2-Month Outcomes of Conbercept in Macular Edema Secondary to Central Retinal Vein Occlusion from a randomized, multicenter, double-blind, sham-controlled phase III study: CRAVE Study

2-Month Outcomes of Conbercept in Macular Edema Secondary to Central Retinal Vein Occlusion from a randomized, multicenter, double-blind, sham-controlled phase III study: CRAVE Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 2-Month Outcomes of Conbercept in Macular Edema Secondary to Central Retinal Vein Occlusion from a randomized, multicenter, double-blind, sham-controlled phase III study: CRAVE Study Wenbin Wei, Xuehui Shi, Xiaorong Li, Xiaoxin Li, Hongquan Han, and 31 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7270611/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Purpose To evaluate the efficacy and safety of intravitreal injection of conbercept for the treatment of macular edema secondary to central retinal vein occlusion (CRVO-ME). Methods Patients with CRVO were randomly divided into the treatment (conbercept injection) and control groups (sham injection) at a ratio of 2:1. The primary endpoint was the mean changes in best-corrected visual acuity (BCVA) from baseline to month 6. Results From baseline to month 6, the mean change in BCVA letters were 13.6 ± 12.1 ( P < 0.0001) and − 2.2 ± 16.5 ( P = 0.2188) in the treatment and control groups. From baseline to month 12, the mean change in BCVA letters were 14.4 ± 13.8 ( P < 0.0001) and 3.0 ± 17.6 ( P < 0.0001). The mean reduction of CRT from baseline to month 6 were 138.4 ± 99.4 µm ( P < 0.0001) and 35.1 ± 98.8 µm ( P = 0.0018). From baseline to month 12, the mean reduction values of CRT were 145.1 ± 105.1 µm ( P < 0.0001) and 81.7 ± 107.9 µm ( P < 0.0001). No new safety events were identified. Conclusions Intravitreal injection of conbercept has definite efficacy and expected controllable safety in patients with CRVO-ME, providing a more flexible strategy for conbercept in the clinical treatment of CRVO-ME. Trial Registration: ClinicalTrials.gov Identifier: NCT03223714, Date: July 21, 2017. conbercept central retinal vein occlusion best-corrected visual acuity central retinal thickness macular edema Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Retinal vein occlusion (RVO) is a common primary retinal vascular disorder. It is categorized into central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), making it the second-largest retinal vascular disorder following diabetic retinopathy 1 . CRVO affects the macular area and causes severe vision loss, significantly reducing patients’ quality of life 2 . The complications of CRVO include retinal neovascularization, neovascular glaucoma, vitreous volume blood, and ME 3 , 4 . Among them, macular edema (ME) causes significant vision loss among patients with RVO. Based on statistics, three million people annually suffer from ME secondary to CRVO (CRVO-ME) worldwide. The Beijing Eye Study found that the prevalence of RVO was 1.3%; BRVO, 1.2%; and CRVO, 0.1%. Furthermore, ME was observed in 37% of patients with RVO, 30% of patients with BRVO, and 71% of patients with CRVO 5 . Recent studies have demonstrated that the pathological changes of CRVO-ME are closely associated with abnormal expression of vascular endothelial growth factor (VEGF), changes in microvascular structure, and inflammatory response 6 . Intraocular VEGF and different inflammatory cytokine levels in patients with CRVO were significantly associated with ME severity 7 , 8 . With the advancing research of anti-VEGF drugs and the popularization of their clinical applications, several clinical studies have suggested that intravitreal injection of antiVEGF drugs can significantly improve the visual and anatomical outcomes of patients with CRVO as well as the visual function of patients with CRVO-ME. It has been reported that bevacizumab, aflibercept, and ranibizumab can effectively treat ME caused by CRVO 8 – 10 . AntiVEGF drugs are the current first-line treatment for ME caused by CRVO. These drugs reduce vascular permeability and leakage, thereby improving ME, and prevent neovascularization 11 . Conbercept (KH902; Chengdu Kanghong Biotech Co., Ltd., Sichuan Province, China) is a novel recombinant fusion protein with key domains from VEGF receptors 1 and 2 with human immunoglobulin Fc. It includes extracellular protein-like region 4 in VEGFR-2, which enhances binding affinity to VEGF, and the blockage effect of VEGF-mediated signaling in neovascularization. Furthermore, it allows for a more effective treatment of ocular pathological vascular diseases 12 . In China, conbercept has been approved for neovascular age-related macular degeneration (nAMD) 13 , diabetic macular edema (DME) 14 , pathological myopic choroidal neovascularization (CNV) 15 , and RVO-ME 16 . The early clinical research of conbercept began with CNV-related diseases. The phase I clinical study (HOPE) evaluated the safety and efficacy of multiple intravitreal conbercept injections in patients with CNV due to age-related macular degeneration (AMD). The results indicated that conbercept can significantly improve the vision of AMD patients and reduce CRT 17 . Subsequent phase II and III studies further confirmed the efficacy and safety of conbercept in the treatment of nAMD 15 , 18 . The SAILING study was a multicenter, randomized, double-blind, phase 3 clinical trial that evaluated the efficacy and safety of conbercept injection versus laser photocoagulation in the treatment of DME. The study found that pro re nata (PRN) intravitreal injections of conbercept improved the best-corrected visual acuity (BCVA) of patients with DME and that it exhibited superior efficacy to laser photocoagulation 14 . As a phase II registration study, FALCON reported that intravitreal injections of conbercept exhibited generally favorable safety and tolerability profiles as well as efficacy in treating RVO-ME 16 . As a phase III registration study, CRAVE further confirmed the efficacy and safety of conbercept in the treatment of CRVO-ME. Materials and Methods Study Design CRAVE was a multicenter, randomized, double-blind, sham-controlled phase III clinical study. It was conducted at 27 sites in China from May 2016 to October 2020. Patients with CRVO-ME were enrolled in the study and randomly assigned to the treatment group (received conbercept ophthalmic injection) or control group (received sham injection) at a ratio of 2:1. The study protocol was approved by the Ethics Committee of Beijing Tongren Hospital Affiliated to Capital Medical University (TREC2015-55). The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines. All patients provided written informed consent to participate in the trial. The study was registered on ClinicalTrials.gov (ID: NCT03223714, Date: July 21, 2017). Participants The inclusion criteria for the were as follows: 1) age ≥ 18 years, 2) CRVO-ME or ME secondary to hemi-central retinal vein occlusion (HRVO) involving the fovea and diagnosed within ≤ 12 months, 3) BCVA ≥ 24 and ≤ 73 (Snellen equivalent, 20/320–20/40), 4) OCT showing central retinal thickness (CRT) ≥ 300 um, and 5) refractive medium opacification and/or pupillary abnormalities not affecting fundus examination or OCT. If both eyes were eligible, the eye with worse BCVA or an OCT showing greater CRT at screening was selected. The exclusion criteria for the study eyes were as follows: 1) active iris and/or retinal neovascularization; 2) presence of epiretinal membrane of the macula or vitreous traction; 3) presence of other diseases including macular foveal atrophy, submacular foveal hemorrhage, hard exudation of the macula area or dense submacular hard exudation, etc.; 4) history of any type of retinal detachment; 5) any other additional ocular diseases which could irreversibly compromise the visual acuity of the study eye including wet AMD, diabetic retinopathy, uveitis or other intraocular inflammatory diseases, neovascular glaucoma and macular cystic edema, etc.; 6) requiring cataract surgery within the next 12 months according