This randomized clinical trial assesses the safety and efficacy of aflibercept, 8 mg, in patients with neovascular age-related macular degeneration.
Key Points
Question
How do the efficacy and safety of intravitreal aflibercept, 8 mg, in patients with neovascular age-related macular degeneration (nAMD) compare with aflibercept, 2 mg?
Findings
In this phase 2 randomized trial of 106 patients, more eyes treated with 8-mg vs 2-mg aflibercept had no fluid in the central subfield at week 16, although the difference was not statistically significant. Safety profiles were similar for both doses.
Meaning
Consistent but not statistically significant anatomic and visual gains favoring 8 mg over 2 mg of aflibercept coupled with no new safety signals suggest potential therapeutic benefit, which is being investigated in pivotal trials.
Abstract
Importance
Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden.
Objective
To assess safety and efficacy of aflibercept, 8 mg, in patients with nAMD.
Design, Setting, and Participants
The CANDELA trial was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted in the US. Treatment-naive patients with active subfoveal choroidal neovascularization secondary to nAMD and a best-corrected visual acuity score of 78 to 24 letters (approximately 20/32 to 20/320) in the study eye were enrolled between November 2019 and November 2021.
Interventions
Eligible participants were randomized 1:1 to receive 3 monthly doses of 8 mg (70 μL) or 2 mg (50 μL) of aflibercept followed by doses at weeks 20 and 32.
Main Outcomes and Measures
Coprimary end points were the proportion of eyes without fluid (absence of intraretinal and subretinal fluid) in the central subfield at week 16 and safety.
Results
All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53). Overall, 66 participants (62.3%) were female. The proportion of eyes without fluid in the central subfield with 8-mg vs 2-mg aflibercept was 50.9% (n = 27) vs 34.0% (n = 18) (difference, 17.0 [95% CI, –1.6 to 35.5] percentage points; P = .08) at week 16 and 39.6% (n = 21) vs 28.3% (n = 15) (difference, 11.3 [95% CI, –6.6 to 29.2] percentage points; nominal P = .22) at week 44. At week 44, mean (SE) change in central retinal thickness was –159.4 (16.4) vs –137.2 (22.8) μm with 8 mg vs 2 mg of aflibercept, respectively (least squares mean difference, –9.5 [95% CI, –51.4 to 32.4]; nominal P = .65) and mean (SE) change in best-corrected visual acuity score was +7.9 (1.5) vs +5.1 (1.5) letters (least squares mean difference, +2.8 [95% CI, –1.4 to +7.0]; nominal P = .20). No differences in safety profiles between the groups were observed.
Conclusions and Relevance
Although aflibercept, 8 mg, did not achieve the primary efficacy end point at week 16 at the 2-sided significance level of 5%, the observed trends in anatomic and visual improvements over 44 weeks with aflibercept, 8 mg, indicate potential additional therapeutic benefit over aflibercept, 2 mg. No new safety signals were observed over 44 weeks. These findings support further evaluation of aflibercept, 8 mg, in pivotal trials of exudative retinal diseases including nAMD and diabetic macular edema.
Trial Registration
ClinicalTrials.gov Identifier: NCT04126317
Introduction
Age-related macular degeneration (AMD) is a leading cause of vision impairment and blindness, estimated to affect 288 million individuals globally by 2040.1,2 Anti–vascular endothelial growth factor (anti-VEGF) therapies represent standard care for neovascular AMD (nAMD), which accounts for approximately 90% of severe vision loss due to AMD.2 Prior pivotal trials of anti-VEGF agents given at fixed monthly dosing intervals in nAMD have consistently achieved approximately 8 to 9 letters of improvement in visual acuity over the first year.3,4,5 In clinical practice, however, patients often experience smaller improvements, in part, due to lack of consistent follow-up associated with a high injection burden and the need for frequent monitoring.6,7,8 These factors may contribute to undertreatment and poorer outcomes with anti-VEGF therapies in routine clinical practice.9,10,11
Increasing the molar dose of an anti-VEGF agent may provide additional anatomic benefits. Historically, the effects of a higher dose of an anti-VEGF agent on clinical outcomes have been variable. The SAVE trial12 with ranibizumab and the HAWK trial13 with brolucizumab both demonstrated positive outcomes with a higher dose of an anti-VEGF agent. In contrast, the HARBOR trial14 did not demonstrate improved outcomes with ranibizumab doses of 2.0 mg vs 0.5 mg.
