Table 8

Trials assessing more than one drug

StudyParticipants and baseline valuesInterventionOutcome (change from baseline at study end)
Ahmadieh et al31
Iran
Design: 3-arm placebo-controlled RCT
Follow-up: 24 weeks
N: 115 eyes of 101 patients
Inclusion criteria: eyes with clinically significant DMO unresponsive to previous macular laser photocoagulation (last session >3 months prior)
Exclusion criteria: visual acuity ≥20/40; history of cataract surgery within past 6 months; prior intraocular injection or vitrectomy, glaucoma or ocular hypertension; PDR with high-risk characteristics; vitreous hemorrhage; significant media opacity; presence of traction on the macula; pregnancy; serum creatinine ≥3 mg/100 ml; monocular patients
Age: 59.7 SD8.3 years (range 39–74)
Sex: 50.5% female
Diabetes type: not reported, 27.6–33.3% on insulin
HbA1c: 9.35–10.06%
Baeline VA: not reported
Baseline CMT: not reported
Comorbidities: (percentage of eyes) 13.9% history of cataract surgery, 81.7% NPDR, 4.3% early PDR, 13.9% regressed PDR; no iris neovascularisation
Group 1 (IVB, n=41 eyes): bevacizumab 1.25 mg (0.05 ml)
Group 2 (IVB/IVT, n=37 eyes): combined bevacizumab (1.25 mg (0.05 ml)) and triamcinolone (2 mg (0.05 ml)), followed by two injections of bevacizumab alone
Group 3 (C, n=37 eyes): sham injection
Regimen for all groups: 3 consecutive IV injections at 6-week intervals
At 24 weeks
BCVA (Snellen chart):
BCVA (logMAR), 95% CIp Value
IVB−0.18 (–0.29, −0.08) (+9 letters (4, 14.5))0.01 vs C, NS vs IVB/IVT
IVB/IVT−0.21 (−0.30, −0.12) (+10.5 letters (6, 15))0.006 vs C
C−0.03 (−0.08, 0.14) (+1.5 letters (−7, 4))
CMT (OCT):
CMT (µm), 95% CIp Value
IVB−95.7 (−172.2, −19.3)0.012 vs C, NS vs IVB/IVT
IVB/IVT−92.1 (−154.4, −29.7)0.022 vs C
C34.9 (7.9, 61.9)
ATEMD Oliveira Neto et al56
Multicenter
Design: 3-arm RCT
Follow-up: 6 months
Note: only 48.3% completion
N: 120 eyes of 120 patients
Inclusion criteria: DMO, BCVA 20/40–20/400, CMT ≥275 µm
Exclusion criteria: PDR, laser photocoagulation in previous 3 months, no IV corticosteroid or anti-VEGF in previous 3 months
Age: not reported
Sex: not reported
Diabetes type: not reported
HbA1c: not reported
Baseline VA: not reported
Baseline CMT: not reported
Comorbidities: not reported
Group 1 (IVB, n=NR eyes): 1.25 mg (0.05 ml) of IV bevacizumab
Group 2 (IVT, n=NR eyes): 4 mg (0.1 ml) of IV triamcinolone acetonide
Group 3 (IVB/IVT, n=NR eyes): 1.25 mg (0.05 ml) of IV bevacizumab plus 4 mg (0.1 ml) of IV triamcinolone acetonide
Regimen for all groups: monthly injections
At 6 months
BCVA:
▸ no significant difference between groups (between 1.7 and 2.3 lines gained in the different groups in 2010 report (n=18))
CMT (OCT):
▸ CMT reduced in all 3 groups (between 17 and 33% reduction in the different groups in 2010 report (n=18)); no significant difference between groups
DRCR Network 2010 (Elman et al)21 46
USA
Multicenter
Design: 4-arm placebo-controlled RCT
Follow-up: 1–2 years; 2 years extension (Elman)46 for consenting patients
N: 854 eyes of 691 patients
Inclusion criteria: ≥18 years, type 1 or 2 DM; study eye: (1) BCVA letter score 78–24 (20/32–20/320), (2) definite retinal thickening due to DMO assessed to be main cause of visual loss, (3) retinal thickness measured on time domain OCT ≥250 µm in central subfield (2 study eyes per patient could be included if both were eligible at study entry)