to the investigator; 7) received intravitreal corticosteroids within 3 months, subconjunctival corticosteroids within 6 months, or topical therapy with ocular steroids within 1 month; 8) underwent scleral buckling surgery or verteporfin photodynamic therapy; 9) underwent YAG laser treatment or any other ophthalmic treatment within 3 months; 10) BCVA > 10 during screening (comparing BCVA measured within 24 h before the first administration (day 0) with that at enrollment); 11) presence of aphakia or posterior lens capsule defect; 12) active inflammation around or in the eye; 13) past or present uncontrollable glaucoma; and 14) received intravitreal injection of any antiVEGF drugs in the previous 3 months. Randomization and Treatment Patients with CRVO-ME were enrolled in the study and randomly assigned to the treatment or control group at a ratio of 2:1 using a central randomization system. Randomization was stratified by region, and a validated system was used to generate a randomization list. The system automatically assigned patient numbers randomly to randomization numbers, which were linked to different treatment groups and then to drug numbers. Patients in the study, researchers responsible for visual assessment and imaging testing, treatment decision-makers, evaluators of imaging test results and treatment outcomes were masked to treatment. From day 0 to month 6, the treatment group received intravitreal injection of conbercept at a dose of 0.5 mg every month for six consecutive months. The control group, alternatively, received a sham injection for six consecutive doses once a month. Primary endpoint assessment was conducted at the end of month 6. All patients were evaluated monthly from months 6 to 12. Based on the results of each evaluation, the investigators decided whether the treatment group required PRN injection of 0.5-mg conbercept until month 11. The control group was given medication as necessary to month 11 after receiving single intravitreal ophthalmic injection of 0.5-mg conbercept in month 6. The final assessment was performed at the end of month 12 of the study. Patients who met any of the following criteria could be given PRN injection of 0.5-mg conbercept: 1) OCT showing increased CRT of ≥ 50 µm from the previous minimum CRT; 2) decreased BCVA of ≥ 5 from the previous maximum score and OCT showing increased CRT than that at the highest BCVA; 3) improved BCVA of ≥ 5 compared with the visual results from the previous follow-up; and 4) OCT showing new, recurrent, or persistent ME as well as retinal or subretinal fluid. Rescue panretinal photocoagulation (PRP) treatment: From month 3, researchers could consider PRP if a confirmed anterior and/or posterior neovascularization, or neovascular glaucoma, occurred in the target eye of the patient. Patients who received PRP treatment should withdraw from the study. Outcome Measurements The primary efficacy outcome measure was the alteration from baseline in BCVA at month 6. The secondary efficacy outcome measures were 1) assessment of the mean change in BCVA from baseline in both groups after 3 and 12 months of treatment; 2) assessment of the mean change in the CRT of patients in both groups compared with baseline after 3, 6, and 12 months of treatment; 3) evaluation of the number of patients in both groups who received PRP treatment after receiving 6 or 12 months as rescue treatment; and 4) safety assessment including ocular and non-ocular adverse events (AEs) and serious AEs (SAEs). Additional outcomes were 1) evaluation of the distribution of BCVA changes from baseline in patients in both groups after 3, 6, and 12 months of treatment; 2) evaluation of the changes in BCVA from baseline during follow-up in both groups; and 3) evaluation of the average change in imaging indicators, including the CRT and total macular volume of patients in both groups, compared with baseline during each follow-up. BCVA, CRT, and macular volume were evaluated monthly from baseline to month 12. BCVA was assessed based on the protocol of the Early Diabetic Treatment Retinopathy Study (ETDRS). Special imaging assessments included CRT and macular volume measured via spectral-domain OCT. Fundus photography and fluorescein angiography were performed at baseline and at 3, 6, 9, and 12 months. Zhongshan Ophthalmic Center, as the central reading center, independently reviewed all the fundus images to ensure standardized evaluation. Masked physicians were asked to supervise the efficacy assessment, decide on the need for retreatment during the PRN phase, and assess the AEs. Safety was monitored by recording ocular AEs, non-ocular AEs, and laboratory measures. Statistical Analyses For the primary outcome, the mean change in BCVA from baseline to month 6 was compared between conbercept group and control group. In this study, a superiority design was used, with a treatment difference of 6 letters. Using α = 0.05, power of 80%, and loss to follow-up of 20%, the minimum sample size for the study was 237 (treatment group, 158; control group, 79). For the primary outcome, the mean change from baseline BCVA letters at month 6 was compared between the groups via analysis of covariance. A p -value of 0.05 (two-sided) was considered to indicate statistical significance. The changes in BCVA, CRT, and macular volume between follow-up and baseline were evaluated using paired t -test with 95% confidence intervals. The Cochran–Mantel–Haenszel test was employed to assess between-group difference in the primary efficacy outcome measure at a two-sided significance level of 5%. Using descriptive statistical methods, the number and proportion of patients with AEs in both groups were summarized. The frequency of all AEs was compared between the groups using the chi-squared test or Fisher’s exact test. Results Baseline Characteristics Data were obtained from May 2016 to October 2020. The flow chart for the CRAVE study is presented in Fig. 1 . A total of 242 patients were randomly assigned to the treatment or control group at a ratio of 2:1. There were 213 patients who completed the core period and proceeded to the extension period (treatment group, 151; control group, 62). A total of 198 patients completed this study, including 141 in the treatment group and 57 in the control group (Fig. 1 ). The demographic characteristics of the patients are presented in Table 1 . Patient demographics and baseline ocular characteristics were similar between the groups. The baseline BCVA of the study eyes were 51.7 ± 14.2 and 53.1 ± 14.2 in the treatment and control groups, respectively ( P = 0.4747). No significant differences were observed between the groups in terms of mean CRT and total macular volume. Table 1 Patient Demographics and Baseline Characteristics Variable Treatment group (N = 157) Control group (N = 83) Age (years) Mean (SD) 57.3 (10.8) 55.0 (12.3) Sex, n (%) Male Female 79 (50.3) 78 (49.7) 50 (60.2) 33 (39.8) Disease course (months) Mean (SD) 2.3 (2.9) 2.3 (2.6) Study eye, n (%) Right Left 72 (57.6) 53 (42.4) 72 (58.5) 51 (41.5) baseline BCVA (ETDRS letters) Mean (SD) 51.7 (14.2) 53.1 (14.2) CRT (µm) Mean (SD) 510.3 (121.0) 520.4 (181.5) Macular volume(mm 3 ) Mean (SD) 14.1 (3.3) 14.4 (4.8) SD, standard deviation; BCVA, Best-Corrected Visual Acuity; CRT, central retinal thickness; ETDRS, Early Treatment Diabetic Retinopathy Study. Efficacy Functional Outcomes Figure 2 demonstrates that the treatment group had significantly improved BCVA letters at 7 days (7.2 ± 7.9 letters), 1 month (8.1 ± 8.7 letters), and 3 months (11.7 ± 10.5 letters) after the first treatment compared with baseline. Compared with the control group, the treatment group had significantly improved BCVA letters at 7 days, 1 month, and 3 months after the first treatment. After 6 months of treatment, the mean change in BCVA letters of the treatment group increased by13.6 ± 12.1 letters ( p < 0.0001) and that of the control group decreased by 2.2 ± 16.5 letters ( P = 0.2188) compared with baseline. A statistical difference was observed between the treatment