Risk Factors for Meeting Criteria for Switching from Bevacizumab to Aflibercept When Treating Eyes with Diabetic Macular Edema and Visual Acuity <20/40

Abstract

Objective:

To identify factors for meeting prespecified criteria for switching from bevacizumab to aflibercept in eyes with center-involved diabetic macular edema (CI-DME) and moderate vision loss initially treated with bevacizumab in DRCR Retina Network Protocol AC.

Design:

Post hoc analysis of data from a randomized clinical trial

Participants:

270 participants with one or both eyes with CI-DME and visual acuity (VA) letter score of 69 to 24 (Snellen equivalent 20/50–20/320)

Methods:

Eligible eyes were assigned to receive intravitreal aflibercept monotherapy (N=158) or bevacizumab followed by aflibercept if prespecified criteria for switching were met between 12 weeks and 2 years (N=154).

Main Outcome Measures:

Meeting switching criteria: 1) at any time, 2) at 12 weeks, and 3) after 12 weeks. Associations between meeting the criteria for switching and factors measured at baseline and 12 weeks were evaluated in univariable analyses. Stepwise procedures were used to select variables for multivariable models.

Results:

In the bevacizumab first group, older participants had higher risk of meeting the switching criteria at any time, with a hazard ratio (HR) for a 10-year increase in age (95% confidence interval) of 1.32 (1.11 – 1.58). Male participants or eyes with worse baseline VA were more likely to switch at 12 weeks (HR for male vs. female = 4.84 [1.32 – 17.81]; HR for 5-letter lower baseline VA: 1.30 [1.03 – 1.63]). Worse 12-week CST (HR for 10-μm greater = 1.06 [1.04 – 1.07]) was associated with increased risk for switching after 12 weeks. The mean (SD) improvement after completing the switch to aflibercept was 3.7 (4.9) letters.

Conclusions:

The identified factors can be used to refine expectations regarding the likelihood that an eye will meet protocol criteria to switch to aflibercept when treatment is initiated with bevacizumab. Older patients are more likely to be switched. At twelve weeks, thicker central subfield thickness was predictive of eyes most likely to be switched in the future.

Precis

DRCR Protocol AC Post-hoc analysis identified factors associated with a higher likelihood of switching to aflibercept when initially treated with bevacizumab for center-involved diabetic macular edema and moderate vision loss.

Introduction

The DRCR Retina Network Protocol AC trial compared two treatment strategies for eyes with center-involved diabetic macular edema vision of 20/50 or worse: aflibercept monotherapy vs. bevacizumab first with switching to aflibercept for suboptimal treatment response.¹ Protocol AC was motivated by the DRCR Retina Network Protocol T finding that eyes with visual acuity of 20/50 or worse treated with bevacizumab monotherapy had less improvement than those treated with aflibercept monotherapy.^2,3 However, the cost for aflibercept is substantially higher than for bevacizumab and some insurers have required initial treatment with bevacizumab with a switch to another anti-VEGF agent if the clinical response is unsatisfactory.⁴ In Protocol AC, patients in the bevacizumab first group were switched to aflibercept if they met switch criteria at 12 weeks or later. The results showed that the treatment strategy of bevacizumab first had similar visual outcomes as aflibercept monotherapy. Therefore, starting with bevacizumab is a reasonable treatment strategy for patients with DME and 20/50 or worse vision.

Over the course of the study, 70% of the patients in the bevacizumab first group met switch criteria. Although patients were not switched in the aflibercept monotherapy group, 30% of those patients also would have met the same switch criteria. This exploratory report analyzes risk factors associated with eyes that met the switch criteria over the course of the study.

Methods

The methods for Protocol AC have been published elsewhere; only salient features are included here. ¹ Principal eligibility criteria for eyes included center-involved diabetic macular edema (CI-DME) on clinical examination with central subfield thickness (CST) on optical coherence tomography (OCT) greater than the machine- and sex-specific thresholds (i.e., 320 μm for men and 305 μm for women on the Spectralis device and 305 μm and 290 μm, respectively, on the Cirrus device), and best corrected Electronic Early Treatment for Diabetic Retinopathy Study (E-ETDRS) visual acuity (VA) letter score between 69 and 24 (Snellen equivalent of 20/50 to 20/320). Study eyes were randomly assigned 1:1 to receive 2.0 mg intravitreous aflibercept (“aflibercept monotherapy”) or 1.25 mg intravitreous bevacizumab with a switch to intravitreous 2.0 mg aflibercept if the eye met the criteria for switching at 12 weeks or later (“bevacizumab first”). Participants could have one or two study eyes; if both eyes were eligible, one eye was assigned to aflibercept monotherapy and the other to bevacizumab first. The study adhered to the tenets of the Declaration of Helsinki and was approved by a central ethics board. Study participants provided written informed consent.

Treatment and follow-up

Visits occurred at baseline, every 4 weeks through 1 year, and every 4 to 16 weeks in year 2 depending on clinical course. Study eyes received 6 monthly injections initially unless the eye achieved VA of 20/20 or better and CST less than eligibility thresholds with no improvement or worsening in VA and CST after two consecutive injections. Starting from 24 weeks, injections were deferred if the eye experienced stability in VA and CST after two consecutive injections; injections resumed if VA or CST worsened later. Beginning at week 12, eyes assigned to the bevacizumab first group were switched to aflibercept treatment if the protocol criteria for switching were met. Switching from bevacizumab to aflibercept required meeting all of the following criteria: 1) persistent CI-DME with CST above the eligibility threshold, 2) suboptimal vision (i.e., 20/50 or worse if prior to 24 weeks, or 20/32 or worse if 24 weeks or later), 3) receipt of bevacizumab injections at the previous two consecutive visits, and 4) lack of improvement in VA (by ≥ 5 letters) and CST (by ≥ 10% reduction) compared with and between the last two consecutive visits.¹ Eyes that switched received two monthly aflibercept injections, followed by aflibercept injections according to the retreatment protocol.