Exclusion criteria: (1) treatment for DMO within the prior 3 months, (2) panretinal photocoagulation within the prior 4 months or anticipated need for panretinal photocoagulation within the next 6 months, (3) major ocular surgery within the prior 4 months, (4) history of open-angle glaucoma or steroid-induced IOP elevation, requiring IOP-lowering treatment, (5) IOP ≥25 mm Hg; systolic pressure >180 mm Hg, diastolic pressure >110 mm Hg; myocardial infarction, other cardiac event requiring hospitalisation, cerebrovascular accident, transient ischemic attack, treatment for acute congestive heart failure within 4 months before randomisation
Age: median 62–64 years (25th, 75th centile 55–58, 69–70)
Sex: 41–46% female
Diabetes type: 6–9% type 1 DM, 89–92% type 2 DM, 2–3% uncertain
HbA1c: median 7.3–7.5% (25th, 75th centile 6.5–6.7, 8.3–8.6)
Baseline VA: letter score 63 SD12 (∼20/63 SD2.4 lines)
Baseline CMT: 405 SD134 µm
Comorbidities: 60–67% prior treatment for DMO; 61–68% with NPDR, 26–36% with PDR or PDR scars
Group 1 (CPL, n=293 eyes): sham injection plus prompt (within 3–10 days after injection) focal/grid photocoagulation
Group 2 (RPL, n=187 eyes): 0.5 mg IV ranibizumab plus prompt focal/grid photocoagulation
Group 3 (RDL, n=188 eyes): 0.5 mg IV ranibizumab plus deferred (≥24 weeks) focal/grid photocoagulation
Group 4 (TPL, n=186 eyes): 4 mg IV triamcinolone plus prompt focal/grid photocoagulation
Regimen for all groups: Baseline treatment 0.5 mg IV ranibizumab and 4 mg preservative free triamcinolone; study treatment every 4 weeks up to 12 weeks, then retreatment algorithm: 16 to 20 weeks, monthly retreatment unless ‘success’ criteria were met (visual acuity letter score ≥84 (20/20) or OCT central subfield thickness <250 µm); 24–48 weeks, patients subdivided (according to predefined criteria) into ‘success’, ‘improvement’, ‘no improvement’ or ‘failure’; ‘improvement’ group continued treatment, other groups treated at investigator discretion; alternative treatment permitted if eye met criteria for ‘failure’ or ‘futility’. In the case of retreatment, ranibizumab could be given as often as every 4 weeks, and triamcinolone every 16 weeks (with sham injections as often as every 4 weeks). Retreatment for focal/grid laser (after ≥13 weeks from previous treatment) if there was oedema involving or threatening the center of the macula and if complete laser had not been given; retreatment algorithms facilitated by web-based real-time data entry system. Median number of drug injections before 1 year visit was 8–9 for ranibizumab, 3 for triamcinolone, and 5 sham injections. Retreatment between 1 and 2 years (Elman 2011): median injections 2 in RPL group, 3 in RDL group; in TPL group 68% of eyes received at least 1 injection; at least one focal/grid laser sessions between 1 and 2 years: 51% CPL, 40% RPL, 29% RDL, 52% TPL
Laser Modified ETDRS protocol as used in prior DRCR.net protocols
At 1 year
BCVA (E-ETDRS Visual Acuity Test):
BCVA (letters) p Value
CPL+3 SD13
RPL+9 SD11<0.001 vs CPL
RDL+9 SD12<0.001 vs CPL
TPL+4 SD13NS vs CPL
BCVA gain categories (letters)
CPL+10 or more: 28%
+9 to −9: 59%
−10 or more: 13%
RPL+10 or more: 50%
+9 to −9: 45%
−10 or more: 4%
<0.001 vs CPL
RDL+10 or more: 47%
+9 to −9: 51%
−10 or more: 3%
<0.001 vs CPL
TPL+10 or more: 33%
+9 to −9: 52%
−10 or more: 14%
NS vs CPL
Subgroups: ▸ BCVA results in TPL group substantially better for pseudophakic eyes than for phakic eyes (comparable to results for RPL and RDL groups) (p not reported)