In the phase 3 VIEW 1 and 2 trials, intravitreal aflibercept, 2 mg, resulted in a higher proportion of participants with no fluid in the central subfield and a shorter time to achieve sustained dryness than with aflibercept, 0.5 mg.15 The potential anatomic benefits of aflibercept, 4 mg, were observed in the phase 2 CLEAR-IT 2 trial, which demonstrated that aflibercept, 4 mg, led to a greater reduction in central retinal/lesion thickness than aflibercept, 2 mg, after a single dose.15,16
Because these studies did not definitively establish whether a higher molar dose of aflibercept could potentially yield improved visual and anatomic outcomes with extended dosing intervals compared with aflibercept, 2 mg, further evaluation is warranted. Aflibercept, 8 mg, a 4-fold higher molar dose of aflibercept, 2 mg, was engineered in a 70-μL formulation following efforts to optimize solubility, viscosity, stability, and tolerability. CANDELA, a phase 2 randomized clinical trial, assessed the safety and efficacy of aflibercept, 8 mg, in participants with treatment-naive nAMD.
Methods
Study Design
CANDELA was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted across 45 sites in the United States between November 2019 and November 2021. All participants provided written informed consent. The study protocol was approved by the institutional review board or ethics committee of each participating site before study start. The trial protocol and statistical analysis plan are available in Supplement 1. The study was performed in adherence to principles of the Declaration of Helsinki17 and local regulations consistent with the International Council for Harmonization Guidelines for Good Clinical Practice. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Participants
Eligible patients (age ≥50 years) with treatment-naive, active subfoveal choroidal neovascularization (CNV) secondary to nAMD, including juxtafoveal lesions affecting the fovea in the study eye, with a best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score of 78 to 24 (Snellen equivalent of 20/32 to 20/320). Patients were excluded if they had evidence of CNV due to any cause other than nAMD, diabetic retinopathy, diabetic macular edema in either eye, or subretinal hemorrhage that was 50% or more of the total lesion area in the study eye. Full inclusion and exclusion criteria are provided in the eMethods in Supplement 2. Participants received a stipend for each visit and travel reimbursement and/or a car service. Participants self-identified one (primary) of the following race categories: American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or other Pacific Islander, White, not reported, or other. Ethnicity was captured as Hispanic or Latino, not Hispanic or Latino, not reported, or unknown.
Study Treatment and Procedures
Eyes were randomized 1:1 to receive 3 monthly doses of either aflibercept, 8 mg (70 μL), or aflibercept, 2 mg (50 μL), followed by doses at weeks 20 and 32 (eFigure 1 in Supplement 2). Critically, both treatment arms were prescribed the same fixed dosing schedule. At the discretion of the investigator, eyes could receive additional treatment at week 16 due to persistent or worsening disease. At weeks 24, 28, 36, and 40, eyes could receive as-needed treatment at their randomization dose if they met either of the following criteria: (1) loss of 5 or more letters from week 20 due to disease progression or (2) vision-threatening anatomic findings per investigator judgment such as worsening or persistent retinal fluid, new or worsening retinal pigment epithelial detachment, or new or persistent hemorrhage.
This was a single-masked study; the participants, visual acuity examiners, and reading center were masked to treatment assignment but study investigators and study site personnel were not. Masked readers from the Duke Reading Center and the Digital Angiography Reading Center, respectively, assessed the spectral-domain optical coherence tomography and fluorescein angiography or fundus photography images. Fluorescein angiography and fundus photography were performed at baseline and at weeks 12, 20, and 44. Further details on study procedures can be found in the eMethods in Supplement 2.