and control groups in the BCVA letter score compared with the mean change at baseline (95% confidence interval (CI), 15.2 (11.7–18.8); P < 0.0001). After 12 months of treatment, the mean BCVA letters of the treatment group increased by 14.4 ± 13.8 letters compared with baseline ( P < 0.0001). Comparing the mean BCVA letters of the two groups between months 6 and 12, the mean change in BCVA letters was 0.8 ± 8.1 letters ( P = 0.2136) and 5.2 ± 8.1 ( P < 0.0001) letters in the treatment and control groups, respectively. After 6 months of treatment, the proportions of patients in whom BCVA letters improved by ≥ 15 letters from baseline were different between the treatment and control groups (49.7% vs. 9.6% p < 0.0001; Fig. 3 ). The proportions of patients in whom BCVA letters improved by ≥ 10 letters from baseline were 67.5% and 25.3% in the control and treatment groups, respectively ( p < 0.0001). After 12 months of treatment, the proportions of patients in whom BCVA letters improved by ≥ 15 letters from baseline were 52.2% and 25.3% in the treatment and control groups, respectively ( p < 0.0001). Conversely, the proportions of patients in whom BCVA letters improved by ≥ 10 letters from baseline were 68.2% and 36.1% in the treatment and control groups, respectively ( p < 0.0001). Anatomic Outcomes After 3 months of treatment, the mean CRT reduction from baseline was significantly greater in the treatment than in the control group (122.5 ± 93.5 vs. 13.5 ± 91.1 µm, P < 0.0001). After 6 months, the mean CRT decreased by 138.4 ± 99.4 µm in the treatment group versus 35.1 ± 98.8 µm in the control group compared with baseline ( P < 0.0001). At the end of the study, the CRT of the treatment group decreased from 510.3 ± 121.0 to 365.2 ± 91.1 µm ( P < 0.0001), but the reduction from months 6 to 12 was only 5.5 ± 58.3 µm ( P = 0.2426). The control group received PRN treatment after 6 months of sham treatment, and a mean CRT reduction of 46.1 ± 71.6 µm from months 6 to 12 was observed ( P < 0.0001) (Fig. 4 ). Changes in macular volume were also observed in this study (Fig. 5 ). After 6 months, the mean reduction of total macular volume was 3.8 ± 2.8 mm 3 in the treatment group versus 1.1 ± 2.7 mm 3 in the control group compared with baseline ( P < 0.0001). At month 12, the total macular volume of the treatment group decreased from 14.1 ± 3.3 to 10.1 ± 2.6 mm 3 ( P < 0.0001). From months 6 to 12, the total macular volume decreased by 0.2 ± 1.6 mm 3 in the treatment group ( P = 0.2369) versus 1.2 ± 1.9 mm 3 in the control group ( P < 0.0001). AEs From day 0 to month 6, ocular AE developed in 43.3% and 37.4% of the patients in the treatment and control groups, respectively. The most common ocular AEs were conjunctival hemorrhage (treatment group, 12.7%; control group, 2.4%) and visual impairment (treatment group, 7.6%; control group, 16.9%). As for non-ocular AEs, the total incidence rates were 51.6% and 45.8% in the treatment and control groups, respectively. The most common non-ocular AEs were elevated blood pressure (treatment group, 10.2%; control group, 9.6%) and upper respiratory tract infections (treatment group, 11.5%; control group, 4.8%). Intravitreal injection of conbercept was well tolerated (Table 2 ). Table 2 Key Ocular (Study Eye) and Non-ocular Adverse Events in control group and treatment group Adverse Events, n (%) Control group* Day 0–Month 6 (n = 83) Control group† Month 6–Month 12 (n = 62) Treatment group Day 0–Month 12 (N = 157) Ocular AEs visual impairment 14(16.9) 3(4.8) 22 (14.0) Vitreous hemorrhage 5(6.0) 0 1(0.6) Conjunctival hemorrhage 2(2.4) 2(3.2) 26(16.6) Epiretinal macular membranes 0 2(3.2) 2(1.3) Vitreous floaters 0 0 2(1.3) Iritis 0 0 2(1.3) Endophthalmitis 0 0 1(0.64) Cataract 0 0 2(1.3) Iris neovascularization 1(1.2) 0 0 Macular hole 0 0 1(0.6) Retinal detachment 1(1.2) 0 0 Non-ocular AEs Elevated blood pressure 8(9.6) 4(6.5) 22(14.0) Upper respiratory tract infections 4(4.8) 4(6.5) 30(19.1) Proteinuria 0 1(1.6) 2(1.3) Coronary artery disease 0 0 2(1.3) Acute coronary syndrome 0 0 1(0.6) Arrhythmia 0 0 2(1.3) Heart failure 0 0 1(0.6) Cardiac discomfort 1(1.2) 0 0 From day 0 to month 6, seven patients (4.46%) in the treatment group developed SAEs, one of which was endophthalmitis (n = 1), which was related to the study intervention. Previous studies have confirmed that endophthalmitis is a medication risk mainly related to intravitreal injection. In the control group, 7 (8.43%) patients developed SAE. From months 6 to 12, 1 (1.6%) patient in the control group developed SAE that was not related to the study drug. No patients died during the study. Treatment Exposure At month 12, the mean numbers of injections in the treatment and control groups were 9.5 ± 2.0 and 7.9 ± 3.8, respectively. In the treatment group, the mean interval between doses achievable with PRN treatment from months 6 to 11 was 84.8 ± 63.1 days. No patients underwent laser rescue therapy during the entire study period. Discussion This study evaluated the efficacy and safety of intravitreal injection of conbercept in the treatment of CRVO-ME. The findings indicate that the improvements in BCVA letters and CRT achieved with monthly intravitreal injections of conbercept in the first 6 months of treatment were largely maintained during the PRN (as needed) phase of the study. In our study, from day 0 to month 6, ophthalmic injection of conbercept was found to effectively improve the vision of patients with CRVO-ME, while the BCVA of the control treatment with sham injection decreased. At the end of the study (12 months), the mean BCVA letter significantly increased by 0.8 ± 8.1 letters compared with the end of month 6 in the treatment group. Conversely, the mean BCVA letters of the control group increased by an average of 5.2 ± 8.1 letters after the administration of PRN treatment, this suggested that delayed PRN conbercept injections can also significantly improve BCVA in patients with CRVO-ME who received sham injection for 6 months. In addition to evaluating CRT improvement after intravitreal injection of conbercept in patients with CRVO-ME, the overall macular volume was analyzed, and the improvement in macular volume after conbercept injection was found to be consistent with the improvement in BCVA. In this study, it was found that after 6 months of treatment with conbercept injection, the mean BCVA letters of the treatment group significantly increased whereas that of the control group significantly decreased compared with baseline. A statistical difference was observed between the treatment and control groups compared with the mean change at baseline in mean BCVA letter score. The COPERNICUS trial of aflibercept for CRVO showed an increase of 17.3 letters in the mean change from baseline BCVA at 6 months in the treatment group treated at a frequency of one dose per month 18 , when PRN treatment to 12 months, the mean BCVA letters in the treatment group keeping stable. After 6 months of sham injection, the mean BCVA letters of the patients in the control group decreased by 4.0 letters compared with baseline. With the continuation of PRN treatment until 12 months, the mean BCVA letters of patients increased by 7.8 letters compared with that at month 6. In the treatment group, the CRT was significantly altered by − 457.2 µm from baseline after 6 months of treatment and was well maintained at 12 months (− 413.0 µm). In the CRUISE trial, at 6 months of intraocular injections of 0.5-mg ranibizumab or sham injections, the mean BCVA letters change from baseline was 14.9 letters in the treatment group versus 0.8 letters in the control group compared with baseline 19 . After 6 months of PRN treatment, a slight decrease in BCVA letters compared with that at month 6 in the treatment group and an increase of 7.3 letters compared with that at baseline in the control group were observed. Our study was consistent with the overall trend of the above studies. COPERNICUS and CRUISE studies have confirmed the efficacy and safety of ranibizumab/aflibercept in