▸ No difference in results according to prior treatment for DMO, baseline VA, baseline CMT, baseline level of retinopathy, focal or diffuse oedema
CMT (OCT):
CMT (µm)p Value
CPL−102 SD151
RPL−131 SD129<0.001 vs CPL
RDL−137 SD136<0.001 vs CPL
TPL−127 SD140<0.001 vs CPL
Subgroups: ▸ pattern of CMT decrease similar for groups with CMT <400 and ≥400 µm at baseline
▸ Significantly more patients with severe NPDR or worse improved by 2 levels or more in the ranibizumab groups (28%, no significant change in the other groups)
At 2 years (expanded results, Elman 2011)
BCVA (E-ETDRS Visual Acuity Test):
BCVA (letters)p Value
CPL (n=211)+3 SD15
RPL (n=136)+7 SD130.03 vs CPL
RDL (n=139)+9 SD14<0.001 vs CPL
TPL (n=142)+2 SD19NS vs CPL
BCVA gain categories (letters)
CPL+10 or more: 36%
+9 to −9: 52%
−10 or more: 13%
RPL+10 or more: 44%
+9 to −9: 49%
−10 or more: 7%
NS vs CPL
RDL+10 or more: 49%
+9 to −9: 48%
−10 or more: 3%
0.01 vs CPL
TPL+10 or more: 41%
+9 to −9: 40%
−10 or more: 19%
NS vs CPL
CMT (OCT):
CMT (µm)p Value
CPL−138 SD149
RPL−141 SD1550.003 vs CPL
RDL−150 SD1430.01 vs CPL
TPL−107 SD145NS vs CPL
Jorge et al51
Brazil
Design: Prospective RCT
Follow-up: 24 and 48 weeks (to date, 73% and 56% of patients completed 24 and 48 weeks, respectively)
N: 63 eyes of 47 patients
Inclusion criteria: Refractory cener-involving DMO
Exclusion criteria: NR
Age: NR
Sex: NR
Diabetes type: NR
HbA1c: NR
Baseline VA: NR
Baseline CMT: NR
Comorbidities: NR
Group 1 (IVB 1.5 mg, n=NR): injections at baseline and monthly if CSFT (central subfield thickness) measured by SDOCT (spectral domain OCT) >275 µm
Group 2 (IVR 0.5 mg, n=NR): injections at baseline and monthly if CSFT >275 µm 
At 48 weeks
BCVA
Mean BCVA reduction from baseline (logMAR)p Value
IVB1.5−0.21vs baseline <0.05 at all-time points
vs IVR0.5: no significant difference at all time-points
IVR0.5−0.21vs baseline <0.05 at all time-points
vs IVB1.5: no significant difference at all time-points
CSFT
Mean CSFT reduction from baselinep Value
IVB1.5−129.6 µmvs baseline <0.05 at all-time points
vs IVR0.5 no significant different at all-time points
IVR0.5−137.9 µmvs baseline <0.05 at all-time points
vs IVB1.5 no significant different at all-time points
Lim et al55
Korea
Design: 3-arm RCT
Follow-up: 12 months
N: 111 eyes of 105 patients
Inclusion criteria: eyes with clinically significant
DMO based on ETDRS and DMO with central macular thickness of at least 300 µm by optical coherence tomography (OCT)
Exclusion criteria: unstable medical status, including glycemic control and blood pressure; any previous treatment for DMO, including intravitreal, sub-Tenon injection or macular photocoagulation, history of vitreoretinal surgery, uncontrolled glaucoma; proliferative diabetic retinopathy with active neovascularisation, previous panretinal photocoagulation, presence of vitreomacular traction, history of systemic corticosteroids within 6 months, contraindications for bevacizumab or triamcinolone acetonide
Age: 60.4 SD 7.4 (range 48–70) years
Sex: 52% female
Diabetes type: NR
HbA1c: 7.2 SD 1.2–7.4 SD1.2
Baseline VA: 0.62 SD 0.23–0.65 SD 0.28 logMAR
Baseline CMT: 447 SD 110–458 SD 92 µm
Comorbidities: NR
Group 1 (IVB/IVT, n=36): IV injection of 1.25 mg (0.05 ml) IVB at 0 and 6 weeks and IV injection of 2 mg (0.05 ml) IVT at 0 weeks. Mean number of addition injection 1.28
Group 2 (IVB, n=38): IV injection of 1.25 mg (0.05 ml) IVB at 0 and 6 weeks. Mean number of injections 2.54.
