Table 8.
Trials assessing more than one drug
| Study | Participants and baseline values | Intervention | Outcome (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% CI | p 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% CI | p 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 | |||
| C | 34.9 (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 |
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| 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 SD13 | NS 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) |
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| 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 SD13 | 0.03 vs CPL | |||
| RDL (n=139) | +9 SD14 | <0.001 vs CPL | |||
| TPL (n=142) | +2 SD19 | NS 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 SD155 | 0.003 vs CPL | |||
| RDL | −150 SD143 | 0.01 vs CPL | |||
| TPL | −107 SD145 | NS 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 | −0.21 | vs baseline <0.05 at all-time points vs IVR0.5: no significant difference at all time-points |
|||
| IVR0.5 | −0.21 | vs baseline <0.05 at all time-points vs IVB1.5: no significant difference at all time-points |
|||
| CSFT | |||||
| Mean CSFT reduction from baseline | p Value | ||||
| IVB1.5 | −129.6 µm | vs baseline <0.05 at all-time points vs IVR0.5 no significant different at all-time points |
|||
| IVR0.5 | −137.9 µm | vs baseline <0.05 at all-time points vs IVB1.5 no significant different at all-time points |
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| 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 | −0.15 | 0.088 (between groups) | |||
| IVB | −0.16 | ||||
| IVT | −0.16 | ||||
| CMT (µm) | p Value | ||||
| IVB/IVT | −199 | 0.132 (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% |
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| MPC | +2 lines or more: 14.8% stable within 2 lines: 66.7% −2 lines or more: 18.5% |
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| CMT (OCT): | |||||
| CMT (µm), SD | p Value | ||||
| IVB | −56 SD140 | 0.044 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) |
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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.