CRVO-ME population. Our study validated the effectiveness and safety of conbercept in the treatment of CRVO-ME in the Chinese population, and the improvement of BCVA in patients was comparable to the results of phase III clinical studies with other anti-VEGF drugs. After receiving continuous monthly administration in loading phase, patients experienced a significant increase in visual acuity. It was also found that PRN treatment could maintain vision and anatomical improvement. Furthermore, the data indicated that delayed antiVEGF treatment compromised the visual benefits. Therefore, patients with CRVO-ME should be given medication immediately after the diagnosis. In this study, the interval between doses achievable with PRN treatment from months 6 to 11 was 84.8 days. This suggests that conbercept has a long-lasting therapeutic effect and long treatment interval and that conbercept PRN treatment could exert a stable therapeutic effect on patients with CRVO-ME after an adequate loading phase, as confirmed by the PHOENIX study 13 . The PHOENIX study explored the efficacy of conbercept (3 + Q3M: intravitreal injections of 0.5-mg conbercept once monthly for the first 3 months and then once quarterly until month 12) in treating patients with nAMD, with an average of 5.8 injections at 12 month and a mean improvement of 9.98 letters in visual acuity compared with baseline. Another interesting result was that unlike the patients from the CRUISE study who experienced a sharp decline in visual acuity between months 6 and 7, conbercept had only a minor reduction between months 6 and 7 of treatment, and visual acuity at month 12 improved by 0.8 ± 8.1 letters compared with month 6. This suggested that the effect of conbercept can be sustained for a longer period. Therefore, intravitreal injection of conbercept for CRVO-ME is effective and has a longer duration of efficacy. In this study, most ocular and non-ocular AEs have been identified in previous conbercept trials. The main ocular AEs observed in the patients were conjunctival hemorrhage (12.7%) and elevated intraocular pressure (10.2%). Their severities were mainly mild to moderate and were related to intravitreal injection. This was consistent with previous AEs reported that were associated with the use of conbercept ophthalmic injection and other antiVEGF drugs. Their severities were mostly mild and mainly associated with intravitreal injection. The SAEs associated with the study intervention were predominantly endophthalmitis and hypertension. Previous studies have confirmed that endophthalmitis is a medication risk. This study has some limitations. First, it was conducted on Asian ethnicity. Thus, more in-depth research on other ethnicities is warranted. Second, the follow-up period of this study was not long enough. The 6 + PRN regimen is safe and effective in treating CRVO-ME, with a mean injection number of 9.5 ± 2.0 during the 12-month period. Future trials should explore the impact of treatment interval extension on further reducing treatment burden. Conclusion In conclusion, patients with CRVO-ME in the treatment group exhibited significantly improved visual acuity, CRT, and total macular volume after receiving continuous monthly administration for 6 months. Furthermore, subsequent PRN treatment was found to maintain the treatment efficacy of conbercept. The control group received PRN treatment after receiving sham injections for 6 months and exhibited significant improvements in visual acuity, CRT, and total MV. The results of the CRAVE study indicated that intravitreal ophthalmic injection of 0.5-mg conbercept showed good efficacy and safety in patients with CRVO-ME. Declarations Synopsis/Precis: Compared with the control group, intravitreal injection of conbercept for 12 months can effectively improve the BCVA and CRT of CRVO-ME patients, and the safety is controllable. Funding No funding was received. Conflict of Interest : Presented in part at: World Ophthalmology Congress (WOC), September 9-12, 2022. Financial Support: This work was supported by Chengdu Kanghong Biotechnology Inc. Financial Disclosures: Wenbin Wei has nothing to declare. Zunhong Ke, Xiao Ke, Zhili Niu, Xinguo Wang, Xu Han, Zhujun Zhang, Tongxin Diao, Qiang Zheng are employees of Chengdu Kanghong Biotechnology, Company, Ltd. Authors’ contributions Concept and design: Wenbin Wei. Data collection: Wenbin Wei, Xiaorong Li, Xiaoxin Li, Hongquan Han, Xiaodong Sun, Luosheng Tang, Lin Lv, Ming Zhang, Youxin Chen, Xiaoling Liu, Guanfang Su, Jian Ye, Minli Huang, Fei Yuan, Lei Li, Linnong Wang, Hongliang Dou, Tiecheng Liu, Liu Yang, Yanling Wang, Yanping Song, Li Qin, Pei Wang, Shaowei Wang, Xueyi Chen, Zheli Liu, and Yan Shao. Analysis, or interpretation of data, and the draft of the manuscript: Wenbin Wei, Xuehui Shi, Xiao Ke, Zhili Niu, Xinguo Wang, Xu Han, Zhujun Zhang, Tongxin Diao, and Qiang Zheng. Manuscript modification: Wenbin Wei and Xuehui Shi. Overall responsibility: Wenbin Wei. Involved in administrative, technical, and material support: Zunhong Ke. Availability of Data and Materials All data generated or analyzed during this study are included in this published article. Declarations Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (each institutional review board or ethics committee (identifier no. NCT03223714)) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All patients provided written informed consent to participate in the trial. The full name of the ethics committee that approved this study and its affiliated institution are as follows: 1. Ethics Committee of Beijing Tongren Hospital (Approval No.: TREC2015-55), Beijing Tongren Hospital; 2. Ethics Committee of Tianjin Medical University Eye Hospital (Approval No.: （2016）药2号), Tianjin Medical University Eye Hospital; 3. Ethics Committee of Peking University People's Hospital (Approval No.: 2016PHA004-01), Peking University People's Hospital; 4. Ethics Committee of Tianjin Eye Hospital (Approval No.: TJYYLL-2016-02), Tianjin Eye Hospital; 5. Ethics Committee of Shanghai General Hospital (Approval No.: 院伦审[2016]06号), Shanghai General Hospital; 6. Ethics Committee of Zhongshan Ophthalmic Center, Sun Yat-sen University (Approval No.: 2016YWNL004), Zhongshan Ophthalmic Center, Sun Yat-sen University; 7. Ethics Committee of the Second Xiangya Hospital of Central South University (Approval No.: （2016）伦审【药】第（058）号), the Second Xiangya Hospital of Central South University; 8. Ethics Committee of Zhongshan Ophthalmic Center, Sun Yat-sen University (Approval No.: 2016YWNL004), Zhongshan Ophthalmic Center, Sun Yat-sen University; 9. Ethics Committee of West China Hospital, Sichuan University (Approval No.: 2016年临床试验（西药）审（40）号), West China Hospital, Sichuan University; 10. Ethics Committee of Peking Union Medical College Hospital, Peking Union Medical College Hospital; 11. Ethics Committee of Eye Hospital, Wenzhou Medical University (Approval No.: 2016-10-Y-5) Eye Hospital, Wenzhou Medical University; 12. Ethics Committee of the Second Norman Bethune Hospital of Jilin University (Approval No.: （2016）临会审第（003）号), the Second Norman Bethune Hospital of Jilin University; 13. Ethics Committee of Army Medical Center of People's Liberation Army (Approval No.: 伦审批药字（2016）第05号), Army Medical Center of People's Liberation Army; 14. Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (Approval No.: 伦审2016第（003）号), the First Affiliated Hospital of Guangxi Medical University; 15. Ethics Committee of Eye & ENT Hospital of Fudan University (Approval No.: [2016]伦审字第（2015051-1）号), Eye & ENT Hospital of Fudan University; 16. Ethics Committee of Nanjing First Hospital (Approval No.: YW20160907-05), Nanjing First Hospital; 17. Ethics Committee of Peking University Third Hospital (Approval No.: （2016）药伦审第（016-02）号), Peking University Third Hospital; 18. Ethics Committee of the General Hospital of the People's Liberation Army (Approval No.: C2016-008-02), the General Hospital of the People's Liberation Army; 19. Ethics Committee of Peking University First Hospital (Approval No.: （2016）药物注册第（03）号), Peking University First Hospital; 20. Ethics Committee of Beijing Friendship Hospital, Capital Medical University (Approval No.: 2016-P1-药002-01), Beijing Friendship Hospital; 21. Ethics Committee of General Hospital of Central Theater Command (Approval No.: [2016]002-2), General Hospital of Central Theater Command; 22. Ethics Committee of the First Affiliated Hospital of Xi'an Jiao Tong University (Approval No.: 2015伦审药临字第（14）号), the First Affiliated Hospital of Xi'an Jiao Tong University; 23. Ethics Committee of Jiangxi Provincial People's Hospital (Approval No.: 【2016】临审第（002）号), Jiangxi Provincial People's Hospital; 24. Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (Approval No.: 2016-药（器）-009), the Second Affiliated Hospital of Harbin Medical University; 25. Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (Approval No.: D160727-04), the First Affiliated Hospital of Xinjiang Medical University; 26. Ethics Committee of the First Hospital of China Medical University (Approval No.: 2016YL013), the First Hospital of China Medical University; 27. Ethics Committee of the Second Hospital of Dalian Medical University (Approval No.: 大医二院伦审2016第080号), the Second Hospital of Dalian Medical University. Consent for publication Not applicable. Acknowledgments The author thanks the researchers and clinical workers who have contributed to the study at each center. Competing interests The authors declare that they have no competing interests. References Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010;117(2):313-319 e311. Song P, Xu Y, Zha M, et al. Global epidemiology of retinal vein occlusion: a systematic review and meta-analysis of prevalence, incidence, and risk factors. J Glob Health 2019;9(1):010427. Iijima H. Mechanisms of vision loss in eyes with macular edema associated with retinal vein occlusion. Japanese journal of ophthalmology 2018;62(3):265-273. Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. The New England journal of medicine 2010;363(22):2135-2144. Liu W, Xu L, Jonas JB. Vein occlusion in Chinese subjects. Ophthalmology 2007;114(9):1795-1796. Noma H, Yasuda K, Shimura M. Cytokines and Pathogenesis of Central Retinal Vein Occlusion. Journal of clinical medicine 2020;9(11). Noma H, Mimura T, Yasuda K, et al. Role of soluble vascular endothelial growth factor receptor signaling and other factors or cytokines in central retinal vein occlusion with macular edema. Invest Ophthalmol Vis Sci 2015;56(2):1122-1128. Noma H, Yasuda K, Mimura T, et al. Retinal Microcirculation and Cytokines as Predictors for Recurrence of Macular Edema after Intravitreal Ranibizumab Injection in Branch Retinal Vein Occlusion. Journal of clinical medicine 2020;10(1). Scott IU, Oden NL, VanVeldhuisen PC, et al. Baseline Characteristics and Outcomes After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema in Participants With Hemiretinal Vein Occlusion Compared With Participants With Central Retinal Vein Occlusion: Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) Report 18. JAMA Ophthalmol 2022; 140(5):458-464. Nanji K, Sarohia GS, Kennedy K, et al. The 12- and 24-Month Effects of Intravitreal Ranibizumab, Aflibercept, and Bevacizumab on Intraocular Pressure: A Network Meta-Analysis. Ophthalmology 2022; 129(5):498-508. Arrigo A, Bandello F. Retinal vein occlusion: drug targets and therapeutic implications. Expert Opin Ther Targets 2021;25(10):847-864. Zhang M, Yu D, Yang C, et al. The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization. Pharm Res 2009;26(1):204-210. Liu K, Song Y, Xu G, et al. Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 PHOENIX Study. American journal of ophthalmology 2019;197:156-167. Liu K, Wang H, He W, et al. Intravitreal conbercept for diabetic macular oedema: 2-year results from a randomised controlled trial and open-label extension study. The British journal of ophthalmology 2022;106(10):1436-1443. Nie X, Wang Y, Yi H, et al. Intravitreal conbercept for choroidal neovascularisation secondary to pathological myopia in a real-world setting in China : Intravitreal conbercept was safe and effective in treating myopic choroidal neovascularization. BMC ophthalmology 2021;21(1):116. Sun Z, Zhou H, Lin B, et al. EFFICACY AND SAFETY OF INTRAVITREAL CONBERCEPT INJECTIONS IN MACULAR EDEMA SECONDARY TO RETINAL VEIN OCCLUSION. Retina (Philadelphia, Pa) 2017;37(9):1723-1730. Chengdu Kanghong Biotech Co. L. A Study Assessing the Safety and Efficacy of Multiple Intravitreal KH902 in Patients With CNV Due to AMD (HOPE) (NCT01242254). https://clinicaltrialsgov/study/NCT01242254 (to be published) 2014. Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol 2013;155(3):429-437 e427. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology 2011;118(10):2041-2049. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 06 Sep, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers invited by journal 20 Aug, 2025 Editor assigned by journal 14 Aug, 2025 Submission checks completed at journal 13 Aug, 2025 First submitted to journal 13 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7270611","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":504208206,"identity":"1cc0e31c-f8f6-4486-87f7-7d00a98f2967","order_by":0,"name":"Wenbin 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1","display":"","copyAsset":false,"role":"figure","size":1020362,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart for the CRAVE study.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7270611/v1/8549a6644654b509a1ca4f26.jpg"},{"id":90308240,"identity":"bd1acf6a-b6ae-4b32-8f4b-9db80a66e18c","added_by":"auto","created_at":"2025-09-01 09:36:46","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":351171,"visible":true,"origin":"","legend":"\u003cp\u003eThe mean change from baseline BCVA to Month 12 (FAS). BCVA, Best-Corrected Visual Acuity; FAS, full analysis set; ETDRS, Early Treatment Diabetic Retinopathy Study.\u003c/p\u003e","description":"","filename":"figure2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7270611/v1/258bf586a1e3e9175a55aeb1.jpg"},{"id":90306873,"identity":"4fa1891a-efdf-4245-aaf7-4c5b70aab105","added_by":"auto","created_at":"2025-09-01 09:28:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":529346,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution for Change from Baseline in BCVA at Month12 (FAS). BCVA, Best-Corrected Visual Acuity; FAS, full analysis set.\u003c/p\u003e","description":"","filename":"figure3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7270611/v1/fb754f0d7e7324d6e85a3adb.jpg"},{"id":90308242,"identity":"d41f3d8b-8bbf-4921-9409-624629c00a52","added_by":"auto","created_at":"2025-09-01 09:36:47","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":326970,"visible":true,"origin":"","legend":"\u003cp\u003eThe mean change from baseline CRT over time to month 12 (FAS). CRT, central retinal thickness; FAS, full analysis set.\u003c/p\u003e","description":"","filename":"figure4.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7270611/v1/20470154b690ebf99b398b80.jpg"},{"id":90306880,"identity":"64256136-a632-4ce9-8cc7-6522866ae082","added_by":"auto","created_at":"2025-09-01 09:28:47","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":478274,"visible":true,"origin":"","legend":"\u003cp\u003eThe mean change from baseline MV over time to month 12 (FAS). MV, macular volume; FAS, full analysis set.\u003c/p\u003e","description":"","filename":"Figure5.