Data Analysis

Although eyes assigned to the aflibercept monotherapy group did not switch treatment, they were also analyzed to identify risk factors for meeting the criteria for switching. Three main outcomes were considered, namely, meeting switching criteria 1) at any time during follow-up; 2) at 12 weeks; 3) and after 12 weeks. Meeting the switching criteria at any time during follow-up and meeting them after 12 weeks were analyzed as time-to-event outcomes and Kaplan-Meier estimates were provided. Because of the low number of switching events at 12 weeks (n = 16) and the change in the visual acuity criterion from 20/50 to 20/32 at 24 weeks, similar analyses were performed for switching before 24 weeks and switching at or after 24 weeks. Data from eyes that did not meet the criteria for switching were censored at the last completed visit. Seventeen variables measured at baseline were evaluated as risk factors for meeting the criteria for switching at any time and additional 5 variables measured at the 12-week visit were evaluated as risk factors for meeting the criteria after 12 weeks. For presentation, each numerical factor was categorized using tertiles into three groups and the percentage of eyes meeting the criteria for switching was reported for each subgroup. A univariable Cox proportional hazards model was used for each factor to obtain a hazard ratio (HR) and a P value for the overall effect. The proportional hazards assumptions were evaluated by testing the interaction of covariates with time and checking Martingale residuals. In addition, for eyes in the bevacizumab first group completing the 12-week visit, risk factors for switching at 12 weeks were evaluated using logistic regression. Variables with less than 5% missing data were considered candidates for multivariable analyses, which were performed only if at least 20 eyes had the outcome of interest. Stepwise procedures with an entry selection criterion of P ≤ .10 and stay criterion of P ≤ .05 was performed to create the final multivariable Cox and logistic regression models. Eyes with missing values for one or more factors were not included in the variable selection process. P values were 2-sided and were not adjusted for multiplicity. All analyses were exploratory and were performed using SAS software version 9.4 (SAS Institute Inc).

Results

All study eyes enrolled in Protocol AC were included in the analysis; 158 eyes in the aflibercept monotherapy group and 154 eyes in the bevacizumab group. Forty-two participants had both eyes eligible, with one eye randomly assigned to aflibercept and the other to bevacizumab. As reported previously, the cumulative proportion (i.e., Kaplan-Meier estimate) of eyes in the bevacizumab first group that switched to aflibercept treatment was 11% (95% CI: 7% – 17%) up to 12 weeks, 39% (95% CI, 32% – 47%) up to 24 weeks, and 70% (95% CI: 62% – 77%) over 2 years.¹ The cumulative proportion (i.e., Kaplan-Meier estimate) of eyes in the aflibercept monotherapy group that met the criteria (without switching treatment) was 2% (95% CI: 1% – 6%) up to 12 weeks, 13% (95% CI, 9% – 20%) up to 24 weeks, and 30% (95% CI: 23% – 38%) over 2 years.¹

Switching at any time during follow-up

The cumulative proportions of eyes meeting the criteria for switching from bevacizumab to aflibercept at any time during follow-up over 2 years are shown in Table 1 by subgroups of each baseline factor. In the univariable analyses of each factor, participants with worse baseline VA and older age had higher risk of meeting the switching criteria. The final model obtained from the stepwise variable selection procedures only included baseline age, with percentages switching at any time of 55% (95% CI, 42% – 70%) for tertile 1 (31 to 56 years), 76% (95% CI, 64% – 87%) for tertile 2 (57 to 65 years), and 77% (95% CI, 64% – 88%) for tertile 3 (66 to 87 years; Figure 1). For every 10-year increase in age, the risk of meeting the criteria for switching during follow-up was increased on average by 32% (HR = 1.32; 95% CI: 1.11 – 1.58; P = .002).

Table 1.

Univariable analysis of baseline factors for meeting the switching criteria at any time during follow-up in the bevacizumab first group

Risk Factor a	Total	No. Meeting Switch Criteria	Kaplan-Meier Estimate at 2 Years (95% CI)	Hazard Ratio (95% CI)	P value
Baseline OCT CST, μm
283 to 428	51	29	62% (48%, 75%)	Per 10-μm greater
429 to 593	52	36	75% (62%, 86%)	1.01 (1.00, 1.02)	0.24
610 to 1002	51	35	73% (59%, 84%)
Baseline visual acuity, letters
68 to 64 (20–50 – 20/50)	49	32	70% (56%, 83%)	Per 5-letter lower
63 to 56 (20–63 – 20/80)	54	33	65% (52%, 78%)	1.09 (1.01, 1.17)	0.03
55 to 25 (20–80 – 20/320)	51	35	74% (60%, 85%)
Age, years
31 to 56	52	26	55% (42%, 70%)	Per 10-year greater
57 to 65	54	39	76% (64%, 87%)	1.32 (1.11, 1.58)	0.002
66 to 87	48	35	77% (64%, 88%)
Race/ethnicity
White	83	52	66% (56%, 77%)	Reference
Black/African American	26	18	78% (59%, 92%)	1.09 (0.67, 1.75)	0.82
Other	45	30	71% (57%, 83%)	0.93 (0.61, 1.41)
Hemoglobin A1c
4.4% to 7.2%	49	36	75% (62%, 86%)	Per 1% greater
7.3% to 8.7%	47	28	63% (49%, 78%)	0.96 (0.87, 1.06)	0.43
8.8% to 15.4%	48	30	70% (56%, 82%)
Baseline DRSS
Mild NPDR (Level 35) or better	20	14	70% (50%, 88%)	Reference	0.15
Moderate NPDR (Level 43)	25	19	81% (63%, 94%)	1.21 (0.61, 2.39)
Moderately Severe NPDR (Level 47)	34	22	68% (51%, 83%)	0.89 (0.45, 1.77)
Severe/Very Severe NPDR (Level 53)	45	29	70% (55%, 83%)	0.82 (0.43, 1.54)
PDR (Level 61 or worse)	23	9	48% (28%, 73%)	0.46 (0.20, 1.05)
Presence of subretinal fluid on OCT at baseline b
No	83	57	74% (64%, 83%)	Reference
Yes	71	43	64% (53%, 76%)	0.78 (0.54, 1.14)	0.21
Presence of epiretinal membrane on OCT at baseline c
No	119	73	66% (57%, 75%)	Reference
Yes	35	27	81% (66%, 93%)	1.44 (0.96, 2.18)	0.08
Sex
Female	74	53	75% (64%, 84%)	Reference
Male	80	47	64% (53%, 75%)	0.87 (0.60, 1.26)	0.45
Duration of diabetes, years
0 to 8	51	35	71% (58%, 83%)	Per 10-year greater
9 to 19	53	30	63% (49%, 76%)	1.08 (0.89, 1.31)	0.44
20 to 60	50	35	75% (62%, 86%)
Prior treatment for DME
No	120	76	69% (60%, 78%)	Reference
Yes	34	24	71% (55%, 85%)	1.19 (0.75, 1.89)	0.47
Baseline retinal volume, mm 3
6.3 to 8.7	41	28	71% (56%, 84%)	Per 1 mm3 greater
8.8 to 10.6	42	21	59% (43%, 75%)	1.03 (0.96, 1.12)	0.41
10.7 to 17.9	42	31	76% (62%, 87%)
Smoking status
Never or Prior Smoker	105	73	72% (63%, 80%)	Reference
Current Smoker	49	27	63% (49%, 77%)	0.90 (0.58, 1.39)	0.62
Presence of hard exudates on fundus photos d
No	23	11	50% (32%, 72%)	Reference
Yes	127	85	72% (64%, 80%)	1.56 (0.81, 3.00)	0.18
Baseline IOP, mmHg
10 to 14	52	32	66% (53%, 79%)	Per 5-mmHg greater
15 to 17	51	37	77% (65%, 88%)	1.07 (0.79, 1.45)	0.68
18 to 26	51	31	66% (52%, 79%)
Baseline lens status
Phakic	124	79	69% (60%, 77%)	Reference
PC IOL	30	21	73% (56%, 88%)	1.02 (0.66, 1.57)	0.93
Number of study eyes
1	112	70	67% (58%, 76%)	Reference
2	42	30	76% (62%, 88%)	1.29 (0.86, 1.93)	0.22