Outcome Measures
The coprimary end points were the proportion of eyes without fluid (defined as absence of intraretinal and subretinal fluid) in the central subfield on spectral-domain optical coherence tomography at week 16 and safety, as assessed by the incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs, through week 4 (primary safety analysis to assess initial safety) and week 44. Additional exploratory end points included the proportions of eyes without fluid in the central subfield at week 44 and in the macula (defined as the region centered on the foveal center point approximately 6 mm × 6 mm) at weeks 16 and 44; the proportion of participants with vision loss or gain at week 44; and change from baseline in central retinal thickness (CRT), total lesion size and CNV size (as determined by reading center analysis of fluorescein angiography images), and BCVA score at week 44. Additional safety outcomes assessed included change from baseline in intraocular pressure (IOP) and systolic and diastolic blood pressure (BP), and assessment of Anti-Platelet Trialists’ Collaboration–defined arterial thromboembolic events (adjudicated by committee). TEAEs were coded using the currently available version of the Medical Dictionary for Regulatory Activities (version 24.0).
Statistical Analysis
An estimated sample size of 50 participants per group was sufficient to provide substantial information regarding safety. With this sample size (total of 100), the 95% CI for the treatment difference in the primary efficacy end point was expected to range from 6.7% to 43.3% for an analysis using normal approximation, assuming a proportion of participants without fluid in the central subfield in the aflibercept, 2 mg, group of 50%, an observed treatment difference of 25%, and an 8% dropout rate.
Efficacy was analyzed in the full analysis set, which comprised all randomized participants. The safety analysis population included all randomized participants who received any study treatment. The primary efficacy analysis was performed using the χ2 test at the 2-sided 5% significance level. Missing values were imputed using the last observation carried forward method for the statistical analysis of the primary efficacy end point at week 16. For eyes that received additional treatment at week 16, data from week 16 (the last value before administration of additional treatment) were carried forward and used for analysis; values collected after additional treatment were censored for the last observation carried forward analysis. Data for participants who received as-needed treatment after week 16 were not censored. Sensitivity analyses based on observed cases, ancillary last observation carried forward, and ancillary observed cases were conducted for the primary efficacy end point. Continuous exploratory end points, including changes in CRT and BCVA score, were summarized descriptively. These data were analyzed using an analysis of covariance model with treatment as the main effect and baseline measurement as a covariate. No adjustment for multiplicity testing was made; all reported P values for exploratory end points are nominal.
Results
All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53) (eFigure 2 in Supplement 2). Overall, 53 eyes in the aflibercept, 8 mg, group and 51 eyes in the aflibercept, 2 mg, group had follow-up beyond the 16-week visit. Study completion rates were 96.2% (n = 51) for aflibercept, 8 mg, and 92.5% (n = 49) for aflibercept, 2 mg.
Baseline participant demographics and study eye ocular characteristics were generally balanced across treatment arms (Table 1). Overall, 106 participants were included of which 66 (62.3%) were female. Mean (SD) BCVA score was 57.9 (13.6) and 58.2 (10.5) letters (Snellen equivalent, 20/70) in the 8-mg and 2-mg aflibercept groups, respectively. Mean (SD) CRT was higher in the aflibercept, 8 mg, group (516.2 [175.6] μm) than the aflibercept, 2 mg, group (488.1 [204.9] μm). CNV lesion types in both 8-mg and 2-mg aflibercept groups were most commonly occult (26 [49.1%] and 22 [41.5%], respectively) or minimally classic (19 [35.8%] and 26 [49.1%]).