Group 3 (IVT, n=37): IV injection of 2 mg (0.05 ml) IVT at 0 weeks. Mean number of injections 1.04
Unclear if rescue laser was available
IVB injections were repeated if CMT appeared >300 µm on OCT in at least 6 weeks in all three groups
At 12 months
BCVA (logMAR)p Value
IVB/IVT−0.150.088 (between groups)
IVB−0.16
IVT−0.16
CMT (µm)p Value
IVB/IVT−1990.132 (between groups)
IVB−17s9
IVT−200
Soheilian et al37 41 54 141
Iran
Design: 3-arm RCT
Follow-up: 36 weeks(Soheilian 2007 reports 12 week results of the same trial, these were not considered here)
N: 150 eyes of 129 patients
Inclusion criteria: eyes with clinically significant DMO (ETDRS criteria)
Exclusion criteria: previous panretinal of focal laser photocoagulation, prior ocular surgery or injection, history of glaucoma or ocular hypertension, VA ≥20/40 or <20/300, iris neovascularisation, high risk PDR, significant media opacity, monocularity, pregnancy, serum creatinine ≥3 mg/dL, uncontrolled DM
Age: 61.2 SD6.1 years
Sex: 47.3% female
Diabetes type: not reported
HbA1c: not reported
Baseline VA: 0.55–0.73 SD0.26–0.28 logMAR
Baseline CMT: 300–359 SD118–149 µm
Comorbidities: 94% NPDR, 6% early PDR
Group 1 (IVB, n=50 eyes): IV injection of bevacizumab 1.25 mg (0.05 ml) (retreatment IVB 14 eyes)
Group 2 (IVB/IVT, n=50 eyes): IV injection of combined bevacizumab (1.25 mg (0.05 ml)) and triamcinolone (2 mg (0.05 ml)), followed by two injections of bevacizumab alone (retreatment IVB/IVT 10 eyes)
Group 3 (MPC, n=50 eyes): focal or modified grid laser (retreatment MPC 3 eyes)
Regimen for all groups: Retreatments performed at 12 week intervals as required
At 36 weeks
BCVA (Snellen chart):
BCVA (logMAR), SD p Value
IVB−0.28 SD0.25 (+14 SD12.5 letters)0.053 vs IVB/IVT or MPC
IVB/IVT−0.04 SD0.33 (+2 SD16.5 letters)NS vs MPC
MPC +0.01 SD0.27 (−0.5 SD13.5 letters)
Snellen line changes
IVB+2 lines or more: 37%
stable within 2 lines: 59.3%
−2 lines or more: 3.7%
NS between groups
IVB/IVT+2 lines or more: 25%
stable within 2 lines: 54.2%
−2 lines or more: 20.8%
MPC+2 lines or more: 14.8%
stable within 2 lines: 66.7%
−2 lines or more: 18.5%
CMT (OCT):
CMT (µm), SDp Value
IVB−56 SD1400.044 vs baseline, NS between groups
IVB/IVT−5 SD113
MPC−8 SD67
Subgroups:
▸ larger CMT reduction in subgroup with ≥400 µm at baseline (36 weeks: IVB −27.2 SD34.8%, IVB/IVT –8.8 SD35.9%, MPC −15.1 SD14.6%, p<0.001 vs baseline in IVB and MPC groups only)
  • 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.