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7270611/v1/b7900870530b751fcc66ca8e.jpg"},{"id":90311622,"identity":"3f6f2cdb-f396-4342-ba8d-7fb7358fb9d1","added_by":"auto","created_at":"2025-09-01 09:52:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3657281,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7270611/v1/d2b9b709-3ab6-47ce-9cd5-023468e42c2a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"2-Month Outcomes of Conbercept in Macular Edema Secondary to Central Retinal Vein Occlusion from a randomized, multicenter, double-blind, sham-controlled phase III study: CRAVE Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRetinal vein occlusion (RVO) is a common primary retinal vascular disorder. It is categorized into central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), making it the second-largest retinal vascular disorder following diabetic retinopathy\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. CRVO affects the macular area and causes severe vision loss, significantly reducing patients\u0026rsquo; quality of life\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The complications of CRVO include retinal neovascularization, neovascular glaucoma, vitreous volume blood, and ME\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Among them, macular edema (ME) causes significant vision loss among patients with RVO. Based on statistics, three million people annually suffer from ME secondary to CRVO (CRVO-ME) worldwide. The Beijing Eye Study found that the prevalence of RVO was 1.3%; BRVO, 1.2%; and CRVO, 0.1%. Furthermore, ME was observed in 37% of patients with RVO, 30% of patients with BRVO, and 71% of patients with CRVO\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eRecent studies have demonstrated that the pathological changes of CRVO-ME are closely associated with abnormal expression of vascular endothelial growth factor (VEGF), changes in microvascular structure, and inflammatory response\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Intraocular VEGF and different inflammatory cytokine levels in patients with CRVO were significantly associated with ME severity\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. With the advancing research of anti-VEGF drugs and the popularization of their clinical applications, several clinical studies have suggested that intravitreal injection of antiVEGF drugs can significantly improve the visual and anatomical outcomes of patients with CRVO as well as the visual function of patients with CRVO-ME. It has been reported that bevacizumab, aflibercept, and ranibizumab can effectively treat ME caused by CRVO\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. AntiVEGF drugs are the current first-line treatment for ME caused by CRVO. These drugs reduce vascular permeability and leakage, thereby improving ME, and prevent neovascularization\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eConbercept (KH902; Chengdu Kanghong Biotech Co., Ltd., Sichuan Province, China) is a novel recombinant fusion protein with key domains from VEGF receptors 1 and 2 with human immunoglobulin Fc. It includes extracellular protein-like region 4 in VEGFR-2, which enhances binding affinity to VEGF, and the blockage effect of VEGF-mediated signaling in neovascularization. Furthermore, it allows for a more effective treatment of ocular pathological vascular diseases \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In China, conbercept has been approved for neovascular age-related macular degeneration (nAMD)\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, diabetic macular edema (DME)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, pathological myopic choroidal neovascularization (CNV)\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, and RVO-ME\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. The early clinical research of conbercept began with CNV-related diseases. The phase I clinical study (HOPE) evaluated the safety and efficacy of multiple intravitreal conbercept injections in patients with CNV due to age-related macular degeneration (AMD). The results indicated that conbercept can significantly improve the vision of AMD patients and reduce CRT\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Subsequent phase II and III studies further confirmed the efficacy and safety of conbercept in the treatment of nAMD\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The SAILING study was a multicenter, randomized, double-blind, phase 3 clinical trial that evaluated the efficacy and safety of conbercept injection versus laser photocoagulation in the treatment of DME. The study found that \u003cem\u003epro re nata\u003c/em\u003e (PRN) intravitreal injections of conbercept improved the best-corrected visual acuity (BCVA) of patients with DME and that it exhibited superior efficacy to laser photocoagulation\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. As a phase II registration study, FALCON reported that intravitreal injections of conbercept exhibited generally favorable safety and tolerability profiles as well as efficacy in treating RVO-ME\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. As a phase III registration study, CRAVE further confirmed the efficacy and safety of conbercept in the treatment of CRVO-ME.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design\u003c/h2\u003e\u003cp\u003eCRAVE was a multicenter, randomized, double-blind, sham-controlled phase III clinical study. It was conducted at 27 sites in China from May 2016 to October 2020. Patients with CRVO-ME were enrolled in the study and randomly assigned to the treatment group (received conbercept ophthalmic injection) or control group (received sham injection) at a ratio of 2:1. The study protocol was approved by the Ethics Committee of Beijing Tongren Hospital Affiliated to Capital Medical University (TREC2015-55). The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines. All patients provided written informed consent to participate in the trial. The study was registered on ClinicalTrials.gov (ID: NCT03223714, Date: July 21, 2017).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eThe inclusion criteria for the were as follows: 1) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, 2) CRVO-ME or ME secondary to hemi-central retinal vein occlusion (HRVO) involving the fovea and diagnosed within \u0026le;\u0026thinsp;12 months, 3) BCVA\u0026thinsp;\u0026ge;\u0026thinsp;24 and \u0026le;\u0026thinsp;73 (Snellen equivalent, 20/320\u0026ndash;20/40), 4) OCT showing central retinal thickness (CRT)\u0026thinsp;\u0026ge;\u0026thinsp;300 um, and 5) refractive medium opacification and/or pupillary abnormalities not affecting fundus examination or OCT. If both eyes were eligible, the eye with worse BCVA or an OCT showing greater CRT at screening was selected.\u003c/p\u003e\u003cp\u003eThe exclusion criteria for the study eyes were as follows: 1) active iris and/or retinal neovascularization; 2) presence of epiretinal membrane of the macula or vitreous traction; 3) presence of other diseases including macular foveal atrophy, submacular foveal hemorrhage, hard exudation of the macula area or dense submacular hard exudation, etc.; 4) history of any type of retinal detachment; 5) any other additional ocular diseases which could irreversibly compromise the visual acuity of the study eye including wet AMD, diabetic retinopathy, uveitis or other intraocular inflammatory diseases, neovascular glaucoma and macular cystic edema, etc.; 6) requiring cataract surgery within the next 12 months according to the investigator; 7) received intravitreal corticosteroids within 3 months, subconjunctival corticosteroids within 6 months, or topical therapy with ocular steroids within 1 month; 8) underwent scleral buckling surgery or verteporfin photodynamic therapy; 9) underwent YAG laser treatment or any other ophthalmic treatment within 3 months; 10) BCVA\u0026thinsp;\u0026gt;\u0026thinsp;10 during screening (comparing BCVA measured within 24 h before the first administration (day 0) with that at enrollment); 11) presence of aphakia or posterior lens capsule defect; 12) active inflammation around or in the eye; 13) past or present uncontrollable glaucoma; and 14) received intravitreal injection of any antiVEGF drugs in the previous 3 months.