CI, confidence interval; CST, central subfield thickness; DME, diabetic macular edema; DRSS, Diabetic Retinopathy Severity Scale; IOP, intraocular pressure; NPDR, nonproliferative diabetic retinopathy; OCT, optical coherence tomography; PC IOL, posterior chamber intraocular lens; PDR, proliferative diabetic retinopathy.

^aContinuous risk factors were categorized by tertiles for presentation and were modeled as continuous variables in the analyses.

^bDefined as presence of subretinal fluid in central 1mm.

^cDefined as presence of epiretinal membrane on OCT within the center 1 mm.

^dDefined as presence of hard exudate within Field 2.

Figure 1.

Graph showing the cumulative proportion of eyes switching from bevacizumab to aflibercept at any time by baseline age. Baseline age was grouped based on tertile values. Data from eyes that did not meet the criteria for switching were censored at the last completed visit.

Switching at different points in follow-up time

The proportions of eyes switched from bevacizumab to aflibercept at 12 weeks in the subgroups of each baseline factor are shown in eTable 2. In the univariable analyses of each factor, male participants had a higher risk of meeting the switching criteria at 12 weeks than female participants (18% vs. 4%; HR = 4.84; 95% CI: 1.32 – 17.81; P = .02), and participants with worse baseline VA were more likely to switch at 12 weeks (0% for eyes with VA of 20/50 vs. 14% with 20/63 to 20/80 vs. 20% with 20/80 to 20/320; HR for 5-letter lower baseline VA = 1.30; 95% CI: 1.03 – 1.63; P = .03; eTable 2). Multivariable analysis was not performed due to the limited number of eyes switching at 12 weeks (n = 16). The results of the univariable analyses for switching prior to 24 weeks are presented in eTable 3. The final multivariable model included baseline VA (HR for 5-letter decrease = 1.17; 95% CI: 1.06 – 1.30; P = .003), similar to the finding at 12 weeks, and prior treatment for DME (HR for yes vs. no = 1.88; 95% CI: 1.04 – 3.41; P = .04), while the finding at 12 weeks was (HR for yes vs. no = 1.54; 95% CI: 0.49 – 4.78; P = .46).

The cumulative proportions of eyes meeting the criteria for switching from bevacizumab to aflibercept after 12 weeks over 2 years are summarized in eTable 4 by the subgroups of baseline and 12-week factors. Eyes that met the criteria at 12-week visit were excluded (n = 16). Participants with older age, worse 12-week CST, worse 12-week VA, and less improvement in CST and VA from baseline at 12 weeks were associated with a higher risk of meeting the switching criteria. The final multivariable model only included CST at 12 weeks (HR for 10-μm greater = 1.06; 95% CI: 1.04 – 1.07; P < .001), with percentages switching after 12 weeks of 35% (95% CI, 22% – 51%) for tertile 1 (211 to 342 μm) , 76% (95% CI, 62% – 87%) for tertile 2 (343 to 426 μm) , and 92% (95% CI, 80% – 98%) for tertile 3 (428 to 844 μm; Figure 2). Similarly, when excluding eyes that were no longer at risk at 24 weeks (n = 47), CST at 12 weeks was the only variable included in the final multivariable model for switching at or after 24 weeks (HR for 10-μm greater = 1.06; 95% CI: 1.04 – 1.08); P < .001), for which the univariable analyses are presented in eTable 5.

Figure 2.

Graph showing the cumulative proportion of eyes switching from bevacizumab to aflibercept after 12 weeks by 12-week central subfield thickness. Central subfield thickness at the 12-week visit was grouped based on tertile values. Eyes switched at the 12-week visit were not included. Data from eyes that did not meet the criteria for switching were censored at the last completed visit.

Meeting the Criteria for Switching Among Aflibercept Monotherapy Group

In the aflibercept monotherapy group, participants who had older age, worse baseline CST, epiretinal membrane (ERM) on OCT within the center 1 mm, or posterior chamber intraocular lenses (PC IOL) in the study eye, were more likely to meet the criteria for switching at any time during follow-up (eTable 6). The final multivariable model included age (HR for 10-year greater = 1.61; 95% CI: 1.26 – 2.06; P < .001), baseline CST (HR for 10-μm greater = 1.03; 95% CI: 1.01 – 1.04; P = .001), and baseline ERM status (HR for present vs. absent = 2.42; 95% CI: 1.34 – 4.38; P = .003; eTable 7).