Table 1. Participant Demographics and Baseline Characteristics.
| Characteristic | Aflibercept, 8 mg (n = 53) | Aflibercept, 2 mg (n = 53) |
|---|---|---|
| Age, mean (SD), y | 77.0 (7.7) | 77.7 (8.3) |
| Female, No. (%) | 30 (56.6) | 36 (67.9) |
| Male, No. (%) | 23 (43.4) | 17 (32.1) |
| Race and ethnicity, No. (%) | ||
| American Indian or Alaska Native | 0 | <5 |
| Hispanic or Latino | <5 | <5 |
| Native Hawaiian or other Pacific Islander | <5 | 0 |
| White | 52 (98.1) | 51 (96.2) |
| Othera | 0 | <5 |
| BCVA score in study eye, mean (SD), ETDRS letters | 57.9 (13.6)b | 58.2 (10.5)b |
| CRT in the study eye, mean (SD), μm | 516.2 (175.6) | 488.1 (204.9) |
| CRT in the study eye, median, μm | 459.0 | 441.0 |
| Lesion size, mean (SD), mm2 | 7.7 (6.8) | 7.9 (6.2) |
| CNV size, mean (SD), mm2 | 7.5 (6.9) | 7.9 (6.2) |
| FA classification, No. (%) | ||
| Occult CNV | 26 (49.1) | 22 (41.5) |
| Minimally classic | 19 (35.8) | 26 (49.1) |
| Predominantly classic | 8 (15.1) | 4 (7.5) |
| Missing | 0 | 1 (1.9) |
| IOP in study eye, mean (SD), mm Hg | 14.8 (3.4) | 14.9 (3.4) |
| Systolic BP, mean (SD), mm Hg | 124.6 (10.6) | 125.4 (10.6) |
| Diastolic BP, mean (SD), mm Hg | 71.7 (8.5) | 70.7 (9.0) |
Abbreviations: BCVA, best-corrected visual acuity; BP, blood pressure; CNV, choroidal neovascularization; CRT, central retinal thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; FA, fluorescein angiograph; IOP, intraocular pressure.
Participants self-reported other, with no further details available.
Equivalent to approximately 20/60 to 20/70 Snellen visual acuity.
Anatomic Outcomes
At week 16 (8 weeks after initial monthly dosing in both groups), the proportion of eyes without fluid in the central subfield was 50.9% (n = 27) in the aflibercept, 8 mg, group and 34.0% (n = 18) in the aflibercept, 2 mg, group (treatment difference, 17.0 [95% CI, –1.6 to 35.5] percentage points; P = .08) (Figure 1A). At week 44, more eyes in the 8-mg (21 [39.6%]) vs 2-mg (15 [28.3%]) aflibercept group achieved a fluid-free central subfield (treatment difference, 11.3 [95% CI, –6.6 to 29.2] percentage points; nominal P = .22). Similarly, higher proportions of eyes in the 8-mg vs 2-mg aflibercept group had no central subfield fluid at each follow-up between weeks 16 and 44. The results of the sensitivity analyses were consistent with those of the primary analysis (eTable in Supplement 2).
Figure 1. Key Anatomic Outcomes in the Full Analysis Set.
For last observation carried forward, missing observations were imputed by the last nonmissing postbaseline observation. For participants receiving additional treatment at week 16, measurements after week 16 were imputed using last observation carried forward prior to additional treatment. Least squares mean difference was determined based on an analysis of covariance model with treatment as the main effect and baseline measurement as covariates. CRT indicates central retinal thickness.
aNo fluid in the central subfield was defined as absence of intraretinal and subretinal fluid in the central subfield on spectral-domain optical coherence tomography.
bScheduled dose visit.
cTreatment difference was 17.0% (95% CI, –1.6% to 35.5%; P = .08) at week 16 (primary efficacy end point).
dTreatment difference was 11.3% (95% CI, –6.6% to 29.2%; nominal P = .22) at week 44.
eLeast squares mean difference at week 44 was –9.5 (95% CI, –51.4 to 32.4) letters vs 2-mg aflibercept (nominal P = .65).
