

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End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Mental Health

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	7.9 ( 19.53 )	10.1 ( 19.90 )
Week 52	12.6 ( 22.42 )	10.1 ( 22.78 )
Week 76	13.5 ( 21.02 )	13.1 ( 23.10 )
Week 100	13.3 ( 20.91 )	11.6 ( 26.31 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Role Difficulties

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Role Difficulties

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	6.9 ( 25.13 )	9.4 ( 23.41 )
Week 52	12.2 ( 24.76 )	8.7 ( 27.21 )
Week 76	14.0 ( 28.44 )	11.4 ( 27.83 )
Week 100	12.3 ( 28.14 )	10.2 ( 27.12 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Dependency

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Dependency

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	5.5 ( 19.39 )	3.6 ( 20.34 )
Week 52	7.6 ( 19.53 )	3.9 ( 22.49 )
Week 76	7.3 ( 20.19 )	5.6 ( 23.24 )
Week 100	6.8 ( 19.85 )	2.9 ( 24.79 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Driving

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End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Driving

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	1.4 ( 18.75 )	4.8 ( 12.24 )
Week 52	6.4 ( 14.63 )	4.2 ( 12.81 )
Week 76	8.9 ( 15.95 )	2.8 ( 15.88 )
Week 100	5.4 ( 15.81 )	1.2 ( 16.75 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Color Vision

Top of page

End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Color Vision

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	3.5 ( 15.10 )	4.2 ( 12.50 )
Week 52	5.8 ( 15.08 )	3.6 ( 13.09 )
Week 76	5.2 ( 15.73 )	3.9 ( 13.79 )
Week 100	4.3 ( 14.70 )	3.2 ( 15.48 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Peripheral Vision

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End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - Peripheral Vision

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	5.3 ( 18.83 )	4.0 ( 16.99 )
Week 52	7.2 ( 18.68 )	3.2 ( 19.77 )
Week 76	9.3 ( 19.64 )	4.3 ( 17.82 )
Week 100	8.5 ( 19.33 )	2.3 ( 19.37 )

No statistical analyses for this end point

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): General Health Rating

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End point title

Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): General Health Rating

End point description

End point type

Secondary

End point timeframe

Baseline, Week 28, Week 52, Week 76, Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	181
Units: Score on a scale
arithmetic mean (standard deviation)
Week 28	3.9 ( 18.66 )	4.3 ( 19.92 )
Week 52	5.8 ( 22.34 )	4.8 ( 23.12 )
Week 76	8.9 ( 21.21 )	7.1 ( 22.57 )
Week 100	6.7 ( 19.14 )	5.7 ( 21.80 )

No statistical analyses for this end point

Secondary: Systemic brolucizumab concentration

Top of page

End point title

Systemic brolucizumab concentration

End point description

Serum samples were taken approximately 24 hours after the first dose and 24 hours after the treatment at Week 24 to confirm the systemic brolucizumab exposure in patients with visual impairment due to diabetic macular edema.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	0 ^[55]
Units: ng/mL
arithmetic mean (standard deviation)
Day 2	56.2 ( 10.4 )	( )
Week 4	0.760 ( 1.98 )	( )
Week 12	999 ( 999 )	( )
Week 24	999 ( 999 )	( )
Week 24 + 1 Day	41.5 ( 80.5 )	( )

Notes
[55] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: Distribution of integrated Anti-Drug Antibody (ADA) status in the brolucizumab arm

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End point title

Distribution of integrated Anti-Drug Antibody (ADA) status in the brolucizumab arm

End point description

Integrated ADA Status was categorized: ADA negative or ADA positive with no boost, Induced or Boosted, Missing ADA at pre-dose or no post-dose ADA data. - ADA negative: (a) ADA negative at all time points (pre-dose and post-dose), (b) ADA negative at pre-dose and no titer values above 40 at all other time points, (c) ADA titer of 40 at pre-dose but negative at all other time points. - ADA positive with no boost: ADA positive at pre-dose, post-dose titer values do not increase from pre-dose by more than 3-fold (1 dilution) at any time point. - Induced: ADA negative at pre-dose, post-dose titer value of 120 or more at any time point. - Boosted: ADA positive at pre-dose, post-dose titer values increase from pre-dose by more than 3-fold (1 dilution) at any time point.

