KINGFISHER: Efficacy and Safety of Brolucizumab vs Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03917472
• Collaborator: (none)
• Enrollment: 517
• Locations: 92
• Arms: 2
• Actual Duration (Months): 20.2
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the efficacy and safety of brolucizumab vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: Brolucizumab; Drug: Aflibercept	Phase 3

Detailed Description

This study was designed as a Phase III, multi-center, randomized, double-masked, active controlled, parallel group prospective study to evaluate if brolucizumab 6 mg dosed q4w is safe and effective in the treatment of subjects with visual impairment due to diabetic macular edema (DME). Subjects who met all the inclusion and none of the exclusion criteria were randomized in a 2:1 ratio to one of two treatment arms i.e., brolucizumab 6 mg and aflibercept 2 mg. Only one eye was selected as study eye and treated with study medication.

The study included a screening period of up to 2 weeks to assess eligibility, followed by a double-masked treatment period (Day 1 to Week 48). For all subjects, the last study assessment was performed at the Week 52/end of study (EOS) visit. All subjects had study visits q4w through Week 52. The primary analysis was performed at the EOS visit (Week 52).

To ensure masking was maintained, the investigational site had both masked and unmasked staff to perform the masked and unmasked study assessments/procedures accordingly.

Study Design

• Study Type: Interventional
• Actual Enrollment: 517 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: A masked evaluating investigator will be responsible for all aspects of the study except the injections and the safety assessment following the injections. An unmasked treating investigator was to perform the injections and assess patient safety following the injections.
• Primary Purpose: Treatment
• Official Title: A 12-Month, 2-Arm, Randomized, Double-Masked, Multicenter Phase III Study Assessing the Efficacy and Safety of Brolucizumab vs. Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema (KINGFISHER)
• Actual Study Start Date: Jul 17, 2019
• Actual Primary Completion Date: Mar 24, 2021
• Actual Study Completion Date: Mar 24, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Brolucizumab 6mg q4w Brolucizumab 6 mg/0.05 mL every 4 weeks.	Drug: Brolucizumab; Intravitreal injection; Other Names: RTH258, ESBA1008
Active Comparator: Aflibercept 2mg q4w Aflibercept 2mg/0.05 mL every 4 weeks	Drug: Aflibercept; Intravitreal injection; Other Names: Eylea

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52 [Baseline, Week 52]

   BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning. Last observation carried forward (LOCF) was used for the imputation of missing values.

Secondary Outcome Measures

1. Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit [Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52]

   Central Subfield Thickness assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.

2. Number and Percentage of Participants With Fluid-free Macula in the Study Eye at Each Post-baseline Visit [Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52]

   Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with simultaneous absence of SRF and IRF in the study eye by visit. Events and censoring after 52 weeks are included in week 52 row.

3. Number and Percentage of Participants With Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) at Each Post-baseline Visit for the Study Eye [Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52]

   Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.

4. Time to First Fluid-free Macula - Time-to-first Absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the Study Eye - Number of Subjects With Absence of SRF / IRF and Number of Subjects Censored by Visit [Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52]

   Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.

5. Time to First Fluid-free Macula - Time-to-first Absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the Study Eye - Kaplan-Meier Analysis - Probability of Absence of SRF/IRF by Visit [Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52]

   Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.

6. Time to First Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the Study Eye at Each Post-baseline Visit - Number of Subjects With Probability of Absence of DME and Number Censored by Visit [Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52]

   Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.

7. Time to First Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the Study Eye at Each Post-baseline Visit - Kaplan-Meier Analysis - Probability of Absence of DME by Visit [Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52]

   Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.

8. Best Corrected Visual Acuity (Letters Read): Change From Baseline in Best-corrected Visual Acuity (BCVA) at Each Post-baseline Visit for the Study Eye [Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52]

   BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.

9. Gain in Best-corrected Visual Acuity (BCVA) (Letters Read): Number (%) of Subjects Who Gained ≥ 5, 10, or 15 Letters in BCVA From Baseline or Reached BCVA ≥ 84 Letters in the Study Eye at Week 52 [Baseline, Week 52]

   BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.

10. Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=2-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye [Baseline, Weeks 12, 24 and 52]

    The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment". A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.

11. Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=3-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye [Baseline, Weeks 12, 24 and 52]

    The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment". A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.

12. Anti-Drug Antibody (ADA): Frequency Distribution of Pre-existing ADA Status in the Brolucizumab Arm [Baseline]

13. Ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm) by Preferred Term in the Study Eye [Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.]

14. Number of Subjects With Non-ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm) [Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent must be obtained prior to participation in the study.

• Patients with type 1 or type 2 diabetes mellitus (DM) and Hemoglobin A1c (HbA1c) ≤ 12% at screening.

