Table 5

Pegaptanib and aflibercept studies

StudyParticipants and baseline valuesInterventionOutcome (change from baseline at study end)
Pegaptanib
Cunningham et al/Adamis et al39 57
USA
Design: 4-arm phase II RCT
Follow-up: 36 weeks
N: 172 eyes of 172 patients
Inclusion criteria: ≥18 years, type 1 or 2 DM, DMO involving the center of the macula with corresponding leakage from microaneurysms, retinal telangiectasis, or both; clear ocular media, BCVA letter scores between 68 and 25 in the study eye and at least 35 in the fellow eye; IOP ≤23 mm Hg, focal photocoagulation could be safely deferred for 16 weeks; no ECG abnormalities, no major serological abnormalities
Exclusion criteria: history of panretinal or focal photocoagulation; neodymium:yttrium–aluminum–garnet laser or peripheral retinal cryoablation in previous 6 months; any ocular abnormality interfering with VA assessment or fundus photography; vitreoretinal traction; vitreous incarceration; retinal vein occlusion involving the macula; atrophy/scarring/fibrosis or hard exudates involving the center of the macula; history of intraocular surgery within previous 12 months, myopia of ≥8 diopters, axial length of ≥25 mm, likelihood of requiring panretinal photocoagulation within following 9 months; cataract surgery within 12 months; active ocular or periocular infection; previous therapeutic radiation to the eye, head, or neck; known serious allergies to fluorescein dye; HbA1c ≥13%, pregnancy
Age: 61.3–64.0 SD9.3–10.1 years
Sex: 45–55% female
Diabetes type: 5–10% IDDM
HbA1c: 7.1–7.7 SD1.2–1.6
Baseline VA: letter score 55.0–57.1 SD9.1–11.5
Baseline CMT: 423.2–476.0 µm
Comorbidities: not reported
Group 1 (IVP0.3, n=44 eyes): 0.3 mg IV pegaptanib (90 µl) (median 5 injections (range 1–6))
Group 2 (IVP1, n=44 eyes): 1 mg IV pegaptanib (90 µl) (median 6 injections (range 3–6))
Group 3 (IVP3, n=42 eyes): 3 mg IV pegaptanib (90 µl) (median 6 injections (range 1–6))
Group 4 (C, n=42 eyes): sham injection (median 5 injections (range 1–6))
Regimen for all groups: injections at baseline, week 6 and week 12; thereafter, additional injections administered every 6 weeks at the discretion of the investigators if judged indicated (maximum of 6 injections up to week 30); laser photocoagulation allowed after week 13 if judged indicated by the study-masked ophthalmologist (25% for IVP0.3, 30% for IVP1, 40% for IVP3, 48% for C)
At 36 weeks
BCVA:
 BCVA (letters)p Value
IVP0.3+4.70.04 vs C
IVP1+4.70.05 vs C
IVP3+1.1NS vs C
C−0.4
Plus10 letters
IVP0.334%0.003 vs C
IVP130%
IVP314%
C10%
CMT (OCT):
CMT (µm, 95% CI)p Value
IVP0.3−68.0 (−118.9 to −9.88)0.02 vs C
IVP1−22.7 (−76.9 to +33.8)NS vs C
IVP3−5.3 (−63.0 to +49.5)NS vs C
C+3.7
▸ Subgroups: of 16 participants with retinal neovascularisation at baseline, 8 of 13 (62%) in the pegaptanib groups and 0 of 3 in the sham group had regression of neovascularisation at 36 weeks
Sultan et al40
Multicenter international
Design: 2-arm placebo-controlled RCT
Follow-up: 2 years (primary efficacy endpoint at 1 year)
N: 260 eyes of 260 patients
Inclusion criteria: ≥18 years, type 1 or 2 DM, DMO involving the center of the macula not associated with ischemia, CMT ≥250 µm, BCVA letter score 65–35, IOP ≤21 mm Hg, clear ocular media