End point type

Secondary

End point timeframe

Up to Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	0 ^[56]
Units: Participants
ADA negative or ADA positive with no boost	146
Induced or Boosted	27
Missing ADA at pre-dose or no post-dose ADA data	6

Notes
[56] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: Distribution of integrated Anti-Drug Antibody (ADA) status in the brolucizumab arm - adjusted for pre-existing ADA status

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End point title

Distribution of integrated Anti-Drug Antibody (ADA) status in the brolucizumab arm - adjusted for pre-existing ADA status

End point description

Integrated ADA Status - adjusted for pre-existing ADA status was categorized: ADA negative, ADA positive with no boost, Induced, Boosted. - ADA negative: (a) ADA negative at all time points (pre-dose and post-dose), (b) ADA negative at pre-dose and no titer values above 40 at all other time points, (c) ADA titer of 40 at pre-dose but negative at all other time points. - ADA positive with no boost: ADA positive at pre-dose, post-dose titer values do not increase from pre-dose by more than 3-fold (1 dilution) at any time point. - Induced: ADA negative at pre-dose, post-dose titer value of 120 or more at any time point. - Boosted: ADA positive at pre-dose, post-dose titer values increase from pre-dose by more than 3-fold (1 dilution) at any time point.

End point type

Secondary

End point timeframe

Up to Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	0 ^[57]
Units: Participants
ADA Negative and/or titer value of 40 at pre-dose	53
ADA positive with no boost and/or at pre-dose	93
Induced/ADA Negative at pre-dose	14
Boosted/ADA Positive at pre-dose	13

Notes
[57] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: Pre-existing ADA status and incidence of Adverse Event of Special Interest (AESI) in the study eye

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End point title

Pre-existing ADA status and incidence of Adverse Event of Special Interest (AESI) in the study eye

End point description

Pre-existing ADA status and incidence of Adverse Event of Special Interest (AESI) in the study eye was categorized: Negative, Positive.

End point type

Secondary

End point timeframe

Up to Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	0 ^[58]
Units: Participants
Negative\|At least 1 AESI	1
Postive\|At least 1 AESI	5
Negative\|No AESI	63
Postive\|No AESI	105

Notes
[58] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Secondary: Integrated ADA status up to Week 100 and incidence of Adverse Event of Special Interest (AESI) in the study eye.

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End point title

Integrated ADA status up to Week 100 and incidence of Adverse Event of Special Interest (AESI) in the study eye.

End point description

Integrated ADA status up to Week 100 and incidence of Adverse Event of Special Interest (AESI) in the study eye was categorized: ADA-negative or no boost, Induced or boosted.

End point type

Secondary

End point timeframe

Up to Week 100

End point values	Brolucizumab 6 mg	Aflibercept 2 mg
Number of subjects analysed	179	0 ^[59]
Units: Participants
ADA-negative or no boost\|At least 1 AESI	4
Induced or boosted\|At least 1 AESI	2
ADA-negative or no boost\|No AESI	142
Induced or boosted\|No AESI	25

Notes
[59] - Endpoint applicable to Brolucizumab treatment arm only

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study treatment up to 30 days after last dose (maximum 35 months)

Adverse event reporting additional description

Consistent with EudraCTdisclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Brolucizumab 6mg