In addition, the univariable analysis of baseline and 12-week factors for meeting the criteria for switching after 12 weeks is summarized in eTable 8. In addition to worse CST, older age, ERM, and PC IOL at baseline, worse VA and worse CST at 12 weeks were also associated with an increased risk of meeting the criteria after 12 weeks. The final multivariable model included baseline lens status (HR for PC IOL vs. phakic = 3.14; 95% CI: 1.57 – 6.26; P = .001), 12-week CST (HR for 10-μm greater = 1.10; 95% CI: 1.06 – 1.13; P < .001), and 12-week VA (HR for 5-letter lower = 1.15; 95% CI: 1.05 – 1.26; P = .002; eTable 7). The univariable analyses of meeting the switching criteria at or after 24 weeks are reported in eTable 9. The final multivariable model included baseline lens status and 12-week CST with HRs similar to those from the model for meeting switching criteria after 12 weeks, as well as baseline visual acuity (HR for 5-letter lower = 1.20; 95% CI: 1.04 – 1.39; P = .001; eTable 7).

Treatment Outcomes after Switching to Aflibercept

Among the 100 eyes that switched to aflibercept, 98 (98%) eyes completed at least one follow-up visit, and 96 (96%) eyes received a second aflibercept injection at a median of 28 days after switching. At the visit when the second aflibercept injection was performed, the mean (SD) visual acuity was 68 (12) letters, with a mean (SD) improvement of 3.7 (4.9) letters from the day of switching and 12.1 (10.2) letters from baseline; and the mean (SD) CST was 388 (93) μm, with a mean (SD) reduction of 64 (96) μm from the day of switching and 151 (146) μm from baseline. Only 14 (14%) eyes experienced a loss of 10 or more letters from baseline at least once after switching to aflibercept. At 2 years, 60 of 90 (67%) eyes that switched had strong VA response (i.e., at least 5-, 10-, or 15-letter gain from baseline when baseline VA was 20/25 to 20/32, 20/40 to 20/63, or 20/80 to 20/320, respectively),⁵ and 58 (64%) had strong CST response (i.e., at least 50-, 100-, or 200-μm reduction from baseline when baseline CST was <75 μm, 75 to <175 μm, and ≥175 μm, respectively, above the CI-DME threshold).

Discussion

In Protocol AC, a majority of participants who received bevacizumab first required switching to aflibercept within the 2-year follow-up period. Therefore, identifying risk factors for meeting switch criteria can help prepare both the clinician and the patient for the possibility of changing drugs. A higher risk of switching at any time over 2 years was associated with older baseline age. At 12 weeks, eyes with worse baseline vision and male participants had a higher risk of meeting switching requirements. After 12 weeks, thicker CST at 12 weeks was found to be the only risk factor for meeting switch criteria.

There was some evidence that eyes with ERM were more likely to meet switching criteria, in that the percentage meeting criteria was higher for these eyes in the analyses for both drugs; however, the effect was statistically significant only for meeting criteria at any time in the aflibercept group. This may be due to ERM hindering the efficacy of the anti-VEGF treatment. Alternatively, because ERMs can cause macular thickening, a component of the central subfield thickness not due to DME may have remained because of the ERM, leading to a higher likelihood of meeting switch criteria.

Although eyes in the worst CST category at 12 weeks were almost certain to meet switch criteria in this study (92%), this does not imply that switching these eyes earlier to aflibercept would necessarily result in better visual or anatomic outcomes. Protocol AC showed that initiating treatment with bevacizumab first and switching to aflibercept as needed results in similar visual acuity outcomes over 2 years compared to initiating treatment with aflibercept monotherapy, with nearly identical proportions of eyes meeting visual acuity thresholds of 20/20 or better (22% in both groups) and 20/40 or better (73% aflibercept, 74% bevacizumab) at 2 years. Even among eyes that had a suboptimal response to initial treatment with bevacizumab, most (67%) that switched to aflibercept had a strong result for VA.¹ This similarity in outcomes between the groups suggests that there is unlikely to be a substantial benefit to beginning aflibercept treatment earlier in eyes that eventually are required to switch. At the same time, using bevacizumab first is more cost-effective based on 2022 Medicare allowable reimbursement rates for drug costs and associated procedures.^4,6,7 The cost differential between aflibercept and bevacizumab is over $1,700, resulting in substantial savings in overall healthcare expenditure each time bevacizumab is used instead of aflibercept.^7,8

Limitations of this study include that these are exploratory analyses that were not prespecified in the statistical analysis plan. The large number of comparisons increased the risk of detecting associations that may have occurred by chance. Risk factors for suboptimal response to treatment with bevacizumab that were identified in this patient group need to be identified in other patient groups treated with bevacizumab to determine whether the associations are due to chance or not. The final models were derived using a data-driven approach, and we were not able to perform external validation because a similar cohort that was treated with the Protocol AC algorithm was not available. The risk factors identified in our AC that are initiating therapy with bevacizumab but is not applicable to the prediction of visual acuity or retinal thickness outcomes over the long term.

The risk factors identified here can be used to refine expectations regarding switching to aflibercept when treatment is initiated with bevacizumab. At baseline, older patients are more likely to be switched. As would be expected, greater CST at 12 weeks was predictive of who is most likely to be switched in the future, after the 12-week visit. These risk factors can be used to enhance counseling for patients who are initiating therapy for DME with bevacizumab.

Members of the DRCR Retina Network that participated in Protocol AC

Network chairs, Coordinating Center Staff, and Committee Members are all compensated for their work as members of the DRCR Retina Network.