Exclusion criteria: any abnormality other than DMO affecting VA assessment, vitreomacular traction; yttrium–aluminium–garnet laser, peripheral retinal cryoablation, laser retinopexy for retinal tears, focal or grid photocoagulation within prior 16 weeks; panretinal photocoagulation <6 months before baseline or likely to be needed within 9 months; significant media opacities; intraocular surgery in prior 6 months; pathological high myopia; prior radiation in region of study eye; history of severe cardiac or peripheral vascular disease, stroke in prior 12 months, major surgery in prior 1 month, treatment in prior 90 days with any investigational agent or with bevacizumab for any nonocular condition, HbA1c ≥10% or signs of uncontrolled diabetes, hypertension, known relevant allergies; pregnant or lactating
Age: 62.3–62.5 SD9.3–10.2 years
Sex: 39–46% female
Diabetes type: 6.3–7.5% type 1 DM, 92.5–93.7% type 2 DM
HbA1c: 42.5–45.9% <7.6%, 54.1–57.5% >7.6%
Baseline VA: letter score 57.0–57.5 SD8.1–8.9
Baseline CMT: 441.6–464.6 SD135.5–148.5 µm
Comorbidities: not reported
Group 1 (IVP, n=133 eyes): 0.3 mg IV pegaptanib sodium (mean number of injections 12.7 SD4.6)
Group 2 (C, n=127 eyes): sham injection (mean number of injections 12.9 SD4.4)
Regimen for all groups: injections every 6 weeks up to week 48 (9 injections); at investigator determination (ETDRS criteria), laser photocoagulation could be performed at week 18, with possible repeat treatment at a minimum of 17 weeks later (maximum 3 treatments per year) (laser treatments in 25.2% of IVP group and 45% of C group); in year 2, injections as judged necessary
At 1 year
BCVA (ETDRS):
BCVA (letters) p Value
IVP+5.2<0.05 vs C
C+1.2
Plus10 letters
IVP36.8%0.0047 vs C
C19.7%
Retinopathy:
Increase in degree by2 steps
IVP4.1%0.047 vs C
C12.4%
Decrease in degree by ≥2 steps
IVP10.2%NS vs C
C3.1%
CMT (OCT):Decrease in CMT
IVP≥25%: 31.7%
≥50%: 14.6%
NS vs C
C≥25%: 23.7%
≥50%: 11.9%
At 2 years
BCVA (ETDRS):
BCVA (letters)p Value
IVP+6.1<0.01 vs C
C+1.3
Plus10 letters
IVP38.3%NS vs C
C30%
Retinopathy:
Increase in degree by2 steps
IVP6.3%NS vs C
C13.8%
Decrease in degree by2 steps
IVP16.3%0.03 vs C
C3.8%
CMT (OCT):
Decrease in CMT
IVP≥25%: 40.4%
≥50%: 19.2%
NS vs C
C≥25%: 44.6%
≥50%: 26.1%
QoL:
NEI VFQ-25: between group differences not significant at 54 weeks; at 102 weeks, significantly greater improvement in composite score and subscales distance vision activities, social functioning and mental health with pegaptanib
EQ-5D: no significant differences between groups in EQ-5D scores at weeks 54 or 102
Aflibercept
DA VINCI 2010 (Do et al)30 58
Multicenter
Design: 5-arm phase II RCT
Follow-up: 24 weeks
N: 221 eyes of 221 patients
Inclusion criteria: aged >18 years and diagnosed with type 1 or 2 diabetes mellitus, with DMO involving the central macula defined as CRT (>250 um in the central subfield. Participants were required to have BCVA letter score at 4 m of 73–24. Women of childbearing potential were included only if they were willing to not become pregnant and to use a reliable form of birth control during the study period
Exclusion criteria: history of vitreoretinal surgery; panretinal or macular laser photocoagulation or use of intraocular or periocular corticosteroids or antiangiogenic drugs within 3 months of screening; vision decrease due to causes other than DMO; proliferative diabetic retinopathy (unless regressed and currently inactive); ocular inflammation; cataract or other intraocular surgery within 3 months of screening, laser capsulotomy within 2 months of screening; aphakia; spherical equivalent of >8 diopters; or any concurrent disease that would compromise visual acuity or require medical or surgical intervention during the study period: active iris neovascularisation, vitreous hemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula; visually significant vitreomacular traction or epiretinal membrane evident biomicroscopically or on OCT; history of idiopathicor autoimmune uveitis; structural damage to the center of the macula that is likely to preclude improvement in visual acuity after the resolution of macular oedema; uncontrolled glaucoma or previous filtration surgery; infectious blepharitis, keratitis, scleritis, or conjunctivitis; or current treatment for serious systemic infection: uncontrolled diabetes mellitus; uncontrolled hypertension; history of cerebral vascular accident or myocardial infarction within 6 months; renal failure requiring dialysis or renal transplant; pregnancy or lactation; history of allergy to fluorescein or povidone iodine; only 1 functional eye (even if the eye met all other entry criteria); or an ocular condition in the fellow eye with a poorer prognosis than the study eye
Age: 60.7–64.0 years (SD 8.1–11.5)
Sex: % female 35.6–47.6%
Diabetes type: percentage of type 2, 88.6–97.7%
HbA1c: 7.85–8.10 (SD 1.71–1.94)
Baseline VA: 57.6–59.9 (SD 10.1–12.5)
Baseline CMT: 426.1–456.6 µm (SD 111.8–152.4)
Comorbidities: history of any cardiac disease was twice as common in the VEGF Trap-Eye groups compared with the laser group
Trial of VEGF Trap-Eye (VTE), randomised on a 1 : 1:1 : 1:1 basis
Group 1 (IVVTE1, n=44 eyes): IVVTE, 0.5 mg every 4 weeks
Group 2 (IVVTE2, n=44 eyes): IVVTE, 2 mg every 4 weeks
Group 3 (IVVTE3, n=42 eyes): IVVTE, 2 mg for 3 initial months then every 8 weeks
Group 4 (IVVTE4, n=45 eyes): IVVTE, 2 mg for 3 initial months then as needed
Group 5 (L, n=44 eyes): laser photocoagulation
Laser modified ETDRS protocol
At 6 months
 BCVA (letters)p Value
IVVTE1+8.60.005 vs L
IVVTE2+11.4<0.0001 vs L
IVVTE3+8.50.008 vs L
IVVTE3+10.30.0004 vs L
L+2.5
plus10 letters
IVVTE150%NR
IVVTE264%NR
IVVTE343%NR
IVVTE358%NR
L32%NR
CMT(um)
IVVTE1−144.60.0002 vs L
IVVTE2−194.5<0.0001 vs L
IVVTE3−127.30.007 vs L
IVVTE3−153.3<0.0001 vs L
L−67.9
At 12 months
BCVA (letters)p Value
IVVTE1+11.0≤0.0001 vs L
IVVTE2+13.1≤0.0001 vs L
IVVTE3+9.7≤0.0001 vs L
IVVTE3+12.0≤0.0001 vs L
L−1.3
Plus15 letters
IVVTE140.9%0.0031 vs L
IVVTE245.5%0.0007 vs L
IVVTE323.8%0.1608 vs L
IVVTE342.2%0.0016 vs L
L11.4%
Plus10 letters
IVVTE157%0.0031 vs L
IVVTE271%0.0007 vs L
IVVTE345%0.1608 vs L
IVVTE362%0.0016 vs L
L
CMT(µm)
IVVTE1−165.4<0.0001 vs L
IVVTE2−227.4<0.0001 vs L
IVVTE3−187.8<0.0001 vs L
IVVTE3−180.3<0.0001 vs L
L−58.4
  • BCVA, best corrected visual acuity; C, control; CMT, central macular thickness; CSME, clinically significant macular oedema; DDS, dexamethasone; DIL, dexamethasone followed by laser; DM, diabetes mellitus; DMO, diabetic macular oedema; DP, diastolic pressure; DR, diabetic retinopathy; HR QoL, health-related quality of life; IOP, intraocular pressure; IV, intravitreal; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; IVR, intravitreal ranibizumab; IVT, intravitreal triamcinolone; IVTL, intravitreal triamcinolone plus laser; IVVTE, intravitreal VEGF Trap Eye; L, laser; MLT/MPC, macular laser therapy/macular photocoagulation; NEI VFQ-25, National Eye Institute Visual Function Questionnaire-25; NPDR, non-proliferative diabetic retinopathy; NR, not reported; OCT, optical coherence tomography; PDR, proliferative diabetic retinopathy; PRP, panretinal photocoagulation; RCT, randomised controlled trial; SOC, standard of care; SP, systolic pressure; SRFA, fluocinolone; VA, visual acuity; VEGF, vascular endothelia growth factor.