Sixty-five eyes were initially recruited into the clinical trial; the patients included 33 males (51%) and 32 females (49%) with an average age of 56.64 ± 13.88 years (range 21–83). Forty-one (63%) patients had hypertension, and 10 (15%) patients had a history of diabetes, but no diabetic retinopathy or diabetic ME was detected. There was no dysfunction in coagulation or infectious disease such as HIV or infection caused by Treponema pallidum, hepatitis B virus or hepatitis C virus at the baseline. The mean time from conscious loss of VA to intravitreal injection was 21 (3–185) days. The mean baseline BCVA letter score for the study eyes was 37.06 ± 16.75, and the mean baseline CRT was 730.17 ± 259.89 μm. The demographic and clinical characteristics of the two groups were similar (Table 1). Forty-one patients received more than three intraocular injections, and 26 of them underwent FFA. Six patients with NPA >10 PD in FFA were treated with panretinal laser photocoagulation (three patients per group), and four cases of neovascular glaucoma were detected during the 12-month follow-up, with an average of 291 days from baseline to neovascular glaucoma.
The follow-up study included 64 eyes, as one patient from the initial cohort in the Conbercept group was lost to follow-up because he relocated to another city.
Table 1
Demographic and baseline characteristics of patients who received Conbercept plus dexamethasone (DEX) or Conbercept alone for macular edema secondary to central retinal vein occlusion
|
Conbercept
(n = 32)
|
Conbercept+DEX
(n = 33)
|
Age
|
|
|
Mean ± SD
|
55.31 ± 12.14
|
57.91 ± 15.42
|
Median
|
56
|
59
|
Range
|
27–77
|
21–83
|
Sex, n (%)
|
|
|
Male
|
17 (53%)
|
16 (48%)
|
Female
|
15 (47%)
|
17 (53%)
|
Hypertension, n (%)
|
18 (56%)
|
23 (70%)
|
DM, n (%)
|
5 (16%)
|
5 (15%)
|
Days from CRVO diagnosis to screening
|
|
|
Median
|
24
|
28
|
Range
|
7–183
|
5–180
|
Distribution, n (%)
|
|
|
≤ 1 month
|
21 (66%)
|
22 (67%)
|
1–3 months
|
9 (28%)
|
9 (27%)
|
≥ 3 months
|
2 (6%)
|
2 (6%)
|
BCVA
|
|
|
ETDRS letter score
|
|
|
Mean ± SD
|
37.97 ± 17.38
|
35.85 ± 16.09
|
Distribution, n (%)
|
|
|
≤ 34
|
14 (44%)
|
16 (48%)
|
35–54
|
11 (34%)
|
10 (30%)
|
≥ 55
|
7 (22%)
|
7 (21%)
|
CRT (µm)
|
|
|
Mean ± SD
|
742.59 ± 275.83
|
718.48 ± 247.70
|
DM, diabetes mellitus; BCVA, best-corrected visual acuity; CRT, central retinal thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; CRVO, central retinal vein occlusion; SD, standard deviation
|
Visual acuity
Patients in the Conbercept and Conbercept + DEX groups gained an average of 14.55 ± 19.19 and 14.88 ± 17.68 ETDRS letters, respectively, at the final follow-up (12 months; resp. t = 4.221, P = 0.000; and t = 4.834, P = 0.000) with no significant difference between the two groups (t = 0.071, P = 0.943). Fifteen patients in the Conbercept group (48%) and 15 in the Conbercept + DEX group (45%) gained ≥ 15 ETDRS letters from baseline. Four participants (6%), including two (6%) in the Conbercept group and two (6%) in the Conbercept + DEX group, lost more than 15 ETDRS letters at the final follow-up. The percentage of participants who obtained more than 60 ETDRS letters (equivalent to 20/40 in the Snellen chart) was 42% in the Conbercept group and 42% in the Conbercept + DEX group. There was no significant difference between the two groups (XU = 0.500, P = 0.779).
BCVA at 1 week and 1 month after each intravitreal injection was improved compared to that before therapy (P < 0.01). There were no significant differences in BCVA between 1 week and 1 month, except after the second injection in the Conbercept + DEX group and the fourth injection in the Conbercept group. BCVA changes throughout the 12 months in the two groups are shown in Table 2. BCVA changes at 1 week and 1 month after each injection are shown in Supplemental Digital Content 1.