DRCR Retina Network Coordinating Center Staff: Jaeb Center for Health Research, Tampa, FL: Adam R. Glassman, MS (Jaeb Center for Health Research Executive Director and DRCR Retina Network Principal Investigator), Roy W. Beck, MD, PhD (Jaeb Center for Health Research President), Alyssa Baptista, BS, Claire T. Calhoun, MS, Sharon R. Constantine, BS, Brian B. Dale, Simone S. Dupre, BS, Crystal A. Franklin, MPH, Sandra Galusic, MSPH, Meagan Huggins, BA, Brenda L. Hunter, BS, Paula A. Johnson, MPH, Kristin Josic, PhD, Brittany Kelly, MSHS, Danni Liu, MSPH, Maureen G. Maguire, PhD, Britney Meadows, BS, Michele Melia, ScM, Carin M. Preston, MPH, Cynthia R. Stockdale, MSPH, Alice Zokruah, BS

DRCR Retina Network Chair: Jennifer K. Sun, MD, MPH (Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology) (2018-present), Daniel F. Martin, MD (Cole Eye Institute at Cleveland Clinic) (2018-Present)

National Eye Institute: Sangeeta Bhargava, PhD (2016-current)

Executive Committee: Andrew J. Barkmeier, MD (2022- Present), Darrell Baskin, MD (2021-Present), Roy W. Beck, MD, PhD (2002-present), Sangeeta Bhargava, PhD (2016-present), Barbra Blodi, MD (2014-present), Emily Chew, MD (2020-present), Frederick L. Ferris III, MD (2002-present), Adam R. Glassman, MS (2005-present), Glenn J. Jaffe, MD (2012-present), Lee M. Jampol, MD (2012-present), Chirag D. Jhaveri, MD (2016-present), Mathew MacCumber, MD, PhD (2018-Present), Daniel F. Martin, MD (2017-present), Raj K. Maturi, MD (2009–2011, 2013-present), Sharon D. Solomon, MD (2020- present), Jennifer K. Sun, MD, MPH (2009-present), Cynthia R. Stockdale, MSPH (2021-present). Prior Members: Andrew N. Antoszyk, MD (2009; 2013–2021), Brandon Lujan, MD (2017–2021)

Steering Committee: Chirag D. Jhaveri, MD, Emily Chew, MD, Raj K. Maturi, MD, Frederick L. Ferris III, MD, Adam R. Glassman, MS, Lee M. Jampol, MD, Daniel F. Martin, Hani Slahi-Had, MD, Jennifer K. Sun, Cynthia R. Stockdale, MSPH, Andrew J. Barkmeier, MD.

Data and Safety Monitoring Committee: Gary Abrams, MD, Deborah R. Barnbaum, PhD, Kyle D. Rudser, PhD, Paul Sternberg, Jr., MD, Sangeeta Bhargava, PhD, Stephen Wisniewski, PhD, Harry Flynn, MD, (2014 – 2023); Ruth S. Weinstock, MD, PhD, (2014 – 2023); Charles P. Wilkinson, MD (2012–2018).

DRCR Retina Network clinical sites that participated on this protocol: Sites are listed in order by number of subjects enrolled into the study. The number of subjects enrolled is noted in parenthesis preceded by the site location and the site name. Personnel are listed as (I) for Study Investigator, (C) for Coordinator, (V) Visual Acuity Technician, and (P) for Photographer