A similar proportion of eyes in the 8-mg and 2-mg aflibercept group had no intraretinal fluid in the central subfield at week 16 (37 [69.8%] vs 36 [67.9%]; treatment difference, 1.9 [95% CI, –15.7 to 19.5] percentage points; nominal P = .83) and 44 (32 [60.4%] vs 34 [64.2%]; difference, –3.8 [95% CI, –22.2 to 14.7] percentage points; nominal P = .69) (eFigure 3 in Supplement 2). More eyes in the 8-mg vs 2-mg aflibercept group had no subretinal fluid in the central subfield at both weeks 16 and 44 (37 [69.8%] vs 27 [50.9%]; treatment difference, 18.9 [95% CI, 0.6-37.1] percentage points; nominal P = .047 for both time points). When the presence of fluid was assessed across the entire macular cube, 17 eyes (32.1%) in the aflibercept, 8 mg, group vs 8 (15.1%) in the aflibercept, 2 mg, group had no macular fluid at week 44 (difference, 17.0 [95% CI, 1.1-32.8] percentage points; nominal P = .04) (eFigure 4 in Supplement 2).
The mean change (SE) from baseline in CRT at week 44 was –159.4 (16.4) μm and –137.2 (22.8) μm for the 8-mg and 2-mg aflibercept groups, respectively (least squares mean difference, –9.5 μm [95% CI, –51.4 to 32.4]; nominal P = .65) (Figure 1B). To mitigate the effect of outliers, median change from baseline in CRT was also examined. At each study visit, the reduction in median change in CRT was greater with 8-mg vs 2-mg aflibercept over 44 weeks (eFigure 5 in Supplement 2).
At week 44, mean change (SE) from baseline in CNV size was –3.7 (0.8) mm2 with aflibercept, 8 mg, compared with –3.1 (0.6) mm2 with aflibercept, 2 mg. Mean change (SE) in total lesion size was –3.7 (0.8) mm2 with aflibercept, 8 mg, and –3.0 (0.6) mm2 with aflibercept, 2 mg.
Visual Outcomes
At week 44, mean (SE) BCVA score increased by 7.9 (1.5) letters with aflibercept, 8 mg, vs 5.1 (1.5) letters with aflibercept, 2 mg (least squares mean difference, 2.8 [95% CI, –1.4 to 7.0] letters; nominal P = .20) (Figure 2A). Fewer participants in the aflibercept, 8 mg, group lost 5 or more letters, 10 or more letters, or 15 or more letters compared with the aflibercept, 2 mg, group at week 44. Conversely, more participants in the aflibercept, 8 mg, group gained 10 or more or 15 or more letters compared with the aflibercept, 2 mg, group (Figure 2B). The proportion of participants gaining 5 or more letters was similar between groups.
Figure 2. Key Visual Outcomes in the Full Analysis Set.
For last observation carried forward, missing observations were imputed by the last nonmissing postbaseline observation. For participants receiving additional treatment at week 16, measurements after week 16 were imputed using the last observation carried forward prior to additional treatment. Least squares mean difference was determined based on an analysis of covariance model with treatment as the main effect and baseline measurement as covariates. BCVA indicates best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study.
aLeast squares mean difference at week 44 was 2.8 (95% CI, –1.4 to 7.0) letters (nominal P = .20) vs 2-mg aflibercept.
bScheduled dose visit.
cTwo participants in the aflibercept, 2 mg, group did not have postbaseline values.
Exposure
Through week 44, participants in the 8-mg (n = 53) and 2-mg (n = 53) aflibercept groups received mean (SD) of 5.8 (1.2) and 5.8 (1.5) injections, respectively. Of the participants completing the study, the mean number of injections through week 44 was 5.8 (1.2) for the aflibercept, 8 mg, group (n = 51) and 5.9 (1.2) for the aflibercept, 2 mg, group (n = 49). Of the participants who completed the week 16 visit, 10 of 53 (18.9%) in the aflibercept, 8 mg, group and 13 of 51 (25.5%) in the aflibercept, 2 mg, group received additional treatment at week 16. Thirty-three and 38 as-needed injections were administered in the 8-mg and 2-mg aflibercept groups, respectively. Of the participants who completed the study, a total of 29 of 51 eyes (56.9%) in the aflibercept, 8 mg, group and 24 of 49 eyes (49.0%) in the aflibercept, 2 mg, group did not receive as-needed/additional treatment.