• Study eye: Visual impairment due to DME with:

• Best-corrected visual acuity (BCVA) score between 73 and 23 letters, inclusive, using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters

• DME involving the center of the macula, with Central Subfield Thickness (CSFT) ≥ 320 µm on Spectral Domain Optical Coherence Tomography (SD-OCT)

Exclusion Criteria:

• High-risk proliferative diabetic retinopathy (PDR) in the study eye

• Concomitant conditions or ocular disorders in the study eye which confound interpretation of study results, compromise visual acuity or require medical or surgical intervention

• Any active intraocular or periocular infection or active intraocular inflammation in the either eye

• Uncontrolled glaucoma in the study eye

• Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA <20/200

• Use of anti-VEGF therapies, intraocular surgery or laser photocoagulation (macular or panretinal) in the study eye during the 3-month period prior to baseline

• Use of intraocular or periocular corticosteroids in the study eye during the 6-month period prior to baseline, and use of fluocinolone acetonide intravitreal (IVT) implant (Iluvien) at any time prior to baseline

• Prior investigational drugs in either eye, vitreoretinal surgery in the study eye at any time prior to baseline

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Phoenix	Arizona	United States	85016
2	Novartis Investigative Site	Phoenix	Arizona	United States	85053
3	Novartis Investigative Site	Tucson	Arizona	United States	85704-5614
4	Novartis Investigative Site	Beverly Hills	California	United States	90211
5	Novartis Investigative Site	Campbell	California	United States	95008
6	Novartis Investigative Site	Fresno	California	United States	93720
7	Novartis Investigative Site	Huntington Beach	California	United States	92647
8	Novartis Investigative Site	Loma Linda	California	United States	92354
9	Novartis Investigative Site	Mountain View	California	United States	94040
10	Novartis Investigative Site	Oakland	California	United States	94609
11	Novartis Investigative Site	Pasadena	California	United States	91107
12	Novartis Investigative Site	Poway	California	United States	92064
13	Novartis Investigative Site	Rancho Cordova	California	United States	95670
14	Novartis Investigative Site	Redlands	California	United States	92374
15	Novartis Investigative Site	Riverside	California	United States	92505
16	Novartis Investigative Site	Sacramento	California	United States	95817
17	Novartis Investigative Site	Sacramento	California	United States	95841
18	Novartis Investigative Site	San Francisco	California	United States	94107
19	Novartis Investigative Site	Santa Ana	California	United States	92705
20	Novartis Investigative Site	Santa Barbara	California	United States	93103
21	Novartis Investigative Site	Torrance	California	United States	90509-2910
22	Novartis Investigative Site	Ventura	California	United States	93003
23	Novartis Investigative Site	Altamonte Springs	Florida	United States	32701
24	Novartis Investigative Site	Deerfield Beach	Florida	United States	33064
25	Novartis Investigative Site	Fort Lauderdale	Florida	United States	33309
26	Novartis Investigative Site	Fort Myers	Florida	United States	33912-7125
27	Novartis Investigative Site	Orlando	Florida	United States	32804
28	Novartis Investigative Site	Pinellas Park	Florida	United States	33782
29	Novartis Investigative Site	Saint Petersburg	Florida	United States	33711
30	Novartis Investigative Site	Tampa	Florida	United States	33609
31	Novartis Investigative Site	Atlanta	Georgia	United States	30342
32	Novartis Investigative Site	Marietta	Georgia	United States	30060
33	Novartis Investigative Site	'Aiea	Hawaii	United States	96701
34	Novartis Investigative Site	Bloomington	Illinois	United States	61704
35	Novartis Investigative Site	Oak Forest	Illinois	United States	60452
36	Novartis Investigative Site	Springfield	Illinois	United States	62704
37	Novartis Investigative Site	Indianapolis	Indiana	United States	46280
38	Novartis Investigative Site	New Albany	Indiana	United States	47150
39	Novartis Investigative Site	West Des Moines	Iowa	United States	50266
40	Novartis Investigative Site	Leawood	Kansas	United States	66211
41	Novartis Investigative Site	Lenexa	Kansas	United States	66215
42	Novartis Investigative Site	Hagerstown	Maryland	United States	21740
43	Novartis Investigative Site	Boston	Massachusetts	United States	02114
44	Novartis Investigative Site	Royal Oak	Michigan	United States	48073
45	Novartis Investigative Site	Minneapolis	Minnesota	United States	55435
46	Novartis Investigative Site	Kansas City	Missouri	United States	64133
47	Novartis Investigative Site	Reno	Nevada	United States	89502
48	Novartis Investigative Site	Bloomfield	New Jersey	United States	07003
49	Novartis Investigative Site	Teaneck	New Jersey	United States	07666
50	Novartis Investigative Site	Rochester	New York	United States	14620
51	Novartis Investigative Site	Hickory	North Carolina	United States	28602
52	Novartis Investigative Site	Southern Pines	North Carolina	United States	28387
53	Novartis Investigative Site	Cleveland	Ohio	United States	44122
54	Novartis Investigative Site	Columbus	Ohio	United States	43210
55	Novartis Investigative Site	Dublin	Ohio	United States	43016
56	Novartis Investigative Site	Eugene	Oregon	United States	97401
57	Novartis Investigative Site	Kingston	Pennsylvania	United States	95403
58	Novartis Investigative Site	Chattanooga	Tennessee	United States	37421
59	Novartis Investigative Site	Germantown	Tennessee	United States	38138
60	Novartis Investigative Site	Abilene	Texas	United States	79606
61	Novartis Investigative Site	Austin	Texas	United States	78705
62	Novartis Investigative Site	Austin	Texas	United States	78731
63	Novartis Investigative Site	Austin	Texas	United States	78750
64	Novartis Investigative Site	Bellaire	Texas	United States	77401
65	Novartis Investigative Site	Dallas	Texas	United States	75231
66	Novartis Investigative Site	Fort Worth	Texas	United States	76104
67	Novartis Investigative Site	Harlingen	Texas	United States	78550
68	Novartis Investigative Site	Houston	Texas	United States	77025
69	Novartis Investigative Site	Houston	Texas	United States	77030
70	Novartis Investigative Site	San Antonio	Texas	United States	78240
71	Novartis Investigative Site	Southlake	Texas	United States	76092
72	Novartis Investigative Site	Norfolk	Virginia	United States	23502
73	Novartis Investigative Site	Morgantown	West Virginia	United States	26506
74	Novartis Investigative Site	Madison	Wisconsin	United States	53705-3611
75	Novartis Investigative Site	Pecs	Baranya	Hungary	7621
76	Novartis Investigative Site	Zalaegerszeg	Zala	Hungary	8900
77	Novartis Investigative Site	Budapest		Hungary	1083
78	Novartis Investigative Site	Debrecen		Hungary	4032
79	Novartis Investigative Site	Szeged		Hungary	H 6725
80	Novartis Investigative Site	Haifa		Israel	3339419
81	Novartis Investigative Site	Haifa		Israel	3436212
82	Novartis Investigative Site	Kfar Saba		Israel	4428164
83	Novartis Investigative Site	Petach Tikva		Israel	4941492
84	Novartis Investigative Site	Tel Aviv		Israel	6789140
85	Novartis Investigative Site	Arecibo		Puerto Rico	00612
86	Novartis Investigative Site	Banska Bystrica		Slovakia	97517
87	Novartis Investigative Site	Bratislava		Slovakia	82606
88	Novartis Investigative Site	Bratislava		Slovakia	85107
89	Novartis Investigative Site	Poprad		Slovakia	058 45
90	Novartis Investigative Site	Trebisov		Slovakia	075 01
91	Novartis Investigative Site	Trencin		Slovakia	91171
92	Novartis Investigative Site	Zvolen		Slovakia	960 01