Site Location	Personnel that participated in Protocol AC
Charlotte, NC Southeast Clinical Research Associates, LLC (25)	John Bradley Allen, MD(I); Andrew N. Antoszyk, MD(I); Omar S. Punjabi, MD(I); David Browning, MD, PhD(I); Amanda H. Wilson (C,V); Sherry L. Fredenberg (C,V); Sarah A. Ennis (C,V); Justin Clark, BS(C); Christina J. Fleming, BS, CCRP (C,V); Brittany A Murphy, BA, COT (C,V); Angela K. Price, MPH (C,V); Christina Mutch(V); Monica D. Nayar, BS(V); Angella K. Gentile(V); Kayla A Bratcher(V); Kaitlin T. McShea, MS(V); Uma M. Balasubramaniam(P); Tracy A. Ross(P); Donna McClain, COA(P); Lisa A. Jackson(P); Loraine M. Clark, COA(P); Lynn Watson(P); Shannon Stobbe(P); Carol A Shore(P)
Lakeland, FL Florida Retina Consultants (21)	Scott M. Friedman, MD(I); Nader Moinfar, MD, MPH(I); Shannon M Rehling (C,P,V); Ceara L Wendel(C); Damanda F. Fagan (C,P); Tammi Marsh(C); Lauren Cadieux(V); Karen L Seyez, COT(V); Jacqueline Andrews(V); Krystal Nikki Holmes(P); Shana E Williams(P); Brenda J. Bobbitt(P)
ORLANDO, FL Florida Retina Institute, James A. Staman, MD, PA- Orlando (13)	Matthew A. Cunningham, MD(I); Samuel K. S. Houston, III, MD(I); Jaya B. Kumar, MD(I); Elias C. Mavrofrides, MD(I); Ramona Gomez(C); Elaine Rodriguez-Roman, OD(C); Martha Haddox(C); Carolina Figueroa Ortiz(V); Alma Rodriguez(P); Timothy S Holle(P); Dianelis Figueroa(P)
Augusta, GA Southeast Retina Center, P.C. (9)	Dennis M. Marcus, MD(I); Siobhan O. Ortiz(C); Thomas Bailey(V); Michele Woodward(V); Ken Ivey, COA(P)
HAGERSTOWN, MD Mid Atlantic Retina Specialists (9)	Adam T. Gerstenblith, MD(I); Robert E. Parnes, MD(I); April L. Stockman (C,P,V); Jennifer Shirey(V); Kylie Stambaugh(V); Lora Glaspell(P); Angie Goldizen(P); Leslie Toomey(P)
Jacksonville, FL Florida Retina Institute, James A. Staman, MD, PA- Jacksonville (9)	Benjamin J. Thomas, MD(I); Jonathan A. Staman, MD(I); James A. Staman, MD(I); Karen D. Yesensky (C,V); Aubrey J Hoekzema, BS(V); Becky Huynh(V); Tiffany Maximin(P); Maxsonne Charleus(P); Heavenly S Carter(P); Massiel Montalvo(P); Steven Epperson(P); Sovanny Brenda Pheng(P); Alamira B Summerville(P)
PADUCAH, KY The Ophthalmology Group, LLC (9)	Carl W. Baker, MD(I); Jil D Baker, MT, ASCP(C); Tracey M. Caldwell, CCRC(C); Margaret J. Orr, COA(V); Mary J. Sharp, COA(V); Kylie S. Sedberry(P); Samantha Kettler(P); Sonya L Alcaraz(P); Alecia B. Camp(P)
San Antonio, TX Retinal Consultants of San Antonio (9)	Calvin E. Mein, MD(I); Darrell E. Baskin, MD(I); Richard Gary Lane, MD(I); Moises A. Chica, MD(I); Lydia Adams(C); Sara L Cloudt(C); Lita Kirschbaum, COA(C); Vanessa D Martinez(C); Celeste A Belmontes(C); Jonathan San Roman(V); Victoria Lopez(V); Samantha Bankston(P); Christopher Sean Wienecke(P); Jorge Castellanos(P); Brenda Nakoski(P)
Fort Myers, FL National Ophthalmic Research Institute (8)	A. Thomas Ghuman, MD(I); Ashish G. Sharma, MD(I); Paul A. Raskauskas, MD(I); Joseph P. Walker, MD(I); Katrina A. Mears, MD, MSc, MRCOphth(I); Eileen Knips, RN, COA, CRA (C,P); Lee T Toleman, COA (C,P); Cheryl Kiesel, C.O.A., R.O.U.B. (C,P); Crystal Y. Peters, CCRC(C); Kristi Maro(C); Alice Arevalo(V); Amanda J. Petersen(V); Anita H. Leslie(V); Raymond K. Kiesel(P)
Indianapolis, IN Raj K. Maturi, M.D., P.C. (8)	Raj K. Maturi, MD(I); Stephen J Saxe(I); Lorraine White (C,P,V); Vinaya Mahesh(C); Ashley M. Harless (C,P,V); Erin Brown(V); Myra K Retrum(V); Carolee K. Novak, CRC(V); Charlotte Harris(P); Holly Fiscus(P); Stephanie J. Morrow, C.O.A.(P); Yesenia Sarmiento(P)
Knoxville, TN Southeastern Retina Associates, P.C. (8)	Joseph M. Googe, MD(I); Stephen L. Perkins, MD(I); Nicholas G. Anderson, MD(I); R. Keith Shuler, MD(I); Kristina Oliver(C); Vicky L. Seitz(C); Julie Asher (C,V); Steve Morris(C); Summer McCoy(V); Katie Milstead(V); Jeff Wheeler(V); Caitlin Gilbreath(P); Sarah M. Oelrich(P); Justin Walsh(P); Hodge A. Griffone(P); Raul E. Lince(P)
Austin, TX Retina Research Center (7)	Brian B. Berger, MD(I); Gowtham Jonna, MD(I); Saradha Chexal, MD(I); Chirag D. Jhaveri, MD(I); Fuad Makkouk, MD(I); Daniela Mariel Wilson(C); Cori Renfroe(C); Daniela Vega Pereira(C); Ivana Gunderson (C,V); Valerie Gatavaski(V); Abla M Harara(V); Yong Ren(P); Christopher C. Stovall(P)
MIAMI, FL Retina Macula Specialists of Miami (7)	Wilfredo C. Lara, MD(I); Marco A. Gonzalez, MD(I); Gary Shienbaum, MD(I); Jaziel Rodriguez (C,P,V); Pamela Garcia(C); Ana Neyra(C); David Lara(P)
Oak Park, IL Illinois Retina Associates SC – Oak Park Site (7)	Mathew W. MacCumber, MD, PhD(I); Pauline Merrill, MD(I); Sara E. Montgomery(C); Ana Maria Merchan (C,P); Annie Hernandez(V); Karen Parque(P); Cristal Cardoza(P)
Oklahoma City, OK Dean A. McGee Eye Institute (7)	Ronald M. Kingsley, MD(I); Vinay A. Shah, MD(I); Alisha N Brewer, BA(C); Myka Thomas(C); Sonny Icks, COA, CCRC (C,V); Shannon R. Almeida(C); Ashley Hughes(V); Russ Burris(P); Rachel Sohl(P); Markeisha Cheadle(P); Amanda M Hollingshead, CRA(P)