Reporting group description

Brolucizumab 6mg

Reporting group title

Overall

Reporting group description

Overall

Reporting group title

Aflibercept 2mg

Reporting group description

Aflibercept 2mg

Serious adverse events	Brolucizumab 6mg	Overall	Aflibercept 2mg
Total subjects affected by serious adverse events
subjects affected / exposed	53 / 179 (29.61%)	113 / 360 (31.39%)	60 / 181 (33.15%)
number of deaths (all causes)	13	22	9
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign oesophageal neoplasm
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary neoplasm
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Cholangiocarcinoma
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Colon adenoma
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer stage I
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Hepatic cancer
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant neoplasm of unknown primary site
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastasis
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Neoplasm malignant
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian cancer
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Pleomorphic adenoma
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Waldenstrom's macroglobulinaemia
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arterial stenosis
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	1 / 179 (0.56%)	3 / 360 (0.83%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 3	0 / 2
Mass
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Breast hypoplasia
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postmenopausal haemorrhage
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoventilation
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Haemoglobin decreased
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fracture
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	2 / 179 (1.12%)	2 / 360 (0.56%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2
Cardiac failure
subjects affected / exposed	2 / 179 (1.12%)	6 / 360 (1.67%)	4 / 181 (2.21%)
occurrences causally related to treatment / all	0 / 3	0 / 10	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Cardiopulmonary failure
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 179 (0.56%)	3 / 360 (0.83%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	2 / 179 (1.12%)	3 / 360 (0.83%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 179 (0.00%)	3 / 360 (0.83%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 0	1 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Arachnoiditis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bickerstaff's encephalitis
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebellar haemorrhage
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebellar stroke
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 179 (1.12%)	4 / 360 (1.11%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 2	1 / 4	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Haemorrhagic stroke
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Headache
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemic coma
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Ischaemic stroke
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	1 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Microcytic anaemia
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Glaucoma - Study eye
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal artery occlusion - Study eye
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal detachment - Study eye
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal tear - Study eye