\u003c/p\u003e\n\u003ch3\u003eRandomization and Treatment\u003c/h3\u003e\n\u003cp\u003ePatients with CRVO-ME were enrolled in the study and randomly assigned to the treatment or control group at a ratio of 2:1 using a central randomization system. Randomization was stratified by region, and a validated system was used to generate a randomization list. The system automatically assigned patient numbers randomly to randomization numbers, which were linked to different treatment groups and then to drug numbers. Patients in the study, researchers responsible for visual assessment and imaging testing, treatment decision-makers, evaluators of imaging test results and treatment outcomes were masked to treatment. From day 0 to month 6, the treatment group received intravitreal injection of conbercept at a dose of 0.5 mg every month for six consecutive months. The control group, alternatively, received a sham injection for six consecutive doses once a month. Primary endpoint assessment was conducted at the end of month 6. All patients were evaluated monthly from months 6 to 12. Based on the results of each evaluation, the investigators decided whether the treatment group required PRN injection of 0.5-mg conbercept until month 11. The control group was given medication as necessary to month 11 after receiving single intravitreal ophthalmic injection of 0.5-mg conbercept in month 6. The final assessment was performed at the end of month 12 of the study. Patients who met any of the following criteria could be given PRN injection of 0.5-mg conbercept: 1) OCT showing increased CRT of \u0026ge;\u0026thinsp;50 \u0026micro;m from the previous minimum CRT; 2) decreased BCVA of \u0026ge;\u0026thinsp;5 from the previous maximum score and OCT showing increased CRT than that at the highest BCVA; 3) improved BCVA of \u0026ge;\u0026thinsp;5 compared with the visual results from the previous follow-up; and 4) OCT showing new, recurrent, or persistent ME as well as retinal or subretinal fluid.\u003c/p\u003e\u003cp\u003eRescue panretinal photocoagulation (PRP) treatment: From month 3, researchers could consider PRP if a confirmed anterior and/or posterior neovascularization, or neovascular glaucoma, occurred in the target eye of the patient. Patients who received PRP treatment should withdraw from the study.\u003c/p\u003e\n\u003ch3\u003eOutcome Measurements\u003c/h3\u003e\n\u003cp\u003eThe primary efficacy outcome measure was the alteration from baseline in BCVA at month 6. The secondary efficacy outcome measures were 1) assessment of the mean change in BCVA from baseline in both groups after 3 and 12 months of treatment; 2) assessment of the mean change in the CRT of patients in both groups compared with baseline after 3, 6, and 12 months of treatment; 3) evaluation of the number of patients in both groups who received PRP treatment after receiving 6 or 12 months as rescue treatment; and 4) safety assessment including ocular and non-ocular adverse events (AEs) and serious AEs (SAEs). Additional outcomes were 1) evaluation of the distribution of BCVA changes from baseline in patients in both groups after 3, 6, and 12 months of treatment; 2) evaluation of the changes in BCVA from baseline during follow-up in both groups; and 3) evaluation of the average change in imaging indicators, including the CRT and total macular volume of patients in both groups, compared with baseline during each follow-up.\u003c/p\u003e\u003cp\u003eBCVA, CRT, and macular volume were evaluated monthly from baseline to month 12. BCVA was assessed based on the protocol of the Early Diabetic Treatment Retinopathy Study (ETDRS). Special imaging assessments included CRT and macular volume measured via spectral-domain OCT. Fundus photography and fluorescein angiography were performed at baseline and at 3, 6, 9, and 12 months. Zhongshan Ophthalmic Center, as the central reading center, independently reviewed all the fundus images to ensure standardized evaluation. Masked physicians were asked to supervise the efficacy assessment, decide on the need for retreatment during the PRN phase, and assess the AEs. Safety was monitored by recording ocular AEs, non-ocular AEs, and laboratory measures.\u003c/p\u003e\n\u003ch3\u003eStatistical Analyses\u003c/h3\u003e\n\u003cp\u003eFor the primary outcome, the mean change in BCVA from baseline to month 6 was compared between conbercept group and control group. In this study, a superiority design was used, with a treatment difference of 6 letters. Using α\u0026thinsp;=\u0026thinsp;0.05, power of 80%, and loss to follow-up of 20%, the minimum sample size for the study was 237 (treatment group, 158; control group, 79).\u003c/p\u003e\u003cp\u003eFor the primary outcome, the mean change from baseline BCVA letters at month 6 was compared between the groups via analysis of covariance. A \u003cem\u003ep\u003c/em\u003e-value of 0.05 (two-sided) was considered to indicate statistical significance. The changes in BCVA, CRT, and macular volume between follow-up and baseline were evaluated using paired \u003cem\u003et\u003c/em\u003e-test with 95% confidence intervals. The Cochran\u0026ndash;Mantel\u0026ndash;Haenszel test was employed to assess between-group difference in the primary efficacy outcome measure at a two-sided significance level of 5%.\u003c/p\u003e\u003cp\u003eUsing descriptive statistical methods, the number and proportion of patients with AEs in both groups were summarized. The frequency of all AEs was compared between the groups using the chi-squared test or Fisher\u0026rsquo;s exact test.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eBaseline Characteristics\u003c/h2\u003e\u003cp\u003eData were obtained from May 2016 to October 2020. The flow chart for the CRAVE study is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 242 patients were randomly assigned to the treatment or control group at a ratio of 2:1. There were 213 patients who completed the core period and proceeded to the extension period (treatment group, 151; control group, 62). A total of 198 patients completed this study, including 141 in the treatment group and 57 in the control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe demographic characteristics of the patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Patient demographics and baseline ocular characteristics were similar between the groups. The baseline BCVA of the study eyes were 51.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.2 and 53.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.2 in the treatment and control groups, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.4747). No significant differences were observed between the groups in terms of mean CRT and total macular volume.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient Demographics and Baseline Characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTreatment group\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;157)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl group\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57.3 (10.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e55.0 (12.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSex, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e79 (50.3) \u003c/p\u003e\u003cp\u003e78 (49.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e50 (60.2) \u003c/p\u003e\u003cp\u003e33 (39.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDisease course (months)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.3 (2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.3 (2.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStudy eye, n (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRight \u003c/p\u003e\u003cp\u003eLeft\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e72 (57.6) \u003c/p\u003e\u003cp\u003e53 (42.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e72 (58.5) \u003c/p\u003e\u003cp\u003e51 (41.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ebaseline BCVA\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(ETDRS letters)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e51.7 (14.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e53.1 (14.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCRT (\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e510.3 (121.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e520.4 (181.