ROCHESTER, NY Retina Associates of Western NY, P.C. (7)	Edward F. Hall, MD(I); Steven J. Rose, MD(I); Brian P. Connolly, MD(I); Matthew T. Witmer, MD(I); Margaret M. Yagoda, RN, BSN(C); Mary Jo Doran, COA(C); Ann Reynard, COA(V); Malinda Goole(V); Mindy Burgess, AAS(V); Margaret Whelehan, BS(P); Joe Territo(P); Ryan W Nelson, BS(P); Susan Warrington(P)
Lenexa, KS Retina Associates, P.A. (6)	Gregory M. Fox, MD(I); Beatty G. Suiter, MD(I); Blake A. Cooper, MD(I); Ivan R. Batlle, MD(I); Ravi S. J. Singh, MD(I); Lexie R. Ainley(C); Holly A Hinkel(V); Amber R VandeVelde, RN(V); Holly Wyrick(V); Samantha Perkins(P); Katherine Pippin(P); Frank T. Yeager(P)
WEST MONROE, LA Joseph E. Humble and Raymond Haik PTRS DBA Eye Assoc of Northeast Louisiana (6)	Ruben A. Grigorian, MD(I); Latha M Jois(C); Sharoon David, MBBS (C,P); Rebecca Webb, BS, CRC (C,P,V); Rebecca Morris (C,P,V); Dusti D Douglas(V); Molly K. Cummings(V); Treasure Ritchey(P)
AYER, MA Valley Eye Physicians and Surgeons (5)	Gisela Velez, MD, MPH, MA(I); Lawrence I. Rand, MD(I); Oksana Mykhaylyk (C,V); Elizabeth I. Johnson, MS(C); Maa Ahema Parry, O.D., M.Ed.(C); Travis Sweeney(C); Nicholas R Mastrodomenico(V); Michael D. Ortega, CMA(P); Jhan Carlos Caro(P); Jean Larkin(P); Bethany A. Haight(P); Daniel Tedstone(P); Crystal Girard(P); Thomas Taylor(P); Chandapilla C. Pallipeedikayil(P); Amanda Aho(P)
Campbell, CA Retinal Diagnostic Center (5)	Lingmin He, MD(I); Clement Chow, MD(I); Amr Dessouki, MD(I); Lynise Cummins (C,V); Danielle Dinh(C); Carla Trujillo(C); Whitney Kuang (C,V); Hienmy Dang(V); Paola Montes(V); Kelly To(V); Pete Donovan Fernandez(P); Tim Kelley(P); Juan Hernandez(P)
Lubbock, TX Texas Retina Associates (5)	Michel Shami, MD(I); Yolanda Saldivar(C); Ashaki Meeks(V); Ginger K. Rhymes, COA(P); Glenn R Gardner, CRA(P)
Monroeville, PA Retina-Vitreous Consultants, Inc. (5)	Karl R. Olsen, MD(I); Robert L. Bergren, MD(I); Bernard H. Doft, MD(I); Avni Patel Vyas, MD(I); P. William Conrad, MD, PhD(I); Jared E. Knickelbein, MD, PhD(I); Lori A. Merlotti(C); Missy A. Forish(C); Lois Stepansky(V); Brittany Stout(V); Julie Walter(V); Dawn Diperna(P); Phyllis P Ostroska(P); Courtney L. Foreman(P)
Southlake, TX Jawad A Qureshi MD PA DBA Retina Center of Texas (5)	Jawad A. Qureshi, MD(I); Johnathan D. Warminski, MD(I); Gregory A Dunn(C); Victoria E. Cowart(C); Pualani Smith (C,V); Andre Watkins(P); Denise Ortiz(P); Diana Murillo(P)
CLEVELAND, OH Case Western Reserve University (4)	Shree K. Kurup, MD(I); Georgios Trichonas, MD(I); Leslie A Richards(C); Jasmeen K Randhawa(C); Margaret N Petrosky(V); Laura M Wash(V); Jennifer O’Malley(V); Claudia Clow(V); Peggy Allchin(V); Ashley Y Tucker(P); Ashley M Nicholson(P); Ahmad Al Moshmosh(P); Irit Baum-Rawraway(P); Stephanie Pelton(P); Geraldo R Miranda(P)
Portland, OR Retina Northwest, PC (4)	Apurva K. Patel, MD(I); Wenlan Zhang, MD(I); Michael S. Lee, MD(I); Paul S. Tlucek, MD(I); Brian S Puckett(C); Ashley M Adamo(C); Megan M Cleary, BS/BA(C); Inessa M Flato(V); David J Clark(V); Marcia Kopfer, BS, COT(V); Joshua Cohen(P); Michele Connaughton(P); Adrian Guardado(P)
SANDY SPRINGS, GA Thomas Eye Group (4)	Paul L. Kaufman, MD(I); Jessica D. McCluskey, MD(I); Kathy T. Wynne, BS, COT (C,V); Adelyn Wetzel, BS(C); Cynthia Weaver, COT(V); Carlos R. Cook(P); Sarah Matloff, COA(P)
St. Louis, MO Retina Research Institute, LLC (4)	Kevin J. Blinder, MD(I); Alia K. Durrani, MD(I); Sabin Dang, MD(I); Rhonda F. Weeks, CCRC(C); Allan L. Braverman, BS(C); Ginny S. Nobel, COT(C); Kara R Bockius(C); Maria A. Stuart, COA(V); Lynda K. Boyd, C.O.T.(V); Brook G. Pulliam, COA(V); Diana Reardon, RNA(V); Steve A Schremp(P); Dana L Gabel(P); Jarrod Wehmeier(P); Nathan A. Kittleman, BA(P)
Wesley Chapel, FL SEASHORE RETINA LLC DBA Retina Specialists of Tampa (4)	Evan N. Dunn, MD(I); Ahmad B. Tarabishy, MD(I); Steve Morris, BBA,COA(C); Marcus Goff (C,P,V); Dana Blair, COA(V); Megan Spear(V); Jessica Meyers(P)
Asheville, NC Western Carolina Clinical Research, LLC (3)	Cameron McLure Stone, MD(I); McCayla Elise Hall(C); Lea R. Raymer, BS(C); Monica Hamrick(C); Andrea K. Menzel, COA(C); Leslie D. Rickman, COA(V); Kaitlyn Marie Cutshaw(V); Julia Crokett Overbey(V); Ashley Hinson Klutz(V); Donna Machen(V); Lisa H. Hawkins, COA(P); Melissa Smith(P); Paula A. Price, COT(P)
AUSTIN, TX Austin Retina Associates (3)	Robert W. Wong, MD(I); Peter A. Nixon, MD(I); Ryan C. Young, MD(I); Jose A. Martinez, MD(I); Phillip V. Le (C,P,V); Chris A. Montesclaros (C,P); Gopal Karsaliya (C,V); Corinne C Vargas (C,P,V); Cory Mangham(P)
Boston, MA Joslin Diabetes Center (3)	Paolo S. Silva, MD(I); Jennifer K. Sun, MD, MPH(I); Deborah K. Schlossman, MD(I); Sabera T. Shah, MD(I); Timothy J. Murtha, MD(I); Margaret E. Stockman (C,V); Tanya Olesker, BS(C); Jae W Rhee(C); Leila Bestourous(V); Jerry D. Cavallerano, OD, PhD(V); Mina Sehizadeh, OD(V); Katie V Tran(V); Steve L. Papaconstantinou, COT(V); William Carli, COA(P); Elizabeth S. Weimann, COT, BS(P); Robert W. Cavicchi(P)
GLENDALE, CA Kent W. Small, MD, AMC (3)	Kent W. Small, MD(I); Fadi S. Shaya (C,V); Cristina Santacruz(P); Alejandra Castro(P)