Safety
No new safety signals were identified for aflibercept, 8 mg, at week 4 (primary safety end point) and through the 44-week study period. The overall safety of aflibercept, 8 mg, was similar to that of 2 mg. Over the 44-week study, 20 participants (37.7%) from each treatment group experienced 1 or more ocular TEAEs in the study eye, most commonly nAMD (aflibercept, 8 mg: 2 [3.8%]; aflibercept, 2 mg: 4 [7.5%]) and vitreous detachment (aflibercept, 8 mg: 4 [7.5%]; aflibercept, 2 mg: 2 [3.8%]) (Table 2). No vascular occlusive events occurred in either group. One case of iritis in the aflibercept, 8 mg, group (mild anterior chamber cells) was reported after the last scheduled dose of the study drug (week 32) and resolved with topical therapy by the week 36 visit. Three participants experienced ocular serious TEAEs in the study eye: 1 (1.9%) each in the aflibercept, 8 mg, group experienced a retinal tear and visual impairment and 1 (1.9%) in the aflibercept, 2 mg, group experienced reduced visual acuity. All ocular serious TEAEs were considered unrelated to study drug. The event of retinal tear was graded as severe and related to the injection procedure. The events of visual impairment and reduced visual acuity were considered as mild in severity. For all 3 events, no changes to the participant’s study treatment were required. Overall, 28 participants (52.8%) in the aflibercept, 8 mg, group and 24 (45.3%) in the aflibercept, 2 mg, group experienced nonocular TEAEs (Table 2), most commonly fall (aflibercept, 8 mg: 3 [5.7%]; aflibercept, 2 mg: 2 [3.8%]). Nonocular serious TEAEs were recorded in 5 participants (9.4%) in the aflibercept, 8 mg, group and 4 (7.5%) in the aflibercept, 2 mg, group. In both groups, predose IOP remained stable through week 44 with no clinically relevant increases (Figure 3A). No participant in the 8-mg and 2-mg aflibercept groups had IOP (predose and postdose) of 35 mm Hg or more in the study eye at any visit.
Table 2. Key TEAEs Through Week 44.
| TEAEa | No. (%) | |
|---|---|---|
| Aflibercept, 8 mg (n = 53) | Aflibercept, 2 mg (n = 53) | |
| Participants with a TEAE | 42 (79.2) | 37 (69.8) |
| Participants with ocular TEAEs | 20 (37.7) | 20 (37.7) |
| Ocular TEAEs occurring in ≥2% of participants in any treatment arm | ||
| Vitreous detachment | 4 (7.5) | 2 (3.8) |
| Conjunctival hemorrhage | 3 (5.7) | 2 (3.8) |
| Dry eye | 2 (3.8) | 2 (3.8) |
| nAMD | 2 (3.8) | 4 (7.5) |
| Retinal tearb | 2 (3.8) | 0 |
| Punctate keratitis | 1 (1.9) | 2 (3.8) |
| Visual acuity reduced | 1 (1.9) | 2 (3.8) |
| Retinal hemorrhage | 1 (1.9) | 2 (3.8) |
| Visual impairment | 1 (1.9) | 2 (3.8) |
| Ocular serious TEAEs in the study eye | 2 (3.8) | 1 (1.9) |
| Retinal tear | 1 (1.9) | 0 |
| Visual acuity reduced | 0 | 1 (1.9) |
| Visual impairment | 1 (1.9) | 0 |
| Participants with nonocular TEAEs | 28 (52.8) | 24 (45.3) |
| Nonocular TEAEs occurring in ≥2 participants in any treatment arm | ||
| Fall | 3 (5.7) | 2 (3.8) |
| Dizziness | 3 (5.7) | 0 |
| COVID-19 | 2 (3.8) | 2 (3.8) |
| Diarrhea | 2 (3.8) | 1 (1.9) |
| Urinary tract infection | 2 (3.8) | 1 (1.9) |
| Nausea | 2 (3.8) | 0 |
| Chest pain | 2 (3.8) | 0 |
| Skin laceration | 2 (3.8) | 0 |
| Sinusitis | 1 (1.9) | 2 (3.8) |
| Arthralgia | 0 | 2 (3.8) |
| Gastroesophageal reflux disease | 0 | 2 (3.8) |
| Nonocular serious TEAEs | 5 (9.4) | 4 (7.5) |
| Acute left ventricle failure | 1 (1.9) | 0 |
| Chest pain | 1 (1.9) | 0 |
| Noncardiac chest pain | 1 (1.9) | 0 |
| Lumbar spinal stenosis | 1 (1.9) | 0 |
| Hepatic encephalopathy | 1 (1.9) | 0 |
