Vascular endothelial growth factor trap-eye (Aflibercept) for the management of diabetic macular edema

Table 1 Summary of some important trials in which vascular endothelial growth factor antagonists have been evaluated for diabetic macular edema

Trial	Drug name
	Pegaptanib	Bevacizumab	Ranibizumab
Study name	Study to Evaluate safety and tolerability of pegaptanib sodium in patients with diabetic macular edema[39]	BOLT study[23,39]	RESOLVE[40]	READ-2[21,20]	READ-3	RISE[22]	RIDE[22]
Study type/phase	Interventional /phase 3	Interventional /phase 2	Interventional /phase 2	Interventional /phase 2	Interventional /phase 2	Interventional /phase 3	Interventional /phase 3
Number of patients	46	80	151	126	142	377	382
Intervention/study design	0.3 mg injections up to a maximum of 48 wk with a minimum-dosing interval of at least 6 wk	(1) Intravitreal Bevacizumab (2) MLT	(1) 0.3 mg Ranibizumab (2) 0.5 mg Ranibizumab (3) Sham	(1) 0.5 mg ranibizumab (group 1) (2) Focal/grid laser (group 2) (3) 0.5 mg ranibizumab + focal/grid laser (group 3)	(1) 0.5 mg ranibizumab (2) 2 mg ranibizumab	(1) Sham (2) 0.3 mg (3) 0.5 mg	(1) Sham (2) 0.3 mg (3) 0.5 mg
Results	No results available yet	Year 1 endpoint: A median gain of 8 ETDRS letters in the bevacizumab group vs a loss of 0.5 ETDRS letters in the MLT group (P = 0.0002) CMT decreased from 507 ± 145 μm to 378 ± 134 μm (P < 0.001) in the bevacizumab group, whereas it decreased from 481 ± 121 μm to 413 ± 135 μm in the MLT group (P = 0.02)[39] Year 2 endpoint: A Mean gain of 8.6 letters for bevacizumab vs a mean loss of 0.5 letters in the MLT group[23]. A mean reduction of 146 μm in the CMT in the bevacizumab arm vs 118 μm in the MLT arm	A gain of 10.3 ± 9.1 letters with ranibizumab and a loss of 1.4 ± 14.2 letters in the sham group (P < 0.0001) A mean CMT reduction of 194.2± 135.1 μm with ranibizumab and 48.4 ± 153.4 μm with sham (P < 0.0001) A gain of ≥ 10 letters in BCVA from baseline in 60.8% of eyes in the ranibizumab group and 18.4% of eyes in the sham group (P < 0.0001)	The mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6 mo primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24 in group 1, group 2 and group 3 respectively The percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. Mean FTH, defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively	The study has completed Results are being analyzed	Year 2 endpoint: 18.1% of sham patients gained ≥15 letters vs 44.8% of 0.3-mg (P < 0.0001) and 39.2% of 0.5-mg ranibizumab patients (P < 0.001)	12.3% of sham patients vs 33.6% of 0.3-mg patients (P < 0.0001) and 45.7% of 0.5-mg ranibizumab patients (P < 0.0001) gained more than 15 letters

DME: Diabetic macular edema; MLT: Macular laser therapy; FTH: Foveal thickness; BOLT: The intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema; READ: The Ranibizumab for Edema of the mAcula in diabetes; CMT: Central macular thickness.

Table 2 Summary of clinical trials in which aflibercept was evaluated for diabetic macular edema

Trial	Study Name
	Phase 1 study of VEGF trap in patients with DME	DA VINCI	VIVID-Japan	VISTA DME	VIVID-DME	Protocol T
Study type	Interventional	Interventional	Interventional	Interventional	Interventional	Interventional
Study phase	Phase 1	Phase 2	Phase 3	Phase 3	Phase 3	Phase 3
Official title	An exploratory study of the safety, tolerability and biological effect of a single intravitreal administration of VEGF trap eye in patients with DME	A double-masked, randomized, controlled study of the safety, tolerability and biological effect of repeated intravitreal administration of VEGF trap-eye in patients with DME	A randomized, double masked, active controlled, phase III study of the efficacy and safety of repeated doses of intravitreal VEGF trap-eye in subjects with DME	A double-masked, randomized, active-controlled, phase 3 study of the efficacy and safety of intravitreal administration of VEGF trap-eye in patients with DME	An open-label phase III study evaluating the safety and tolerability of repeated doses of intravitreal VEGF trap-eye in Japanese subjects with DME	A comparative effectiveness study of intravitreal aflibercept,bevacizumab and ranibizumab for DME
Study design
Allocation	Non-randomized	Randomized	Randomized	N/A	Randomized	Randomized
Endpoint classification	Safety Study	Safety/Efficacy study	Safety/Efficacy study	Safety/Efficacy study	Safety/Efficacy study	Safety/Efficacy study
Intervention model	Single group assignment	Parallel assignment	Parallel assignment	Single group assignment	Parallel assignment	Parallel assignment
Masking	Open label	Double blind (subject, investigator, outcomes assessor)	Double blind (subject, investigator, outcomes assessor)	Open label	Double blind (subject, investigator, outcomes assessor)	single blind (subject)
Primary purpose	Treatment	Treatment	Treatment	Treatment	Treatment	Treatment
Enrollment	5	219	65	466	406	660
Study period	6 wk	52 wk	48 wk	2 yr	52 wk	2 yr
Recruitment status	Completed	Completed	Recruiting	Active, not recruiting	Active, not recruiting	Active, recruiting
Primary outcome measure	To assess the ocular and systemic safety and tolerability of a single IVT injection of VEGF Trap-eye in patients with DME	Change in BCVA	Adverse event collection	Change from baseline of BCVA in ETDRS letter score	Change from baseline of BCVA in ETDRS letter score	Change in visual acuity from baseline to one year adjusted for baseline visual acuity
Estimated study completion date	Completed	Completed	2013	2014	2015	2016

BCVA: Best corrected visual acuity; DME: Diabetic macular edema; VEGF: Vascular endothelial growth factor; ETDRS: Early treatment diabetic retinopathy study.