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jun 8, 2020
• Statistical Analysis Plan - Jun 28, 2021

More Information

Additional Information:

• A Plain Language Trial Summary is available on novctrd.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03917472
• Other Study ID Numbers: CRTH258B2305; 2019-001004-37
• First Posted: Apr 17, 2019
• Last Update Posted: Aug 12, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Diabetic Macular Edema; intravitreal injection; brolucizumab; aflibercept; double-masked; Diabetic Macular edema (DME); macular edema; diabetic retinopathy
• Additional relevant MeSH terms: Vision Disorders; Vision, Low; Macular Edema; Edema; Aflibercept

Study Results

Participant Flow

Recruitment Details	Study centers (no. of sites): Hungary (5), Israel (5), Slovakia (7), United States (78). Approximately, 495 subjects were planned to be randomized. Overall, 517 subjects were randomized either to brolucizumab 6 mg q4w arm (n=346) or aflibercept 2 mg q4w arm (n=171).
Pre-assignment Detail	The study included a screening period of up to 2 weeks to assess eligibility, followed by a double-masked treatment period (Day 1 to Week 48). For all subjects, the last study assessment was performed at the Week 52/end of study (EOS) visit. All subjects had study visits q4w through Week 52. The primary analysis was performed at the EOS visit (Week 52).

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Period Title: Overall Study
STARTED	346	171
COMPLETED	311	156
NOT COMPLETED	35	15

Baseline Characteristics

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w	Total
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks	Total of all reporting groups
Overall Participants	346	171	517
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	208 60.1%	115 67.3%	323 62.5%
>=65 years	138 39.9%	56 32.7%	194 37.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.9 (10.59)	60.2 (9.31)	60.7 (10.18)
Sex: Female, Male (Count of Participants)
Female	152 43.9%	66 38.6%	218 42.2%
Male	194 56.1%	105 61.4%	299 57.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.6%	1 0.2%
Asian	14 4%	7 4.1%	21 4.1%
Native Hawaiian or Other Pacific Islander	1 0.3%	0 0%	1 0.2%
Black or African American	40 11.6%	15 8.8%	55 10.6%
White	288 83.2%	145 84.8%	433 83.8%
More than one race	2 0.6%	0 0%	2 0.4%
Unknown or Not Reported	1 0.3%	3 1.8%	4 0.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52
Description	BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning. Last observation carried forward (LOCF) was used for the imputation of missing values.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - Last observation carried forward (LOCF)

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	12.2	11.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Superiority
	Comments	(1-sided)
Statistical Test of Hypothesis	p-Value	0.099
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -0.6 to 2.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.89
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	(4-letter margin) (1-sided)
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit
Description	Central Subfield Thickness assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
Time Frame	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - Last observation carried forward (LOCF)

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Week 4	-146.9	-119.5
Week 8	-174.4	-144.1
Week 12	-191.3	-156.7
Week 16	-200.5	-162.4
Week 20	-209.5	-168.7
Week 24	-217.5	-178.8
Week 28	-222.4	-183.6
Week 32	-227.2	-185.9
Week 36	-229.7	-186.7
Week 40	-233.6	-188.4
Week 44	-237.5	-188.1
Week 48	-237.7	-192.0
Week 52	-237.8	-196.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Superiority
	Comments	(1-sided); Week 52
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-41.4
	Confidence Interval	(2-Sided) 95%; -58.9 to -23.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.94
	Estimation Comments

3. Secondary Outcome

Title	Number and Percentage of Participants With Fluid-free Macula in the Study Eye at Each Post-baseline Visit
Description	Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with simultaneous absence of SRF and IRF in the study eye by visit. Events and censoring after 52 weeks are included in week 52 row.
Time Frame	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - Last observation carried forward (LOCF).