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uveitis - Fellow eye
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uveitis - Study eye
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vitreous haemorrhage - Fellow eye
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	2 / 179 (1.12%)	2 / 360 (0.56%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 179 (0.00%)	3 / 360 (0.83%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic nephropathy
subjects affected / exposed	1 / 179 (0.56%)	3 / 360 (0.83%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysuria
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephropathy
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Bone abscess
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	4 / 179 (2.23%)	7 / 360 (1.94%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0
COVID-19 pneumonia
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Endophthalmitis - Study eye
subjects affected / exposed	2 / 179 (1.12%)	3 / 360 (0.83%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	1 / 2	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fungal oesophagitis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	3 / 179 (1.68%)	5 / 360 (1.39%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ophthalmic herpes zoster - Study eye
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 179 (2.23%)	7 / 360 (1.94%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Pneumonia viral
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 179 (0.00%)	2 / 360 (0.56%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 179 (0.00%)	1 / 360 (0.28%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 179 (0.56%)	2 / 360 (0.56%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	1 / 179 (0.56%)	1 / 360 (0.28%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Brolucizumab 6mg	Overall	Aflibercept 2mg
Total subjects affected by non serious adverse events
subjects affected / exposed	131 / 179 (73.18%)	265 / 360 (73.61%)	134 / 181 (74.03%)
Vascular disorders
Hypertension
subjects affected / exposed	15 / 179 (8.38%)	32 / 360 (8.89%)	17 / 181 (9.39%)
occurrences all number	18	41	23
Peripheral arterial occlusive disease
subjects affected / exposed	4 / 179 (2.23%)	6 / 360 (1.67%)	2 / 181 (1.10%)
occurrences all number	4	6	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 179 (1.68%)	10 / 360 (2.78%)	7 / 181 (3.87%)
occurrences all number	3	10	7
Chest pain
subjects affected / exposed	4 / 179 (2.23%)	5 / 360 (1.39%)	1 / 181 (0.55%)
occurrences all number	5	6	1
Peripheral swelling
subjects affected / exposed	0 / 179 (0.00%)	4 / 360 (1.11%)	4 / 181 (2.21%)
occurrences all number	0	4	4
Oedema peripheral
subjects affected / exposed	4 / 179 (2.23%)	6 / 360 (1.67%)	2 / 181 (1.10%)
occurrences all number	4	6	2
Pyrexia
subjects affected / exposed	8 / 179 (4.47%)	13 / 360 (3.61%)	5 / 181 (2.76%)
occurrences all number	10	15	5
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	4 / 179 (2.23%)	7 / 360 (1.94%)	3 / 181 (1.66%)
occurrences all number	4	7	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 179 (2.79%)	15 / 360 (4.17%)	10 / 181 (5.52%)
occurrences all number	5	16	11
Investigations
Blood creatinine increased
subjects affected / exposed	8 / 179 (4.47%)	10 / 360 (2.78%)	2 / 181 (1.10%)
occurrences all number	8	10	2
Blood pressure increased
subjects affected / exposed	5 / 179 (2.79%)	9 / 360 (2.50%)	4 / 181 (2.21%)
occurrences all number	5	9	4
Blood triglycerides increased
subjects affected / exposed	2 / 179 (1.12%)	8 / 360 (2.22%)	6 / 181 (3.31%)
occurrences all number	2	8	6
Blood urea increased
