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Evidence for Anti-vascular Endothelial Growth Factor Treatment of Diabetic Macular Oedema

Nguyen et al. investigated the role of ranibizumab in DME in the open-label study Ranibizumab for oedema of the macula in diabetes: Phase I (READ-1).13

Ten patients with chronic DME received intraocular

injections of 0.5 mg ranibizumab at baseline and at one, two, four and six months. Mean and median values of BCVA improved at seven months by 12.3 and 11 letters, respectively, and foveal thickness showed a significant reduction.

Recently, the results of the second phase of the READ study14,15 (READ-2, a phase II, prospective, randomised clinical trial conducted at 14 sites in the US) were reported. The aim of this study was to compare ranibizumab with focal/grid laser, alone or in combination. One hundred and twenty-six patients were randomised to receive 0.5 mg ranibizumab (group 1, n=42), focal/grid laser photocoagulation (group 2, n=42) or a combination of 0.5 mg ranibizumab and focal/grid laser (group 3, n=42). Baseline characteristics were well balanced in the randomisation groups. Subjects with BCVA between 20/40 and 20/320 due to DME and CRT of 250 μm or more were recruited. Patients in the ranibizumab group received an injection at baseline and months one three and five. Patients in the laser group received focal or grid laser photocoagulation at baseline and again at month three if central subfield thickness (CST) was 250 μm or more. At baseline and month three, patients in the combined therapy group received an intraocular injection of ranibizumab followed by focal or grid laser treatment one week later.

At month six, the group receiving ranibizumab alone showed a significant improvement in mean BCVA compared with patients receiving focal/grid laser. BCVA in the group receiving combined therapy was not statistically different from the other groups. A resolution of 50, 33, and 45 % of excess foveal thickening was observed, respectively, in the three groups after six months. After the primary endpoint (six months), patients in all groups were seen every two months, and if they had persistent or recurrent DME, defined as CRT of 250 μm or more, patients in group 1 could receive an intraocular injection of 0.5 mg, patients in group 2 ranibizumab alone or laser, and patients in group 3 ranibizumab alone or combined with laser. The two-year outcomes of READ-2 showed an improvement in BCVA of 7.7, 5.1 and 6.8 letters compared with baseline in groups 1, 2 and 3, respectively. CRT at month 24 was 340, 286 and 258 μm for groups 1, 2 and 3, respectively, and the percentages of patients with CRT of 250 μm or less were 36, 47 and 68 %. The mean number of injections was 5.3, 4.4 and 2.9 in the respective groups. Twenty-eight patients were left the study before the two-year endpoint: 10 in group 1, eight in group 2 and 10 in group 3.

The study reported a single case of severe adverse event: one subject died of a cerebrovascular accident six weeks after the first ranibizumab injection. This event was considered unrelated to ranibizumab because of pre-existent cardiovascular pathology and because a long period elapsed between injection and vascular event. No statistically significant differences in mean systolic and diastolic blood pressure were found between the groups. Ocular adverse events included vitreous haemorrhages in eight patients. The visual outcomes of the READ-2 study at month 24 were not significantly different in the three treatment groups, whereas the anatomical outcomes were better, with fewer injections of ranibizumab in groups 2 and 3. This suggests that the additional focal/grid laser treatment in groups 2 and 3 helped to reduce persistent or recurrent macular oedema as well as the number of ranibizumab injections required.


The Randomised, double-masked, multicenter, phase II study assessing the safety and efficacy of two concentrations of ranibizumab compared with non-treatment control for the treatment of diabetic macular oedema with center involvement (RESOLVE) trial evaluated the effect of ranibizumab on retinal oedema and VA in 151 patients with clinically significant DME. Patients with central macular thickness (CMT) of 300 μm or greater were randomised to receive three monthly injections of either 0.3 or 0.5 mg ranibizumab or placebo and afterwards on a pro re nata (PRN) basis for nine months; retinal photocoagulation could be administered if needed. After month one, the ranibizumab dose (or sham) could be doubled by increasing the injection volume from 0.05 to 0.1 ml based on specific CMT criteria. When injection volume was increased to 0.1 ml, subsequent administrations remained at 0.1 ml with a double dose (0.6 or 1.0 mg ranibizumab). Baseline characteristics were similar in the ranibizumab and sham arms. However, there were more discontinuations in the sham arm than in the ranibizumab arm (18.4 and 9.8 %, respectively). During the 12 months of follow-up, the mean BCVA increased and mean CMT decreased continuously over time. The groups receiving 0.3 mg and 0.5 mg gained, respectively, 11.8 letters and 8.8 letters16

regimens) showed a gain of 10.3 letters.17

and pooled data (including both dosing The RESOLVE study showed

that there are no imbalances in the rates of ocular and non-ocular severe adverse effects (SAEs) or adverse effects (AEs) between patients receiving ranibizumab and those receiving sham injections. Most of the SAEs were non-ocular in origin (ranibizumab, 14 [13.7 %]; sham, 8 [16.3 %]). Two cases of endophthalmitis occurred. Also, the rate of subjects reporting non-ocular AEs was comparable between the ranibizumab and sham arms. One of the limitations of the study was the absence of a laser treatment arm; patients could receive rescue laser photocoagulation after three months. Approximately 5 and 35 % of patients received laser treatment in the ranibizumab and sham arms, respectively. However, the effect of laser on BCVA was not evaluated. In conclusion, the study confirmed the efficacy of ranibizumab in improving BCVA in patients with DME.

The Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema (RESTORE) study,18 a 12-month, phase III, randomised, double-masked, multicentre, sham-controlled, laser-controlled trial, included 345 patients affected by DME randomised to three groups: ranibizumab and sham laser (n=116), ranibizumab and laser photocoagulation (n=118), or sham injections and laser (n=111). Ranibizumab/sham was given for three months and then on a PRN basis; laser/sham laser was performed at baseline then PRN. The percentages of patients with complete follow-up were similar in the three groups: 87.9 % (ranibizumab), 87.3 % (ranibizumab + laser) and 88.3 % (laser). Baseline and diabetes characteristics were comparable across the three treatment arms. After 12 months, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6 and 53 %, respectively) and ranibizumab + laser (22.9 and 44.9 %), versus laser (8.2 and 23.6 %). At one year of follow-up, no significant differences were detected between ranibizumab monotherapy and ranibizumab associated with laser photocoagulation. In the RESTORE study18

no cases of

endophthalmitis were reported. Increased intraocular pressure was reported for one patient each in the ranibizumab arms. No increased risk of cardiovascular or cerebrovascular events was documented in this study. Overall, the RESTORE study demonstrates that ranibizumab monotherapy provides superior outcomes compared


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