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Week 4	23 6.6%	4 2.3%
Week 8	31 9%	4 2.3%
Week 12	38 11%	10 5.8%
Week 16	48 13.9%	11 6.4%
Week 20	54 15.6%	9 5.3%
Week 24	84 24.3%	19 11.1%
Week 28	65 18.8%	13 7.6%
Week 32	76 22%	17 9.9%
Week 36	91 26.3%	21 12.3%
Week 40	96 27.7%	23 13.5%
Week 44	96 27.7%	20 11.7%
week 48	92 26.6%	23 13.5%
Week 52	144 41.6%	38 22.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Superiority
	Comments	(1-sided) Week 52
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Clopper-Pearson exact method.
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	20.0
	Confidence Interval	(2-Sided) 95%; 12.5 to 28.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number and Percentage of Participants With Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) at Each Post-baseline Visit for the Study Eye
Description	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
Time Frame	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - Last observation carried forward (LOCF)

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Week 4	61 17.6%	9 5.3%
Week 8	93 26.9%	24 14%
Week 12	124 35.8%	33 19.3%
Week 16	147 42.5%	42 24.6%
Week 20	167 48.3%	47 27.5%
Week 24	177 51.2%	52 30.4%
Week 28	186 53.8%	57 33.3%
Week 32	195 56.4%	62 36.3%
Week 36	206 59.5%	63 36.8%
Week 40	211 61%	65 38%
Week 44	216 62.4%	69 40.4%
Week 48	222 64.2%	68 39.8%
Week 52	229 66.2%	71 41.5%

5. Secondary Outcome

Title	Time to First Fluid-free Macula - Time-to-first Absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the Study Eye - Number of Subjects With Absence of SRF / IRF and Number of Subjects Censored by Visit
Description	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
Time Frame	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment.

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	344	170
Number of subjects with absence of SRF / IRF at Week 0 (n=344,170)	0 0%	0 0%
Number of subjects with absence of SRF / IRF at Week 4 (n=344,170)	6 1.7%	1 0.6%
Number of subjects with absence of SRF / IRF at Week 8 (n=335,168)	18 5.2%	3 1.8%
Number of subjects with absence of SRF / IRF at Week 12 (n=314, 165)	13 3.8%	2 1.2%
Number of subjects with absence of SRF / IRF at Week 16 (n=297, 161)	17 4.9%	4 2.3%
Number of subjects with absence of SRF / IRF at Week 20 (n=277, 156)	8 2.3%	6 3.5%
Number of subjects with absence of SRF / IRF at Week 24 (n=265,150)	16 4.6%	2 1.2%
Number of subjects with absence of SRF / IRF at Week 28 (n=246,146)	18 5.2%	7 4.1%
Number of subjects with absence of SRF / IRF at Week 32 (n=224,139)	3 0.9%	1 0.6%
Number of subjects with absence of SRF / IRF at Week 36 (n=220,138)	8 2.3%	2 1.2%
Number of subjects with absence of SRF / IRF at Week 40 (n=211, 134)	16 4.6%	4 2.3%
Number of subjects with absence of SRF / IRF at Week 44 (194, 129)	11 3.2%	2 1.2%
Number of subjects with absence of SRF / IRF at Week 48 (n=181, 125)	3 0.9%	0 0%
Number of subjects with absence of SRF / IRF at Week 52 (n=177, 122)	30 8.7%	12 7%
Number of subjects censored at Week 0 (n=344, 170)	0 0%	0 0%
Number of subjects censored at Week 4 (n-344, 170)	3 0.9%	1 0.6%
Number of subjects censored at Week 8 (n=335,168)	3 0.9%	0 0%
Number of subjects censored at Week 12 (n=314, 165)	4 1.2%	2 1.2%
Number of subjects censored at Week 16 (n=297, 161)	3 0.9%	1 0.6%
Number of subjects censored at Week 20 (n=277, 156)	4 1.2%	0 0%
Number of subjects censored at Week 24 (n=265, 150)	3 0.9%	2 1.2%
Number of subjects censored at Week 28 (n=246, 146)	4 1.2%	0 0%
Number of subjects censored at Week 32 (n=224,139)	1 0.3%	0 0%
Number of subjects censored at Week 36 (220, 138)	1 0.3%	2 1.2%
Number of subjects censored at Week 40 (n=211,134)	1 0.3%	1 0.6%
Number of subjects censored at Week 44 (n=194,129)	2 0.6%	2 1.2%
Number of subjects censored at Week 48 (n=181, 125)	1 0.3%	3 1.8%
Number of subjects censored at Week 52 (n=177, 122)	147 42.5%	110 64.3%

6. Secondary Outcome

Title	Time to First Fluid-free Macula - Time-to-first Absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the Study Eye - Kaplan-Meier Analysis - Probability of Absence of SRF/IRF by Visit
Description	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
Time Frame	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment.