subjects affected / exposed	3 / 179 (1.68%)	7 / 360 (1.94%)	4 / 181 (2.21%)
occurrences all number	3	7	4
Glycosylated haemoglobin increased
subjects affected / exposed	7 / 179 (3.91%)	12 / 360 (3.33%)	5 / 181 (2.76%)
occurrences all number	7	12	5
Intraocular pressure increased - Fellow eye
subjects affected / exposed	2 / 179 (1.12%)	7 / 360 (1.94%)	5 / 181 (2.76%)
occurrences all number	2	8	6
Intraocular pressure increased - Study eye
subjects affected / exposed	6 / 179 (3.35%)	10 / 360 (2.78%)	4 / 181 (2.21%)
occurrences all number	8	13	5
Protein urine present
subjects affected / exposed	4 / 179 (2.23%)	9 / 360 (2.50%)	5 / 181 (2.76%)
occurrences all number	4	10	6
White blood cells urine positive
subjects affected / exposed	1 / 179 (0.56%)	5 / 360 (1.39%)	4 / 181 (2.21%)
occurrences all number	1	6	5
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 179 (0.56%)	5 / 360 (1.39%)	4 / 181 (2.21%)
occurrences all number	1	6	5
Headache
subjects affected / exposed	8 / 179 (4.47%)	12 / 360 (3.33%)	4 / 181 (2.21%)
occurrences all number	10	14	4
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 179 (4.47%)	16 / 360 (4.44%)	8 / 181 (4.42%)
occurrences all number	8	17	9
Eye disorders
Blepharitis - Fellow eye
subjects affected / exposed	2 / 179 (1.12%)	7 / 360 (1.94%)	5 / 181 (2.76%)
occurrences all number	2	7	5
Blepharitis - Study eye
subjects affected / exposed	2 / 179 (1.12%)	6 / 360 (1.67%)	4 / 181 (2.21%)
occurrences all number	2	6	4
Cataract - Fellow eye
subjects affected / exposed	11 / 179 (6.15%)	27 / 360 (7.50%)	16 / 181 (8.84%)
occurrences all number	11	27	16
Cataract - Study eye
subjects affected / exposed	12 / 179 (6.70%)	31 / 360 (8.61%)	19 / 181 (10.50%)
occurrences all number	12	32	20
Conjunctival haemorrhage - Fellow eye
subjects affected / exposed	1 / 179 (0.56%)	10 / 360 (2.78%)	9 / 181 (4.97%)
occurrences all number	1	11	10
Conjunctival haemorrhage - Study eye
subjects affected / exposed	9 / 179 (5.03%)	15 / 360 (4.17%)	6 / 181 (3.31%)
occurrences all number	9	17	8
Diabetic retinal oedema - Fellow eye
subjects affected / exposed	18 / 179 (10.06%)	34 / 360 (9.44%)	16 / 181 (8.84%)
occurrences all number	18	35	17
Diabetic retinopathy - Fellow eye
subjects affected / exposed	5 / 179 (2.79%)	6 / 360 (1.67%)	1 / 181 (0.55%)
occurrences all number	5	6	1
Dry eye - Fellow eye
subjects affected / exposed	9 / 179 (5.03%)	16 / 360 (4.44%)	7 / 181 (3.87%)
occurrences all number	9	16	7
Dry eye - Study eye
subjects affected / exposed	9 / 179 (5.03%)	18 / 360 (5.00%)	9 / 181 (4.97%)
occurrences all number	9	18	9
Eye pain - Study eye
subjects affected / exposed	6 / 179 (3.35%)	10 / 360 (2.78%)	4 / 181 (2.21%)
occurrences all number	7	14	7
Eye pruritus - Fellow eye
subjects affected / exposed	5 / 179 (2.79%)	5 / 360 (1.39%)	0 / 181 (0.00%)
occurrences all number	5	5	0
Eye pruritus - Study eye
subjects affected / exposed	5 / 179 (2.79%)	5 / 360 (1.39%)	0 / 181 (0.00%)
occurrences all number	5	5	0
Macular fibrosis - Fellow eye
subjects affected / exposed	2 / 179 (1.12%)	6 / 360 (1.67%)	4 / 181 (2.21%)
occurrences all number	2	6	4
Macular oedema - Fellow eye
subjects affected / exposed	5 / 179 (2.79%)	8 / 360 (2.22%)	3 / 181 (1.66%)
occurrences all number	9	13	4
Vision blurred - Study eye
subjects affected / exposed	1 / 179 (0.56%)	6 / 360 (1.67%)	5 / 181 (2.76%)
occurrences all number	1	7	6
Vision blurred - Fellow eye
subjects affected / exposed	0 / 179 (0.00%)	4 / 360 (1.11%)	4 / 181 (2.21%)
occurrences all number	0	4	4
Visual acuity reduced - Fellow eye
subjects affected / exposed	4 / 179 (2.23%)	7 / 360 (1.94%)	3 / 181 (1.66%)
occurrences all number	5	11	6
Visual acuity reduced - Study eye