GRAND RAPIDS, MI Foundation for Vision Research and Retina Specialists of Michigan, P.C. (3)	Nathan F. Pezda, MD(I); Liliya Shevchenko, DO(I); Scott J. Westhouse, DO(I); Thomas M. Aaberg, MD(I); Holly L. Vincent, COA (C,P,V); Kristyn Jae Fredrick(C); Kimberly Barrett(V); Olivia P Rainey, BFA(P); Shymaa Mohamed(P)
Houston, TX Baylor College of Medicine, Baylor Eye Physicians and Surgeons (3)	Christina Y. Weng, MD, MBA(I); Ella Leung, MD(I); Tahira Scholle, MD(I); Becky R. Chatham (C,V); Laura A Baker (C,V); Annika S. Joshi, COA, CCRC (C,V); Jiping Cai, M.D. (C,V); April Leger, COT(V); Joseph F. Morales(P); Dana B. Barnett(P)
OAKLAND, CA East Bay Retina Consultants, Inc. (3)	Soraya Rofagha, MD, MPH(I); Heidi A. Winje (C,P); Denise Joy Bustamante(V); Mae Kwan(V); Helen Ricks(V); Maria Miranda(P); Afsoon Jamali(P)
PINELLAS PARK, FL Southeast Eye Institute, P.A. dba Eye Associates of Pinellas (3)	Jason M. Handza, DO(I); Bronson Oudshoff, CCRC(C); Christina Glover(P); Annette M. Carey, COA(P)
Grand Rapids, MI VitreoRetinal Associates (2)	Louis C. Glazer, MD, FACS(I); Jeffrey D. Zheutlin, MD(I); Kathleen U. DeHorn, MD(I); Frank W. Garber, MD(I); Angela D. Listerman, BS (C,V); Melissa A. Homann, BS(C); Ashley L Igoe(C); Darra S. McLouth(V); Heather L. Cruz, AAS(V); Christine E. Feehan(V); Sue Weatherbee, AAS(P); Donald E. Kuitula, BS(P); Paul D. Crown(P); Elizabeth Truax(P)
Loma Linda, CA Loma Linda University (2)	David Isaiah Sierpina, MD(I); Michael E. Rauser, MD(I); Raquel Hernandez(C); Tina L Ramirez(C); Marcia Easterly (C,P,V); Moises Tellez(P); Adel E Alset, COA(P)
McAllen, TX Valley Retina Institute (2)	Victor Hugo Gonzalez, MD(I); Nehal R. Patel, MD(I); Amber B Ibarra, BS(C); Nancy L Salinas(C); Ana L Pina, B.A.(C); Elyssa Navarro(C); Angelina Garza, B.S.(C); Rebecca R. Flores, COA(V); Isaac Cabrera(V); Samuel Alonso(P); Georgia L. Villarreal(P); Santos Garza(P)
New Albany, IN John Kenyon American Eye Institute, LLC (2)	Howard S. Lazarus, MD(I); Debra Paige Bunch, COA (C,V); Liana C. Davis, LPN, COA (C,V); Jay Moore, COA(P); Nick Drudge(P)
New York, NY MaculaCare (2)	Daniel F. Rosberger, MD, PhD, MPH(I); Phuntsho Wangmo, BA(C); Sonam Gyaltshen (C,P,V)
Orlando, FL Ophthalmic Partners of Florida, PA dba Central Florida Retina (2)	Gokul Kumar, MD(I); Eric Feinstein, MD(I); John Olson, MD(I); Ginny G. Bell, COA(C); Sonia Philibin(V); Cathy Huertas(V); John Fulgencio(P); Sarah Daffron(P)
Overland Park, KS MidAmerica Retina Consultants, P.A. (2)	William N. Rosenthal, MD(I); Elizabeth N. Heim, BSN, RN(C); Sarah N. Lamaster, RN, BSN (C,V); Courtney J Dunn(P); R. Scott Varner(P); Mary C Stewart, RN(P)
Sarasota, FL Sarasota Retina Institute (2)	Melvin Chen, MD(I); Peggy A. Jelemensky (C,V); Samantha R. Basham(V); Tara L. Raphael(V); Rosa Miller(P); Mark Sneath, COA(P)
ALBUQUERQUE, NM Eye Associates of New Mexico (1)	Mark T. Chiu, MD(I); Ashok K. Reddy, MD(I); Kamalesh J. Ramaiya, MD(I); Bonnie J Gutierrez(C); Marlena A Daniels(C); Shirley Maerki, COA(V); Lorraine J. Carter, MPH(V); Janet L Atkinson(P); Michael G Miera, BS(P)
Bellaire, TX Retina Consultants of Texas, PA (1)	Charles C. Wykoff, MD, PhD(I); Christopher R. Henry, MD(I); Richard H. Fish, MD, FACS(I); Tyneisha McCoy(C); Amy Hutson(C); Melina Vela(V); Belinda A. Almanza(V); Veronica A. Sneed(V); Eric N. Kegley(P); David Garcia(P); Beau A Richter(P)
Milwaukee, WI The Medical College of Wisconsin, Inc. (1)	David V. Weinberg, M.D.(I); William J. Wirostko, M.D.(I); Kaitlin C McKenney, MS(C); Eleanor Dorsey, BS(C); Nickolas Chen(V); Erika Nelson(V); Brittany Rego(P); Amber N Irons(P); Hannah Sheppard(P)
PHILADELPHIA, PA Mid Atlantic Retina (1)	Jason Hsu, MD(I); Allen Chiang, MD(I); Carl Regillo, MD(I); Brianna Kenney(C); Hannah Benfield, COA(C); Dylon Williams(C); Michelle Millard(V); Lisa Grande(V); Megan Huntzberry(V); Elaine Gonzales(P)
Plantation, FL Eye Physicians of Florida LLC DBA Fort Lauderdale Eye Institute LLC (1)	Stuart K. Burgess, MD(I); Tirso M. Lara, MD(I); Noel H. Pereda, MD (C,V); Adriana Villa(V); Mark Oberlander(P); Karen Workman(P)
Spokane, WA Spokane Eye Clinical Research, PLLC (1)	Loren S. Jack, MD(I); Robert S. Wirthlin, MD(I); Andrew G. Cheek, MD(I); Eileen A. Dittman, CCRC, RN (C,V); Brian G Skea(C); Dylan C. Waidelich, COA (C,P,V); Jillian N Erstad (C,P,V)
SPRINGFIELD, IL Springfield Clinic, LLP (1)	Ramanath Bhandari, MD(I); Jennifer Shaw (C,P); Bradley C. Evans, LPN, COA(C); Amanda Fox(V); Gaylan W Moushon, OD(V); Kris Karrick, COA(P); Caitlyn Wessel(P)
Springfield, OR Cascade Medical Research Institute, LLC (1)	Allan A. Hunter, MD(I)
Tampa, FL Retina Associates of Florida, LLC (1)	Marc C. Peden, MD(I); Ivan J. Suner, MD(I); Janet R. Traynom, COT (C,P); Stephanie Munoz, COA(C); Heidi Vargo, COT(V); Susan Ramsey(V); Kim Henderson(P); Anita Kim Malzahn(P); Demi DeSilva(P)
Venice, FL Retina Associates of Sarasota (1)	Elizabeth R. Richter, MD, PhD(I); John H. Niffenegger, MD(I); Donna Scully, OD (C,V); Arysol Niffenegger, MD(C); Marianne Cottrill(C); Bruce A. Bentsen, COT(V); Amy Volpigno(P); Marisol Lopez(P)