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	344	170
Probability of absence of SRF/IRF at Week 0 (n=344,170)	0.000	0.000
Probability of absence of SRF/IRF at Week 4 (n=344,170)	0.018	0.006
Probability of absence of SRF/IRF at Week 8 (n=335,168)	0.071	0.024
Probability of absence of SRF/IRF at Week 12 (n=314, 165)	0.109	0.036
Probability of absence of SRF/IRF at Week 16 (n=297, 161)	0.161	0.060
Probability of absence of SRF/IRF at Week 20 (n=277, 156)	0.185	0.096
Probability of absence of SRF/IRF at Week 24 (n=265,150)	0.234	0.108
Probability of absence of SRF/IRF at Week 28 (n=246,146)	0.291	0.151
Probability of absence of SRF/IRF at Week 32 (n=224,139)	0.300	0.157
Probability of absence of SRF/IRF at Week 36 (n=220,138)	0.326	0.169
Probability of absence of SRF/IRF at Week 40 (n=211, 134)	0.377	0.194
Probability of absence of SRF/IRF at Week 44 (194, 129)	0.412	0.206
Probability of absence of SRF/IRF at Week 48 (n=181, 125)	0.422	0.206
Probability of absence of SRF/IRF at Week 52 (n=177, 122)	0.653	0.328

7. Secondary Outcome

Title	Time to First Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the Study Eye at Each Post-baseline Visit - Number of Subjects With Probability of Absence of DME and Number Censored by Visit
Description	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
Time Frame	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Number of subjects with Probability of absence of DME at Week 0 (n=346,171)	0 0%	0 0%
Number of subjects with Probability of absence of DME at Week 4 (n=346,171)	14 4%	1 0.6%
Number of subjects with Probability of absence of DME at Week 8 (n=329,169)	54 15.6%	12 7%
Number of subjects with Probability of absence of DME at Week 12 (n=272, 157)	32 9.2%	13 7.6%
Number of subjects with Probability of absence of DME at Week 16 (n=239, 142)	33 9.5%	11 6.4%
Number of subjects with Probability of absence of DME at Week 20 (n=204, 130)	26 7.5%	10 5.8%
Number of subjects with Probability of absence of DME at Week 24 (n=174,120)	12 3.5%	4 2.3%
Number of subjects with Probability of absence of DME at Week 28 (n=161,115)	13 3.8%	7 4.1%
Number of subjects with Probability of absence of DME at Week 32 (n=146,107)	9 2.6%	5 2.9%
Number of subjects with Probability of absence of DME at Week 36 (n=135,102)	10 2.9%	2 1.2%
Number of subjects with Probability of absence of DME at Week 40 (n=125, 98)	7 2%	1 0.6%
Number of subjects with Probability of absence of DME at Week 44 (117, 96)	11 3.2%	2 1.2%
Number of subjects with Probability of absence of DME at Week 48 (n=106, 92)	6 1.7%	3 1.8%
Number of subjects with Probability of absence of DME at Week 52 (n=99, 88)	13 3.8%	4 2.3%
Number censored at Week 0 (n=346,171)	0 0%	0 0%
Number censored at Week 4 (n=346,171)	3 0.9%	1 0.6%
Number censored at Week 8 (n=329,169)	3 0.9%	0 0%
Number censored at Week 12 (n=272, 157)	1 0.3%	2 1.2%
Number censored at Week 16 (n=239, 142)	2 0.6%	1 0.6%
Number censored at Week 20 (n=204, 130)	4 1.2%	0 0%
Number censored at Week 24 (n=174,120)	1 0.3%	1 0.6%
Number censored at Week 28 (n=161,115)	2 0.6%	1 0.6%
Number censored at Week 32 (n=146,107)	2 0.6%	0 0%
Number censored at Week 36 (n=135,102)	0 0%	2 1.2%
Number censored at Week 40 (n=125, 98)	1 0.3%	1 0.6%
Number censored at Week 44 (117, 96)	0 0%	2 1.2%
Number censored at Week 48 (n=106, 92)	1 0.3%	1 0.6%
Number censored at Week 52 (n=99, 88)	86 24.9%	84 49.1%

8. Secondary Outcome

Title	Time to First Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the Study Eye at Each Post-baseline Visit - Kaplan-Meier Analysis - Probability of Absence of DME by Visit
Description	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.
Time Frame	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Probability of absence of DME at Week 0 (n=346,171)	0.000	0.000
Probability of absence of DME at Week 4 (n=346,171)	0.041	0.006
Probability of absence of DME at Week 8 (n=329,169)	0.199	0.076
Probability of absence of DME at Week 12 (n=272, 157)	0.293	0.153
Probability of absence of DME at Week 16 (n=239, 142)	0.391	0.219
Probability of absence of DME at Week 20 (n=204, 130)	0.470	0.279
Probability of absence of DME at Week 24 (n=174,120)	0.506	0.303
Probability of absence of DME at Week 28 (n=161,115)	0.547	0.346
Probability of absence of DME at Week 32 (n=146,107)	0.575	0.376
Probability of absence of DMEE at Week 36 (n=135,102)	0.606	0.389
Probability of absence of DME at Week 40 (n=125, 98)	0.628	0.395
Probability of absence of DME at Week 44 (117, 96)	0.663	0.408
Probability of absence of DME at Week 48 (n=106, 92)	0.682	0.427
Probability of absence of DME at Week 52 (n=99, 88)	0.866	0.516