subjects affected / exposed	6 / 179 (3.35%)	12 / 360 (3.33%)	6 / 181 (3.31%)
occurrences all number	7	18	11
Vitreous floaters - Study eye
subjects affected / exposed	4 / 179 (2.23%)	8 / 360 (2.22%)	4 / 181 (2.21%)
occurrences all number	4	9	5
Vitreous haemorrhage - Fellow eye
subjects affected / exposed	5 / 179 (2.79%)	11 / 360 (3.06%)	6 / 181 (3.31%)
occurrences all number	5	15	10
Vitreous haemorrhage - Study eye
subjects affected / exposed	2 / 179 (1.12%)	6 / 360 (1.67%)	4 / 181 (2.21%)
occurrences all number	2	11	9
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	4 / 179 (2.23%)	6 / 360 (1.67%)	2 / 181 (1.10%)
occurrences all number	4	7	3
Diarrhoea
subjects affected / exposed	3 / 179 (1.68%)	10 / 360 (2.78%)	7 / 181 (3.87%)
occurrences all number	5	13	8
Nausea
subjects affected / exposed	5 / 179 (2.79%)	10 / 360 (2.78%)	5 / 181 (2.76%)
occurrences all number	6	11	5
Vomiting
subjects affected / exposed	0 / 179 (0.00%)	4 / 360 (1.11%)	4 / 181 (2.21%)
occurrences all number	0	4	4
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	4 / 179 (2.23%)	7 / 360 (1.94%)	3 / 181 (1.66%)
occurrences all number	4	7	3
Renal and urinary disorders
Chronic kidney disease
subjects affected / exposed	4 / 179 (2.23%)	8 / 360 (2.22%)	4 / 181 (2.21%)
occurrences all number	4	8	4
Diabetic nephropathy
subjects affected / exposed	5 / 179 (2.79%)	12 / 360 (3.33%)	7 / 181 (3.87%)
occurrences all number	5	12	7
Proteinuria
subjects affected / exposed	6 / 179 (3.35%)	19 / 360 (5.28%)	13 / 181 (7.18%)
occurrences all number	7	20	13
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 179 (2.23%)	10 / 360 (2.78%)	6 / 181 (3.31%)
occurrences all number	4	12	8
Back pain
subjects affected / exposed	7 / 179 (3.91%)	9 / 360 (2.50%)	2 / 181 (1.10%)
occurrences all number	7	9	2
Pain in extremity
subjects affected / exposed	0 / 179 (0.00%)	4 / 360 (1.11%)	4 / 181 (2.21%)
occurrences all number	0	4	4
Infections and infestations
Bronchitis
subjects affected / exposed	7 / 179 (3.91%)	12 / 360 (3.33%)	5 / 181 (2.76%)
occurrences all number	7	13	6
COVID-19
subjects affected / exposed	3 / 179 (1.68%)	7 / 360 (1.94%)	4 / 181 (2.21%)
occurrences all number	3	7	4
Conjunctivitis - Fellow eye
subjects affected / exposed	4 / 179 (2.23%)	6 / 360 (1.67%)	2 / 181 (1.10%)
occurrences all number	4	6	2
Conjunctivitis - Study eye
subjects affected / exposed	6 / 179 (3.35%)	7 / 360 (1.94%)	1 / 181 (0.55%)
occurrences all number	6	7	1
Gastroenteritis
subjects affected / exposed	4 / 179 (2.23%)	4 / 360 (1.11%)	0 / 181 (0.00%)
occurrences all number	4	4	0
Herpes zoster
subjects affected / exposed	2 / 179 (1.12%)	7 / 360 (1.94%)	5 / 181 (2.76%)
occurrences all number	2	7	5
Influenza
subjects affected / exposed	7 / 179 (3.91%)	11 / 360 (3.06%)	4 / 181 (2.21%)
occurrences all number	8	18	10
Nasopharyngitis
subjects affected / exposed	16 / 179 (8.94%)	33 / 360 (9.17%)	17 / 181 (9.39%)
occurrences all number	20	42	22
Pulpitis dental
subjects affected / exposed	2 / 179 (1.12%)	6 / 360 (1.67%)	4 / 181 (2.21%)
occurrences all number	2	6	4
Rhinitis
subjects affected / exposed	2 / 179 (1.12%)	6 / 360 (1.67%)	4 / 181 (2.21%)
occurrences all number	3	8	5
Upper respiratory tract infection
subjects affected / exposed	5 / 179 (2.79%)	8 / 360 (2.22%)	3 / 181 (1.66%)
occurrences all number	5	8	3
Urinary tract infection
subjects affected / exposed	5 / 179 (2.79%)	9 / 360 (2.50%)	4 / 181 (2.21%)
occurrences all number	7	12	5
Metabolism and nutrition disorders
Gout
subjects affected / exposed	1 / 179 (0.56%)	8 / 360 (2.22%)	7 / 181 (3.87%)
occurrences all number	1	12	11
Hyperlipidaemia
subjects affected / exposed	8 / 179 (4.47%)	10 / 360 (2.78%)	2 / 181 (1.10%)
occurrences all number	8	10	2

