Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients with Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial

NCT04126317 | CANDELA Trial | Wykoff CC et al. (2023)

Wykoff CC, Brown DM, Reed K, et al. Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients with Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial. JAMA Ophthalmology, 2023; 141(9):834-842.

Locations

Conducted across 45 sites in the United States

Study Period

November 2019 – November 2021

Study Design

Phase 2, randomized, single-masked, open-label clinical trial

Study Population

Characteristic:

Type of AMD:

2 (Wet AMD)

AMD Stage:

3 (Late)

Total Sample Size:

106 randomized patients

Age:

Phase 2, randomized, single-masked, open-label clinical trial

Sex (Male) n%:

40 (37.7%)

Experimental Group

Intervention Therapy:

Intravitreal aflibercept 8 mg

Dose & Frequency:

3 monthly doses (Weeks 0, 4, 8) followed by additional injections at Weeks 20 and 32

Age (Years):

77.0 ± 7.7

Number of Patients:

53 randomized and treated

Male N %:

23 (43.4%)

Patients Followed Up:

51 (96.2%)

Control Group

Intervention Therapy:

Intravitreal aflibercept 2 mg

Dose & Frequency:

3 monthly doses (Weeks 0, 4, 8) followed by additional injections at Weeks 20 and 32

Age (Years):

77.7 ± 8.3

Number of Patients:

53 randomized and treated

Male N %:

17 (32.1%)

Patients Followed Up:

49 (92.5%)

Follow-up Time: 44 weeks

Outcomes

Durability

The number of Injections The mean (SD) of number of injections through week 44:
• 8 mg group: 5.8 (1.2)
• 2 mg group: 5.8 (1.5)

Participants received additional treatment at week 16:
• 8 mg group: 10 of 53 (18.9%)
• 2 mg group: 13 of 51 (25.5%)

Vision

Best-Corrected Visual Acuity (BCVA)
BCVA change at Week 44:
• 8 mg group: +7.9 letters
• 2 mg group: +5.1 letters
• Difference: +2.8 letters (95% CI -1.4 to 7.0); p-value: 0.20.

Vision Maintaining
• 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.
• More participants in the aflibercept (8 mg) group gained 10 or more or 15 or more letters compared with the aflibercept (2 mg) group.
• The proportion of participants gaining 5 or more letters was similar between groups.

Other

N/A

Immunognicity

Not reported

Pharmokinetics

Not reported

Anatomic

Retinal Fluid
Absence of intraretinal and subretinal fluid in central subfield at Week 16 (Primary Outcome):
• 8 mg group: 50.9% (27/53)
• 2 mg group: 34.0% (18/53)
• Difference: 17.0% (95% CI -1.6 to 35.5); p-value: 0.08

Absence of intraretinal and subretinal fluid at Week 44:
• 8 mg group: 39.6% (21/53)
• 2 mg group: 28.3% (15/53)
• Difference: 11.3% (95% CI -6.6 to 29.2); p-value: 0.22.

Central Retinal Thickness (CRT)
CRT change at Week 44:
• 8 mg group: -159.4 µm
• 2 mg group: -137.2 µm
• Difference: -9.5 µm (95% CI -51.4 to 32.4); p-value: 0.65.

Choroidal Neovascularization (CNV)
The mean change (SE) from baseline in CNV leakage size to Week 44:
• 8 mg group: -3.7 (0.8) mm2
• 2 mg group: -3.1 (0.6) mm2

The mean change (SE) from baseline in CNV lesion size to Week 44:
• 8 mg group: -3.7 (0.8) mm2
• 2 mg group: -3.0 (0.6) mm2

Safety

Treatment-emergent AEs (TEAEs)
Participants with a TEAE from baseline to Week 44 (Co-Primary Outcome):
• 8 mg group: 42 (79.2%)
• 2 mg group: 37 (69.8%)
Participants with ocular TEAEs:
• 8 mg group: 20 (37.7%)
• 2 mg group: 20 (37.7%)
• Most common are Vitreous detachment, Conjunctival hemorrhage, and Dry eye
Participants with nonocular TEAEs:
• 8 mg group: 28 (52.8%)
• 2 mg group: 24 (45.3%)
• Most common: falls, dizziness, COVID-19, and diarrhea.

Serious TEAEs
Patients with ocular serious TEAEs in the study eye:
• 8 mg group: Retinal tear (1.9%); visual impairment (1.9%)
• 2 mg group: Reduced visual acuity (1.9%)

Patients with non-ocular serious TEAEs:
• 8 mg group: 5 (9.4%)
• 2 mg group: 4 (7.5)

Outcomes

Conclusion

Aflibercept 8 mg trended toward better anatomic and visual outcomes but did not reach statistical significance. Safety was comparable to aflibercept 2 mg, supporting further investigation in larger pivotal trials.

Risk of Bias Assessment for Primary Outcome

Randomization Process

Low risk

Note: According to the attached protocol: “randomization was according to a central randomization scheme provided by an interactive web response system (IWRS) to the designated study pharmacist (or qualified designee).”
“Baseline participant demographics and study eye ocular characteristics were generally balanced across treatment arms”

Missing Outcome Data

Low risk

Note: The evidence that the primary outcome data analysis was not biased by the missingness: “Sensitivity analyses based on observed cases, ancillary last observation carried forward, and ancillary observed cases were conducted for the primary efficacy end point.”

Selection of the Reported Results

Low risk Note: “Masked readers from the Duke Reading Center and the Digital Angiography Reading Center…”

Deviations from Intended Observations

Low risk Note: “…the participants, visual acuity examiners, and reading center were masked to treatment assignment.” “Efficacy was analyzed in the full analysis set, which comprised all randomized participants.

Measurement of the Outcome

Low risk Note: “…the participants, visual acuity examiners, and reading center were masked to treatment assignment.”

Overall

Low risk