| Transient ischemic attack | 1 (1.9) | 0 |
| Acute respiratory failure | 1 (1.9) | 0 |
| Colitis | 0 | 1 (1.9) |
| Small intestinal obstruction | 0 | 1 (1.9) |
| COVID-19 | 0 | 1 (1.9) |
| Femur fracture | 0 | 1 (1.9) |
Abbreviations: nAMD, neovascular age-related macular degeneration; TEAE, treatment-emergent adverse event.
A participant could have more than 1 TEAE. TEAEs were coded per Medical Dictionary for Regulatory Activities Coding Dictionary, version 24.0.
These participants experienced a horseshoe tear and a small operculum. The horseshoe tear, which was related to the injection procedure, was considered serious TEAE.
Figure 3. Mean Change From Baseline in Predose Intraocular Pressure (IOP) and Blood Pressure (BP) in the Safety Analysis Set.
aScheduled dose visit.
No Anti-Platelet Trialists’ Collaboration–defined arterial thromboembolic events were reported over 44 weeks. One nonserious case of worsening hypertension occurred in each treatment group. Neither 8-mg nor 2-mg aflibercept appeared to be associated with any increases in systolic or diastolic BP (Figure 3B). There was 1 death in the aflibercept, 8 mg, group, which occurred after study withdrawal due to glioblastoma; this event was not considered related to study treatment.
Discussion
In the phase 2 CANDELA trial, a statistically significant difference in the primary efficacy end point (proportion of eyes without fluid in the central subfield) at week 16 was not achieved at the 2-sided 5% significance level. However, aflibercept, 8 mg, consistently showed numerically greater improvements in anatomic and visual outcomes, including the proportion of eyes that were fluid-free in the central subfield and mean change in BCVA score, compared with aflibercept, 2 mg, in participants with treatment-naive nAMD.
This trial was intended to evaluate safety and the drying effect of 8-mg compared with 2-mg aflibercept. Dosing intervals beyond 12 weeks were not permitted during this 44-week study. Although a smaller number of participants in the aflibercept, 8 mg, group received additional and/or as-needed treatment compared with aflibercept, 2 mg, there was only a small difference in the mean number of injections between groups of participants completing the study. The treatment regimen used in this trial was structured to be comparable with a real-world paradigm in which patients often receive treatment at intervals of 8 weeks or longer following an initial monthly dosing period, regardless of the anti-VEGF agent.18,19
In the CANDELA trial, participants receiving aflibercept, 8 mg, achieved an approximate 8-letter gain by week 44. Similar improvements have been reported in phase 3 trials of currently approved anti-VEGF agents with dosing regimens of every 4 weeks and every 8 weeks.3,4,5
Variable findings have been reported across studies evaluating higher molar anti-VEGF agents. Differences in study designs, including the patient population and the outcomes assessed, limit our current understanding of the potential effects of higher molar dose anti-VEGF agents. In the ANCHOR5 and MARINA20 trials, ranibizumab, 0.5 mg, was favored for most functional and anatomic outcomes compared with ranibizumab, 0.3 mg. Data from the SAVE trial12 among patients with recalcitrant nAMD showed ranibizumab, 2 mg, may confer incremental functional and anatomic benefit, and possibly increased durability, compared with ranibizumab, 0.5 mg. Similar observations were noted in the phase 3 HAWK trial,13 in which a numerically greater proportion of patients maintained 12-week dosing intervals over 48 weeks with 6-mg vs 3-mg brolucizumab. In contrast, improved visual or anatomic outcomes were not observed with 2.0-mg vs 0.5-mg ranibizumab among treatment-naive patients with nAMD.14