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Were there any global substantial amendments to the protocol? Yes

18 May 2018

Amendment No. 1: ● Definition of “personal data” was added and “withdrawal of study consent (WOC)” was updated. ● Added clarification on the framework of analysis on study information collected from withdrawn subjects. ● The PK of aflibercept was removed from testing and analysis, as the pharmacokinetics data for aflibercept has been available. The PK samples are collected at approximately 24 hours after first dose and the treatment at Week 24. ● Inclusion criteria no. 5 was revised to allow enrollment of subjects with central subfield retinal thickness cutoff value on SDOCT of ≥ 320 μm instead ≥ 340 μm. ● The assessment schedule table was corrected according to protocol body text and adjustment of appearance for clarity. ● The contraception requirement specified in exclusion criteria no. 26 was extended from 40 days to 3 months after last dose, for consistency with the approved label of comparator in EU and US. ● Other minor corrections and clarifications.

11 Jun 2020

Amendment No. 2: ● Changes in relation to emerging safety issue are: ● Information was added to describe a new safety signal from post-marketing case reports. ● Additional guidance was added emphasizing that if any sign of intraocular inflammation is present, an IVT injection must not be performed and subjects should be treated for intraocular inflammation according to clinical practice. ● Additional examination and assessments included to fully characterize cases of intraocular inflammation were made. ● Modifications were made to include importance of Estimands per ICH E9(R1) guidance ● Changes were incorporated to address the COVID-19 pandemic ● Other changes incorporated in this amendment: ● Three endpoints were moved from Secondary to Exploratory ● Aflibercept was removed from ADA and systemic exposure ● Clarifications were added regarding unmasked investigator/site personnel, injection procedure, IOP measurement procedure, and SAE reporting period.

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 for complete trial results.

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Clinical trials

Clinical Trial Results: A Two-Year, Two-Arm, Randomized, Double Masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in Adult Patients with Visual Impairment due to Diabetic Macular Edema

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean change from Baseline in best-corrected visual acuity (BCVA) at Week 52 for the study eye

Primary: Mean change from Baseline in best-corrected visual acuity (BCVA) at Week 52 for the study eye

Secondary: Average mean change from Baseline in BCVA over the period Week 40 through Week 52 for the study eye

Secondary: Average mean change from Baseline in BCVA over the period Week 40 through Week 52 for the study eye

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w up to Week 52 and up to q12w/q16w up to Week 100.

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w up to Week 52 and up to q12w/q16w up to Week 100.

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w up to Week 52 within those patients that qualified for q12w at Week 36

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w up to Week 52 within those patients that qualified for q12w at Week 36

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w/q16w up to Week 100, within those patients that qualified for q12w at Week 36

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained at q12w/q16w up to Week 100, within those patients that qualified for q12w at Week 36

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained on q16w up to Week 100 within the patients on q12w at Week 68 and on q16w at Week 76

Secondary: (Brolucizumab treatment arm only): Percentage of participants maintained on q16w up to Week 100 within the patients on q12w at Week 68 and on q16w at Week 76

Secondary: (Brolucizumab treatment arm only): Percentage of participants re-assigned and maintained on q12w up to Week 100 within the patients on q8w at Week 68 and on q12w at Week 80

Secondary: (Brolucizumab treatment arm only): Percentage of participants re-assigned and maintained on q12w up to Week 100 within the patients on q8w at Week 68 and on q12w at Week 80

Secondary: (Brolucizumab treatment arm only): Number of participants with injections per planned dosing regimen (every 8, 12 or 16 weeks)

Secondary: (Brolucizumab treatment arm only): Number of participants with injections per planned dosing regimen (every 8, 12 or 16 weeks)

Secondary: Mean change from Baseline in Best Corrected Visual Acuity (BCVA) at each visit up to Week 100 for the study eye

Secondary: Mean change from Baseline in Best Corrected Visual Acuity (BCVA) at each visit up to Week 100 for the study eye

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 4 to Week 52/100 for the study eye

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 4 to Week 52/100 for the study eye

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 20 to Week 52/100 and Week 28 to Week 52/100 for the study eye

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 20 to Week 52/100 and Week 28 to Week 52/100 for the study eye

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 88 to 100 for the study eye

Secondary: Average mean change from Baseline in Best Corrected Visual Acuity (BCVA) over the period Week 88 to 100 for the study eye

Secondary: Percentage of participants who gained >= 5 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

Secondary: Percentage of participants who gained >= 5 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

Secondary: Percentage of participants who gained >= 10 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

Secondary: Percentage of participants who gained >= 10 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

Secondary: Percentage of participants who gained >= 15 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

Secondary: Percentage of participants who gained >= 15 letters in BCVA from Baseline or reached BCVA >= 84 letters at each post-baseline visit for the study eye

Secondary: Percentage of participants who lost >= 5 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

