Clinical Studies:
PHOTON
Citation: Brown DM, Boyer DS, Do DV, Wykoff CC, Sakamoto T, Win P, Joshi S, Salehi-Had H, Seres A, Berliner AJ, Leal S, Vitti R, Chu KW, Reed K, Rao R, Cheng Y, Sun W, Voronca D, Bhore R, Schmidt-Ott U, Schmelter T, Schulze A, Zhang X, Hirshberg B, Yancopoulos GD, Sivaprasad S. Intravitreal aflibercept 8 mg in diabetic macular oedema (Photon): 48-week results from a randomised, double-masked, noninferiority, phase 2/3 trial. Lancet (London, England).
Key Points
- PHOTON was a randomized, double-masked, non-inferiority trial comparing intravitreal aflibercept 2mg every 8 weeks, aflibercept 8mg every 12 weeks, and aflibercept 8mg every 16 weeks.
- Primary endpoint was change from baseline BCVA at week 48.
- At 48 weeks, aflibercept 8q12 and 8q16 demonstrated noninferior BCVA to aflibercept 2q8.
- A similar number of patients experienced ocular adverse events across groups.
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Objective
To study the safety and efficacy of aflibercept 8mg vs aflibercept 2mg in patients with treatment-naïve or previously treated DME.
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Study Design
Randomized, multi-center, double-masked, non-inferiority, phase 2/3 trial.
Study Subjects
- Major Inclusion Criteria:
- Patients age 18 or older
- Type 1 or Type 2 diabetes
- Treatment naïve or previously treated DME
- Central involvement and central retinal thickness (CRT) of at least 300 micrometers
- BCVA of 24-78 ETDRS letters, decreased vision primarily attributable to DME
- Major Exclusion Criteria:
- Macular edema secondary to a cause other than diabetes
- Active proliferative diabetic retinopathy
- History of pan retinal laser photocoagulation
- History of macular laser photocoagulation
- Intravitreal anti-VEGF in study eye within 12 weeks of screening
Randomization Scheme/Study Interventions
- Randomized 1:2:1 to:
- Aflibercept 2mg every 8 weeks after 5 initial monthly doses (2q8)
- Aflibercept 8mg every 12 weeks after 3 initial monthly doses (8q12)
- Aflibercept 8mg every 16 weeks after 3 initial monthly doses (8q16)
- Dose regimen modification (DRM) was permitted for the aflibercept 8q12 and 8q16 arms starting at week 16. DRM criteria: 1) 10 letter loss in BCVA from week 12 AND 2) > 50 micron increase in CRT.
Endpoints
- Primary Endpoint (48 weeks reported, 96 weeks study): Mean change from baseline in BCVA at week 48.
- Secondary Endpoints:
- Two-step improvement in Diabetic Retinopathy Severity Score (DRSS) from baseline at week 48 (noninferiority margin of 15% was prespecified)
- Mean change in baseline CRT at week 48
- Proportion of patients assigned to aflibercept 8q12 and 8q16 that maintained 12 and 16 week intervals respectively up to 48 weeks
- Safety including incidence of ocular and non-ocular treatment-emergent adverse events up to week 48
Results
- Study population: 660 patients enrolled overall (329 in aflibercept 8q12, 164 in aflibercept 8q16, and 167 in aflibercept 2q8). 658 patients (99.7%) were treated and included in full analysis and safety analysis.
- Primary Outcome Results:
- Aflibercept 8q12 and 8q16 groups met the primary endpoint and demonstrated non-inferior BCVA compared to the aflibercept 2q8 group.
- Mean change in ETDRS letters from baseline at week 48 by group: -8.8 in the 8q12 group, -7.9 in the 8q16 group, -9.2 in the 2q8 group.
- Least squares mean change in ETDRS letters from baseline in BCVA at week 48 by group: 8.1 in the 8q12 group, 7.2 in the 8q16 group, 8.7 in the 2q8 group.
- Difference in least square means in ETDRS letters between groups: -0.57 between 8q12 and 2q8 groups and -1.44 between 8q16 and 2q8 groups.
- Secondary Outcome Results:
- 273 (91%) patients in 8q12 group and 139 (89%) patients in 8q16 group maintained randomly assigned dosing interval up to 48 weeks.
- Proportion of patients that achieved two-step improvement from baseline DRSS at 48 weeks: 29.0% in 8q12 group, 19.6% in 8q16 group, 26.6% in 2q8 group. Noninferiority was achieved between 8q12 and 2q8, but not between 8q16 and 2q8 groups.
- Mean change from baseline CRT at week 48: -171.7 micrometers in the 8q12 group, -148.3 micrometers in the 8q16 group, -165.3 micrometers in the 2q8 group.
- Safety Outcome Results:
- Treatment emergent adverse events (TEAE) including conjunctival hemorrhage, vitreous floaters, vitreous detachment: 104 (32%) patients in 8q12 group, 48 (29%) patients in 8q16 group, 46 (28%) patients in the 2q8 group.
- Serious TEAE including subcapsular cataract, retinal detachment, ulcerative keratitis, vitreous hemorrhage and increased IOP: n=2 (1%) 8q12 group, n=1 (1%) 8q16 group, n=1 (1%) in 2q8 group.
- Intraocular Inflammation (IOI) was minimal in all groups: n=4 (1%) in 8q12, n=0 (0%) in 8q16, n=1 (1%) in 2q8.
- No cases of endophthalmitis or vasculitis in any group.
- Mean change in IOP did not exceed 1 mm Hg from baseline pre-dose IOP in any group at week 48.
Conclusions
- Aflibercept 8mg effectively demonstrated noninferiority to aflibercept 2mg in treatment of DME by requiring fewer initial and total injections.