Within the CANDELA trial, consistent improvements in anatomic and visual outcomes were achieved with aflibercept, 8 mg, that trended toward a numeric benefit vs aflibercept, 2 mg. Treatment with aflibercept, 8 mg, was well tolerated with a similar safety profile to aflibercept, 2 mg, through week 44. Despite the 20-μL increase in injection volume for eyes receiving aflibercept, 8 mg, predose IOP was similar to the aflibercept, 2 mg, group and no cases of IOP of 35 mm Hg or higher were reported at any visit in the 2 treatment arms. Consistent with prior studies showing that aflibercept does not affect BP,21,22 stable systolic and diastolic BP readings were observed, with low and similar between-visit variability in systolic and diastolic BP in both groups.
The anatomic and visual benefits of aflibercept, 8 mg, observed in the CANDELA trial are supported by recently released 48-week primary end point data from the ongoing phase 3 PULSAR trial in nAMD, which showed participants receiving aflibercept, 8 mg, every 12 or 16 weeks following 3 initial monthly injections achieved noninferior visual gains and a significantly greater proportions of participants achieved dryness in the center subfield at weeks 16 and 48 compared with aflibercept, 2 mg, dosed every 8 weeks.23,24 Moreover, no new safety signals were observed with 8-mg vs 2-mg aflibercept through 48 weeks in the phase 3 trial.
Limitations
CANDELA was a proof-of-concept study with a small sample size and duration of 44 weeks. Furthermore, aflibercept, 2 mg, was intentionally not dosed per label, which allowed for more direct comparison of 8 mg vs 2 mg of aflibercept. Despite these limitations, positive trends in anatomic and visual outcomes observed in this study suggest aflibercept, 8 mg, may offer potential therapeutic benefits.
Conclusions
Findings from this phase 2 proof-of-concept study showed that aflibercept, 8 mg, trended toward better anatomic and visual outcomes with a similar safety profile as aflibercept, 2 mg. Further evaluation in the pivotal 96-week PULSAR (in nAMD) and PHOTON (in diabetic macular edema) trials may support the long-term therapeutic potential of aflibercept, 8 mg, for improving outcomes and decreasing treatment burden for patients with exudative retinal diseases.
Trial protocol and statistical analysis plan
eMethods.
eFigure 1. Study design
eFigure 2. CONSORT Diagram
eFigure 3. Proportion of Eyes Without (A) Intraretinal or (B) Subretinal Fluid in the Central Subfield at Week 16 and 44
eFigure 4. Proportion of Eyes Without Fluid in the Macula
eFigure 5. Median Change From Baseline in CRT Through Week 44
eTable. Sensitivity Analyses of the Proportion of Patients Without Fluid in the Central Subfield
Nonauthor Collaborators. CANDELA Study Investigators
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol and statistical analysis plan
eMethods.
eFigure 1. Study design
eFigure 2. CONSORT Diagram
eFigure 3. Proportion of Eyes Without (A) Intraretinal or (B) Subretinal Fluid in the Central Subfield at Week 16 and 44
eFigure 4. Proportion of Eyes Without Fluid in the Macula
eFigure 5. Median Change From Baseline in CRT Through Week 44
eTable. Sensitivity Analyses of the Proportion of Patients Without Fluid in the Central Subfield
Nonauthor Collaborators. CANDELA Study Investigators
Data sharing statement
