As noted earlier, the study was discontinued early prior to any patient completing the original two year study period. Enrollment of the originally intended, entire study population (N=671) was complete; however, at the time of termination, patients had participated for variable periods of time within the study. Before termination, 14 (4%) patients in Group I and 27(8%) patients in Group II had discontinued mostly due to withdrawal of consent (8[2.4%] in Group I and 9[2.7%] in Group II).Of the 671 enrolled patients (Group I [n=335], Group II [n=336]), 305 completed at least 12 months and had a VA measurement at M12 (Group I [n=151] and Group II [n=154], Fig. 1). All enrolled patients were included in the safety set, except for one patient in Group I for whom neither study drug was administered nor safety assessments performed.
Here, we present baseline and safety data for the entire population, but analyses of efficacy data only for patients who completed at least one year within the study, so as to compare groups with a comparable time period of exposure to treatment.
The mean age of enrolled patients was 74.6 years, and most were female (60.7%) and Caucasian (96.1%). Mean (standard deviation [SD]) IOP at baseline was 15.1
(2.8) mmHg. Baseline demographic and ocular characteristics were comparable between the treatment groups in the randomized set and between treatment groups in patients who completed one year of treatment (Table 1). The most common lesion type was occult with no classic component and CNV location was extrafoveal in approximately one-third of patients. Baseline imaging data (OCT, FA) were also comparable between the randomized set and those who completed 12 months of treatment (Table 1).
Mean (SD) BCVA increased from baseline to Month 12 (Fig. 2). At Month 12, mean (SD) gain was numerically lower in Group I compared with Group II (6.7 [13.48] vs 8.3 [13.53] letters; Fig. 2). BCVA gain of ≥10 or ≥15 letters at Month 12 was observed in both groups, but there was a trend towards more patients in Group II versus Group I achieving these gains (Fig. 3). Similarly, a numerically higher proportion of patients in Group II achieved BCVA ≥73 letters at Month 12 (54% vs 49%) than Group I. The mean (SD) CSFT decreased from baseline over time (Fig. 4) and at Month 12 was −161.3 (163.48) µm in Group I and −175.3 (170.45) µm in Group II.
Effect of extrafoveal CNV lesions, SRF, cysts, and thickness of cysts at baseline on BCVA and CSFT outcomes
In both groups, there were differences in baseline BCVA and CSFT between patients with extrafoveal CNV lesions versus those with foveal (centerpoint is occupied by CNV) and juxtafoveal (border of CNV is 1–200 μm away from centerpoint) CNV lesions. There was a trend towards higher mean (SD) BCVA gains in patients with foveal and juxtafoveal lesions than those with extrafoveal CNV lesions in both groups; the gains were numerically higher in Group II than in Group I (see Fig, Additional file 3). Mean (SD) decrease in CSFT from baseline at Month 12 was observed irrespective of the presence or absence of extrafoveal CNV lesions at baseline; the reduction was numerically higher in Group II in those with extrafoveal CNV lesions (see Fig, Additional file 3). In both groups, the mean change in BCVA or CSFT from baseline at Month 12 did not differ based on the presence or absence of SRF at baseline; the change was numerically higher in Group II irrespective of SRF (see Fig, Additional file 4).
Patients with cysts had a lower BCVA at baseline that stayed low over time compared with BCVA in patients without cysts at baseline, exploratory p< 0.05 for the difference in BCVA gain between presence/absence of cysts in both groups (linear regression, see Table, Additional file 5). The presence of cysts at baseline was associated with slightly lower BCVA gain from baseline at Month 12 in Group I versus Group II, whereas in those without baseline cysts, the BCVA gains from baseline at Month 12 were similar between both groups (see Fig, Additional file 4). The difference in mean BCVA change from baseline to Month 12 by presence or absence of cysts at baseline was higher in Group I compared with Group II (7.64 vs 4.80 letters), as estimated by linear regression. The mean CSFT decrease from baseline to Month 12 was higher in both groups in patients with cysts at baseline than those without. The absolute reduction in CSFT was comparable between groups in those with baseline cysts and was numerically higher in Group II in those without baseline cysts (see Fig, Additional file 4). The BCVA gain from baseline at Month 12 and reduction in mean CSFT from baseline at Month 12 were higher in both groups in those with cysts larger than 400µm at baseline (see Fig, Additional file 4).
The mean (SD) number of injections was 8.2 (2.46) and 8.4 (2.87) in Groups I and II, respectively.. The frequencies of ranibizumab injections administered over 12 months were generally comparable in both treatment groups (Fig. 5).
Ocular serious AEs (SAEs) were reported in a small but comparable proportion of patients in both groups (Table 2). Non-ocular SAEs were reported in 8.1% of patients in Group I and in 12.8% of patients in Group II (Table 2). Seven patients died during the study; one patient in Group I (due to cardiopulmonary failure) and six patients in Group II (due to myocardial infarction, cardiovascular insufficiency, pneumonia, squamous cell carcinoma, congestive cardiac failure, and unknown causes [n=1 each]). One death reported in Group II due to unknown causes was suspected to have a causal relationship with the study drug.
Overall, ocular and non-ocular AEs were reported in a comparable proportion of patients in both groups (Table 3). The ocular AE with the highest incidence in Group I was conjunctival hemorrhage (5.7%) and IOP increase in Group II (6.3%, Table 3). There were no cases of endophthalmitis.
Ocular and non-ocular AEs suspected to be related to the study drug and/or ocular injection were also reported in a comparable proportion of patients in both groups. Conjunctival hemorrhage in Group I and IOP in Group II were the most common ocular AEs (see Table, Additional file 6). Ocular AEs leading to study drug discontinuation were reported by 2 patients, one in each group (Group 1: retinal detachment and VA reduced; Group II: vitreous hemorrhage). Nine patients discontinued from study drug due to non-ocular AEs, one from Group I (asthma) and eight from Group II (cardiac failure, presyncope, migraine, cholestasis, chronic myeloid leukemia, ischemic stroke, neutropenic sepsis, squamous cell carcinoma, and death [n=1 each])