Secondary: Percentage of participants who lost >= 5 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

Secondary: Percentage of participants who lost >= 10 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

Secondary: Percentage of participants who lost >= 10 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

Secondary: Percentage of participants who lost >= 15 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

Secondary: Percentage of participants who lost >= 15 ETDRS letters in Best Corrected Visual Acuity (BCVA) from Baseline at each post-baseline visit for the study eye

Secondary: Percentage of participants with an Absolute Best Corrected Visual Acuity (BCVA) >= 73 ETDRS letters at each post-baseline visit for the study eye

Secondary: Percentage of participants with an Absolute Best Corrected Visual Acuity (BCVA) >= 73 ETDRS letters at each post-baseline visit for the study eye

Secondary: Mean change from Baseline in Central Subfield Thickness (CSFT) at each post-baseline visit for the study eye

Secondary: Mean change from Baseline in Central Subfield Thickness (CSFT) at each post-baseline visit for the study eye

Secondary: Average mean change from Baseline in Central Subfield Thickness (CSFT) over the period Week 40 through Week 52 / Week 88 through Week 100 for the study eye

Secondary: Average mean change from Baseline in Central Subfield Thickness (CSFT) over the period Week 40 through Week 52 / Week 88 through Week 100 for the study eye

Secondary: Average mean change from baseline in CSFT over the period Week 4 to Week 52 / 100 for the study eye

Secondary: Average mean change from baseline in CSFT over the period Week 4 to Week 52 / 100 for the study eye

Secondary: Percentage of participants with normal CSFT thickness (<280 micrometers) at each post-baseline visit for the study eye

Secondary: Percentage of participants with normal CSFT thickness (<280 micrometers) at each post-baseline visit for the study eye

Secondary: Percentage of patients with presence of Subretinal Fluid (SRF) in the study eye at each post-baseline visit

Secondary: Percentage of patients with presence of Subretinal Fluid (SRF) in the study eye at each post-baseline visit

Secondary: Percentage of patients with presence of Intraretinal Fluid (IRF) in the study eye at each post-baseline visit

Secondary: Percentage of patients with presence of Intraretinal Fluid (IRF) in the study eye at each post-baseline visit

Secondary: Percentage of patients with presence of Subretinal Fluid (SRF) and/or Intraretinal Fluid (IRF) in the study eye at each post-baseline visit

Secondary: Percentage of patients with presence of Subretinal Fluid (SRF) and/or Intraretinal Fluid (IRF) in the study eye at each post-baseline visit

Secondary: Percentage of participants with presence of leakage on Fluorescein Angiography (FA) at Weeks 52 and 100

Secondary: Percentage of participants with presence of leakage on Fluorescein Angiography (FA) at Weeks 52 and 100

Secondary: Percentage of Participants with with >=2-step improvement from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Secondary: Percentage of Participants with with >=2-step improvement from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Secondary: Percentage of Participants with with >=3-step improvement from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Secondary: Percentage of Participants with with >=3-step improvement from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Secondary: Percentage of Participants with with >=2-step worsening from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Secondary: Percentage of Participants with with >=2-step worsening from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Secondary: Percentage of Participants with with >=3-step worsening from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Secondary: Percentage of Participants with with >=3-step worsening from Baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score

Secondary: Percentage of participants with progression to proliferative diabetic retinopathy (PDR) as assessed by ETDRS-DRSS Score of at least 61 by Week 100

Secondary: Percentage of participants with progression to proliferative diabetic retinopathy (PDR) as assessed by ETDRS-DRSS Score of at least 61 by Week 100

Secondary: Number of Participants with Ocular and Non-ocular Adverse Events (AEs)

Secondary: Number of Participants with Ocular and Non-ocular Adverse Events (AEs)

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): composite score

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): composite score

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - General Vision

Secondary: Change from Baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): subscale score - General Vision

Clinical Trial Results:
A Two-Year, Two-Arm, Randomized, Double Masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in Adult Patients with Visual Impairment due to Diabetic Macular Edema