9. Secondary Outcome

Title	Best Corrected Visual Acuity (Letters Read): Change From Baseline in Best-corrected Visual Acuity (BCVA) at Each Post-baseline Visit for the Study Eye
Description	BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
Time Frame	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - Last observation carried forward (LOCF)

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Week 4	5.7	5.4
Week 8	7.7	7.4
Week 12	9.1	8.0
Week 16	9.6	8.5
Week 20	10.2	9.2
Week 24	10.7	9.6
Week 28	10.9	10.7
Week 32	11.5	10.5
Week 36	11.6	10.8
Week 40	11.7	10.7
Week 44	12.0	10.6
Week 48	12.2	10.7
Week 52	12.2	11.0

10. Secondary Outcome

Title	Gain in Best-corrected Visual Acuity (BCVA) (Letters Read): Number (%) of Subjects Who Gained ≥ 5, 10, or 15 Letters in BCVA From Baseline or Reached BCVA ≥ 84 Letters in the Study Eye at Week 52
Description	BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - Last observation carried forward (LOCF)

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
≥ 5 letters gain from baseline or BCVA ≥ 84 letters at Week 52	286 82.7%	127 74.3%
≥ 10 letters gain from baseline or BCVA ≥ 84 letters at Week 52	211 61%	95 55.6%
≥ 15 letters gain from baseline or BCVA ≥ 84 letters at Week 52	151 43.6%	69 40.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments	≥ 5 letters gain from baseline or BCVA ≥ 84 letters at Week 52
	Type of Statistical Test	Other
	Comments	Descriptive
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	9.3
	Confidence Interval	(2-Sided) 95%; 1.7 to 17.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments	≥ 10 letters gain from baseline or BCVA ≥ 84 letters at Week 52
	Type of Statistical Test	Other
	Comments	Descriptive
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	7.7
	Confidence Interval	(2-Sided) 95%; -1.5 to 17.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments	≥ 15 letters gain from baseline or BCVA ≥ 84 letters at Week 52
	Type of Statistical Test	Other
	Comments	Descriptive
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	5.5
	Confidence Interval	(2-Sided) 95%; -2.7 to 14.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=2-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye
Description	The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment". A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.
Time Frame	Baseline, Weeks 12, 24 and 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - Last observation carried forward (LOCF). Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded from analysis. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	221	118
Week 12	56 16.2%	21 12.3%
Week 24	82 23.7%	38 22.2%
Week 52	95 27.5%	45 26.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Other
	Comments	descriptive; week 12
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	8.3
	Confidence Interval	(2-Sided) 95%; 0.2 to 16.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Other
	Comments	descriptive; week 24
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	6.0
	Confidence Interval	(2-Sided) 95%; -3.0 to 14.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	(10% margin); week 52
Statistical Test of Hypothesis	p-Value	0.002
	Comments	(10% margin) (1-sided)
	Method	Clopper-Pearson exact method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	6.0
	Confidence Interval	(2-Sided) 95%; -3.9 to 16.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=3-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye
Description	The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the ≥2-step and ≥3-step change from baseline for each post-baseline assessment". A lower score represents better functioning. Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.
Time Frame	Baseline, Weeks 12, 24 and 52

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - Last observation carried forward (LOCF). Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded from analysis. DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	221	118
Week 12	18 5.2%	8 4.7%
Week 24	33 9.5%	16 9.4%
Week 52	40 11.6%	18 10.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Other
	Comments	descriptive; week 12
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -2.5 to 6.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Other
	Comments	descriptive; week 24
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	2.4
	Confidence Interval	(2-Sided) 95%; -3.0 to 7.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brolucizumab 6mg q4w, Aflibercept 2mg q4w
	Comments
	Type of Statistical Test	Other
	Comments	descriptive; week 52
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference - %
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; -2.0 to 9.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Anti-Drug Antibody (ADA): Frequency Distribution of Pre-existing ADA Status in the Brolucizumab Arm
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Brolucizumab 6mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.
Measure Participants	342
Negative	112 32.4%
Positive	230 66.5%

14. Secondary Outcome

Title	Ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm) by Preferred Term in the Study Eye
Time Frame	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Number of subjects with at least one AE	105 30.3%	59 34.5%
Vitreous detachment	10 2.9%	7 4.1%
Cataract	9 2.6%	6 3.5%
Conjunctival haemorrhage	9 2.6%	7 4.1%
Punctate keratitis	9 2.6%	2 1.2%
Uveitis	8 2.3%	1 0.6%
Vitreous floaters	8 2.3%	5 2.9%
Dry eye	7 2%	4 2.3%
Eye pain	6 1.7%	5 2.9%
Corneal abrasion	0 0%	5 2.9%
Diabetic retinal oedema	0 0%	4 2.3%

15. Secondary Outcome

Title	Number of Subjects With Non-ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm)
Time Frame	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Brolucizumab 6mg q4w	Aflibercept 2mg q4w
Arm/Group Description	Brolucizumab 6 mg/0.05 mL every 4 weeks.	Aflibercept 2mg/0.05 mL every 4 weeks
Measure Participants	346	171
Count of Participants [Participants]	209 60.4%	96 56.1%