Table 2
Changes in the best-corrected visual acuity from baseline to month 12 in patients who received Conbercept plus dexamethasone (DEX) or Conbercept alone for macular edema secondary to central retinal vein occlusion
|
Conbercept
|
Conbercept+DEX
|
|
(n= 31)
|
(n= 33)
|
ETDRS Letter
|
|
|
Mean ± SD
|
51.61 ± 20.90
|
51.42 ± 23.78
|
Difference in means (vs. baseline)
|
14.55 ± 19.19
|
14.88 ± 17.68
|
t, P (vs. baseline)
|
t =4.221, P= 0.000
|
t =4.834, P= 0.000
|
Distribution of BCVA change at month 6, n (%)
|
|
Gain (ETDRS letters)
|
|
|
≥15
|
15 (48%)
|
15 (45%)
|
10–14
|
5 (16%)
|
6 (18%)
|
5–9
|
2(6%)
|
5 (15%)
|
No change, ±4 ETDRS letters
|
3 (10%)
|
3 (9%)
|
Loss (ETDRS letters)
|
|
|
5–9
|
3 (10%)
|
2 (6%)
|
10–14
|
1 (3%)
|
0
|
≥15-letter loss
|
2(6%)
|
2 (6%)
|
≥15-letter gain
|
|
|
First injection
|
|
|
N
|
31
|
33
|
7-day
|
11 (35%)
|
16 (48%)
|
1-month
|
16 (52%)
|
17 (52%)
|
Second injection
|
|
|
N
|
29
|
31
|
7-day
|
11 (38%)
|
12 (39%)
|
1-month
|
14 (48%)
|
16 (52%)
|
Third injection
|
|
|
N
|
17
|
24
|
7-day
|
9 (53%)
|
13 (54%)
|
1-month
|
7 (41%)
|
16 (67%)
|
Central retinal thickness
Each intravitreal injection led to a reduction in CRT for all patients. At day 7 after the first intravitreal injection, the mean CRT reduction was 384.16 ± 237.85 μm, while it was 393.58 ± 275.70 μm at 1 month. At month 12, the mean reduction in CRT was 296.92.00 ± 146.15 μm. In the Conbercept group, the mean reduction in CRT from baseline to month 12 was 435.26 ± 293.37 μm (t = 8.261, P = 0.000) compared to 431.36 ± 294.55 (t = 8.413, P = 0.000) in the Conbercept + DEX group. There was no significant difference between the two groups (t = 0.053, P = 0.958). The mean CRT was 297.00 ± 119.21 μm in the Conbercept group and 296.85 ± 169.50 μm in the Conbercept + DEX group after 12 months (t = 0.004, P = 0.997). The percentage of patients with CRT less than 250 μm at month 12 was 42% in the Conbercept + DEX group and 45% in the Conbercept group. At 1 month after injection, CRT was significantly reduced relative to that at 1 week after the first and third intravitreal injections in the Conbercept + DEX group (P < 0.05); following the second injection for the Conbercept group, CRT at 1 month was higher than at 1 week (360.97 ± 167.57 μm vs. 297.69 ± 55.62 μm, P < 0.05). The change in CRT from baseline to month 12 is shown in Supplemental Digital Content 2. CRT before treatment and at 1 week and 1 month after intravitreal injection in the first three therapies is shown in Supplemental Digital Content 3.
Injection frequency and intervals
Sixty-four patients received 5.13 ± 1.96 intravitreal injections, and 60 eyes (94%) received repeat treatments. The mean treatment interval was 70.48 ± 48.52 days. The second, third and fourth intravitreal injections were administered at 60.10 ± 22.96, 114.20 ± 33.14 and 182.18 ± 62.49 days, respectively. Patients in the Conbercept + DEX group received 4.82 ± 1.94 intravitreal injections compared to 5.45 ± 1.95 intravitreal injections in the Conbercept group (Z = -2.674, P = 0.007). Patients in the Conbercept + DEX group received the third and fourth intravitreal injections later than patients in the Conbercept group (125.13 ± 20.72, 209.40 ± 67.59 in the Conbercept + DEX group; 92.82 ± 32.09, 161.14 ± 52.32 in the Conbercept group; P < 0.01, P = 0.032, respectively). The first injection interval (injection 1 to 2) was positively correlated with the second injection interval (injection 2 to 3; Pearson’s r = 0.464, P = 0.002; Fig. 1). The second injection interval in the Conbercept + DEX group was longer than in the Conbercept group (P = 0.000). Intravitreal injection frequency and intervals in the two groups are shown in Table 3.
Table 3
Intravitreal injection frequency and intervals for patients who received Conbercept plus dexamethasone (DEX) or Conbercept alone for macular edema secondary to central retinal vein occlusion
|
Conbercept group
(n = 31)
|
Conbercept+DEX group (n = 33)
|
t
|
P
|
|
|
|
Frequency, Mean ± SD
|
5.52±1.96
|
4.82±1.94
|
1.302
|
0.198
|
Second intravitreal injection
(First injection interval)
|
59.14 ± 30.90
|
61.00 ± 11.98
|
0.304
|
0.763
|
Third intravitreal injection
|
92.82 ± 32.09
|
125.13 ± 20.72
|
3.919
|
<0.01
|
Fourth intravitreal injection
|
161.14 ± 52.32
|
209.40 ± 67.59
|
2.239
|
0.032
|
Second injection interval
|
45.29 ± 16.84
|
65.75 ± 12.57
|
4.457
|
0.000
|
Safety
A total of 328 intravitreal injections was carried out in this study, with 169 for the Conbercept group and 159 for the Conbercept + DEX group, respectively. The most frequent TEAEs were conjunctival haemorrhaging and conjunctival hyperaemia (Table 4). There was no systemic treatment-related adverse event. Obviously aggravated cataracts were reported in four of the 64 patients (6.25%) and two cases in each group. No study eye accepted cataract surgery during the 12-month study period. Four patients in each group had an increase in IOP (>25 mmHg) on the first day after intravitreal injection; in one case, the elevated IOP persisted for more than one week. IOP elevations were controlled with IOP-lowering medication. No glaucoma surgeries were performed during the 12-month study period. One case of vitreous haemorrhaging was recorded in the Conbercept group, which completely resolved without therapy during the 12-month follow-up period.