Adverse Events

Time Frame	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.
Arm/Group Title	Brolucizumab 6mg		Aflibercept 2mg		Overall
Arm/Group Description	Brolucizumab 6mg		Aflibercept 2mg		Overall
All Cause Mortality
	Brolucizumab 6mg		Aflibercept 2mg		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/346 (2%)		5/171 (2.9%)		12/517 (2.3%)
Serious Adverse Events
	Brolucizumab 6mg		Aflibercept 2mg		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/346 (21.4%)		36/171 (21.1%)		110/517 (21.3%)
Blood and lymphatic system disorders
Anaemia	1/346 (0.3%)		1/171 (0.6%)		2/517 (0.4%)
Hypochromic anaemia	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Iron deficiency anaemia	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Cardiac disorders
Acute coronary syndrome	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Acute left ventricular failure	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Acute myocardial infarction	1/346 (0.3%)		1/171 (0.6%)		2/517 (0.4%)
Angina pectoris	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Arrhythmia	2/346 (0.6%)		0/171 (0%)		2/517 (0.4%)
Atrioventricular block second degree	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Cardiac arrest	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Cardiac failure	3/346 (0.9%)		1/171 (0.6%)		4/517 (0.8%)
Cardiac failure congestive	4/346 (1.2%)		0/171 (0%)		4/517 (0.8%)
Cardiopulmonary failure	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Coronary artery disease	3/346 (0.9%)		1/171 (0.6%)		4/517 (0.8%)
Left ventricular failure	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Myocardial infarction	3/346 (0.9%)		1/171 (0.6%)		4/517 (0.8%)
Myocardial ischaemia	2/346 (0.6%)		1/171 (0.6%)		3/517 (0.6%)
Ear and labyrinth disorders
Vertigo	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Eye disorders
Cataract - Fellow eye	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Cataract subcapsular - Study eye	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Diabetic retinopathy - Fellow eye	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Retinal vasculitis - Study eye	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Vitreous haemorrhage - Fellow eye	2/346 (0.6%)		0/171 (0%)		2/517 (0.4%)
Vitreous haemorrhage - Study eye	2/346 (0.6%)		0/171 (0%)		2/517 (0.4%)
Gastrointestinal disorders
Abdominal pain	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Diabetic gastroparesis	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Dyspepsia	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Gastrointestinal perforation	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Vomiting	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
General disorders
Chest pain	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Generalised oedema	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Oedema peripheral	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Peripheral swelling	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Sudden death	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Hepatobiliary disorders
Cholecystitis	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Cholecystitis acute	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Liver disorder	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Infections and infestations
Abscess bacterial	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Abscess limb	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Appendicitis	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Bronchitis viral	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
COVID-19	8/346 (2.3%)		1/171 (0.6%)		9/517 (1.7%)
COVID-19 pneumonia	4/346 (1.2%)		0/171 (0%)		4/517 (0.8%)
Cellulitis	3/346 (0.9%)		0/171 (0%)		3/517 (0.6%)
Chest wall abscess	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Cholecystitis infective	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Cytomegalovirus infection	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Diabetic foot infection	1/346 (0.3%)		2/171 (1.2%)		3/517 (0.6%)
Diabetic gangrene	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Gangrene	2/346 (0.6%)		1/171 (0.6%)		3/517 (0.6%)
Kidney infection	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Lymphangitis	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Osteomyelitis	3/346 (0.9%)		2/171 (1.2%)		5/517 (1%)
Pneumonia	3/346 (0.9%)		2/171 (1.2%)		5/517 (1%)
Sepsis	2/346 (0.6%)		1/171 (0.6%)		3/517 (0.6%)
Septic shock	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Staphylococcal sepsis	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Subcutaneous abscess	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Urinary tract infection	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Wound infection staphylococcal	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Injury, poisoning and procedural complications
Anastomotic ulcer haemorrhage	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Ankle fracture	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Cataract operation complication - Fellow eye	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Contusion	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Forearm fracture	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Limb injury	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Patella fracture	2/346 (0.6%)		0/171 (0%)		2/517 (0.4%)
Post-traumatic neck syndrome	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Postoperative ileus	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Rib fracture	2/346 (0.6%)		0/171 (0%)		2/517 (0.4%)
Subdural haematoma	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Investigations
Blood glucose increased	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Blood potassium increased	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Troponin increased	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Metabolism and nutrition disorders
Fluid retention	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Hyperglycaemia	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Hyperkalaemia	1/346 (0.3%)		1/171 (0.6%)		2/517 (0.4%)
Hypoglycaemia	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Musculoskeletal and connective tissue disorders
Pathological fracture	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adrenal adenoma	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Bladder cancer	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Gastric neoplasm	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Leukaemia	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Nervous system disorders
Cerebral haemorrhage	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Cerebrovascular accident	6/346 (1.7%)		6/171 (3.5%)		12/517 (2.3%)
Epilepsy	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Ischaemic stroke	1/346 (0.3%)		1/171 (0.6%)		2/517 (0.4%)
Lacunar stroke	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Lumbar radiculopathy	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Thrombotic stroke	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Transient ischaemic attack	1/346 (0.3%)		1/171 (0.6%)		2/517 (0.4%)
Renal and urinary disorders
Acute kidney injury	4/346 (1.2%)		1/171 (0.6%)		5/517 (1%)
Chronic kidney disease	3/346 (0.9%)		0/171 (0%)		3/517 (0.6%)
Hydronephrosis	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Renal colic	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Renal failure	2/346 (0.6%)		0/171 (0%)		2/517 (0.4%)
Renal impairment	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Renal mass	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Acute respiratory failure	1/346 (0.3%)		1/171 (0.6%)		2/517 (0.4%)
Dyspnoea	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Interstitial lung disease	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Pulmonary embolism	1/346 (0.3%)		1/171 (0.6%)		2/517 (0.4%)
Pulmonary oedema	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Respiratory failure	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Skin and subcutaneous tissue disorders
Diabetic foot	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Diabetic wound	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Vascular disorders
Extremity necrosis	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Hypertension	1/346 (0.3%)		2/171 (1.2%)		3/517 (0.6%)
Hypertensive emergency	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Hypertensive urgency	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Orthostatic hypotension	1/346 (0.3%)		1/171 (0.6%)		2/517 (0.4%)
Peripheral arterial occlusive disease	1/346 (0.3%)		0/171 (0%)		1/517 (0.2%)
Peripheral vascular disorder	0/346 (0%)		1/171 (0.6%)		1/517 (0.2%)
Other (Not Including Serious) Adverse Events
	Brolucizumab 6mg		Aflibercept 2mg		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	144/346 (41.6%)		92/171 (53.8%)		236/517 (45.6%)
Blood and lymphatic system disorders
Anaemia	8/346 (2.3%)		4/171 (2.3%)		12/517 (2.3%)
Eye disorders
Cataract - Fellow eye	6/346 (1.7%)		4/171 (2.3%)		10/517 (1.9%)
Cataract - Study eye	9/346 (2.6%)		6/171 (3.5%)		15/517 (2.9%)
Conjunctival haemorrhage - Fellow eye	4/346 (1.2%)		5/171 (2.9%)		9/517 (1.7%)
Conjunctival haemorrhage - Study eye	9/346 (2.6%)		7/171 (4.1%)		16/517 (3.1%)
Diabetic retinal oedema - Fellow eye	10/346 (2.9%)		7/171 (4.1%)		17/517 (3.3%)
Diabetic retinal oedema - Study eye	0/346 (0%)		4/171 (2.3%)		4/517 (0.8%)
Dry eye - Fellow eye	6/346 (1.7%)		6/171 (3.5%)		12/517 (2.3%)
Dry eye - Study eye	7/346 (2%)		4/171 (2.3%)		11/517 (2.1%)
Eye pain - Fellow eye	3/346 (0.9%)		4/171 (2.3%)		7/517 (1.4%)
Eye pain - Study eye	6/346 (1.7%)		5/171 (2.9%)		11/517 (2.1%)
Punctate keratitis - Study eye	9/346 (2.6%)		2/171 (1.2%)		11/517 (2.1%)
Uveitis - Study eye	8/346 (2.3%)		1/171 (0.6%)		9/517 (1.7%)
Vitreous detachment - Study eye	10/346 (2.9%)		7/171 (4.1%)		17/517 (3.3%)
Vitreous floaters - Study eye	8/346 (2.3%)		5/171 (2.9%)		13/517 (2.5%)
Vitreous haemorrhage - Fellow eye	10/346 (2.9%)		4/171 (2.3%)		14/517 (2.7%)
Gastrointestinal disorders
Nausea	3/346 (0.9%)		4/171 (2.3%)		7/517 (1.4%)
General disorders
Oedema peripheral	3/346 (0.9%)		4/171 (2.3%)		7/517 (1.4%)
Pyrexia	4/346 (1.2%)		4/171 (2.3%)		8/517 (1.5%)
Infections and infestations
COVID-19	11/346 (3.2%)		11/171 (6.4%)		22/517 (4.3%)
Cellulitis	7/346 (2%)		4/171 (2.3%)		11/517 (2.1%)
Influenza	2/346 (0.6%)		4/171 (2.3%)		6/517 (1.2%)
Nasopharyngitis	8/346 (2.3%)		6/171 (3.5%)		14/517 (2.7%)
Urinary tract infection	11/346 (3.2%)		2/171 (1.2%)		13/517 (2.5%)
Injury, poisoning and procedural complications
Corneal abrasion - Study eye	0/346 (0%)		5/171 (2.9%)		5/517 (1%)
Fall	9/346 (2.6%)		4/171 (2.3%)		13/517 (2.5%)
Investigations
Blood creatinine increased	4/346 (1.2%)		7/171 (4.1%)		11/517 (2.1%)
Blood pressure increased	7/346 (2%)		5/171 (2.9%)		12/517 (2.3%)
Metabolism and nutrition disorders
Diabetes mellitus	7/346 (2%)		0/171 (0%)		7/517 (1.4%)
Type 2 diabetes mellitus	5/346 (1.4%)		4/171 (2.3%)		9/517 (1.7%)
Musculoskeletal and connective tissue disorders
Back pain	3/346 (0.9%)		4/171 (2.3%)		7/517 (1.4%)
Nervous system disorders
Headache	3/346 (0.9%)		7/171 (4.1%)		10/517 (1.9%)
Renal and urinary disorders
Acute kidney injury	8/346 (2.3%)		4/171 (2.3%)		12/517 (2.3%)
Chronic kidney disease	8/346 (2.3%)		4/171 (2.3%)		12/517 (2.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/346 (0.9%)		9/171 (5.3%)		12/517 (2.3%)
Vascular disorders
Hypertension	18/346 (5.2%)		13/171 (7.6%)		31/517 (6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.