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMacular volume(mm\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14.1 (3.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e14.4 (4.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eSD, standard deviation; BCVA, Best-Corrected Visual Acuity; CRT, central retinal thickness; ETDRS, Early Treatment Diabetic Retinopathy Study.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eFunctional Outcomes\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e demonstrates that the treatment group had significantly improved BCVA letters at 7 days (7.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9 letters), 1 month (8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7 letters), and 3 months (11.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.5 letters) after the first treatment compared with baseline. Compared with the control group, the treatment group had significantly improved BCVA letters at 7 days, 1 month, and 3 months after the first treatment. After 6 months of treatment, the mean change in BCVA letters of the treatment group increased by13.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1 letters (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and that of the control group decreased by 2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5 letters (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2188) compared with baseline. A statistical difference was observed between the treatment and control groups in the BCVA letter score compared with the mean change at baseline (95% confidence interval (CI), 15.2 (11.7\u0026ndash;18.8); \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). After 12 months of treatment, the mean BCVA letters of the treatment group increased by 14.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8 letters compared with baseline (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Comparing the mean BCVA letters of the two groups between months 6 and 12, the mean change in BCVA letters was 0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1 letters (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2136) and 5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) letters in the treatment and control groups, respectively.\u003c/p\u003e\u003cp\u003eAfter 6 months of treatment, the proportions of patients in whom BCVA letters improved by \u0026ge;\u0026thinsp;15 letters from baseline were different between the treatment and control groups (49.7% vs. 9.6% \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The proportions of patients in whom BCVA letters improved by \u0026ge;\u0026thinsp;10 letters from baseline were 67.5% and 25.3% in the control and treatment groups, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). After 12 months of treatment, the proportions of patients in whom BCVA letters improved by \u0026ge;\u0026thinsp;15 letters from baseline were 52.2% and 25.3% in the treatment and control groups, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Conversely, the proportions of patients in whom BCVA letters improved by \u0026ge;\u0026thinsp;10 letters from baseline were 68.2% and 36.1% in the treatment and control groups, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eAnatomic Outcomes\u003c/h2\u003e\u003cp\u003eAfter 3 months of treatment, the mean CRT reduction from baseline was significantly greater in the treatment than in the control group (122.5\u0026thinsp;\u0026plusmn;\u0026thinsp;93.5 vs. 13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;91.1 \u0026micro;m, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). After 6 months, the mean CRT decreased by 138.4\u0026thinsp;\u0026plusmn;\u0026thinsp;99.4 \u0026micro;m in the treatment group versus 35.1\u0026thinsp;\u0026plusmn;\u0026thinsp;98.8 \u0026micro;m in the control group compared with baseline (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). At the end of the study, the CRT of the treatment group decreased from 510.3\u0026thinsp;\u0026plusmn;\u0026thinsp;121.0 to 365.2\u0026thinsp;\u0026plusmn;\u0026thinsp;91.1 \u0026micro;m (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), but the reduction from months 6 to 12 was only 5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;58.3 \u0026micro;m (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2426). The control group received PRN treatment after 6 months of sham treatment, and a mean CRT reduction of 46.1\u0026thinsp;\u0026plusmn;\u0026thinsp;71.6 \u0026micro;m from months 6 to 12 was observed (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eChanges in macular volume were also observed in this study (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). After 6 months, the mean reduction of total macular volume was 3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8 mm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e in the treatment group versus 1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 mm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e in the control group compared with baseline (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). At month 12, the total macular volume of the treatment group decreased from 14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 to 10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6 mm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). From months 6 to 12, the total macular volume decreased by 0.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 mm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e in the treatment group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2369) versus 1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 mm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e in the control group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eAEs\u003c/h2\u003e\u003cp\u003eFrom day 0 to month 6, ocular AE developed in 43.3% and 37.4% of the patients in the treatment and control groups, respectively. The most common ocular AEs were conjunctival hemorrhage (treatment group, 12.7%; control group, 2.4%) and visual impairment (treatment group, 7.6%; control group, 16.9%). As for non-ocular AEs, the total incidence rates were 51.6% and 45.8% in the treatment and control groups, respectively. The most common non-ocular AEs were elevated blood pressure (treatment group, 10.2%; control group, 9.6%) and upper respiratory tract infections (treatment group, 11.5%; control group, 4.8%). Intravitreal injection of conbercept was well tolerated (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eKey Ocular (Study Eye) and Non-ocular Adverse Events in control group and treatment group\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdverse Events, n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eControl group*\u003c/p\u003e\u003cp\u003eDay 0\u0026ndash;Month 6\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl group\u0026dagger;\u003c/p\u003e\u003cp\u003eMonth 6\u0026ndash;Month 12\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTreatment group\u003c/p\u003e\u003cp\u003eDay 0\u0026ndash;Month 12\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;157)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eOcular AEs\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003evisual impairment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14(16.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22 (14.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVitreous hemorrhage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5(6.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(0.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConjunctival hemorrhage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2(3.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26(16.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEpiretinal macular membranes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2(3.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVitreous floaters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIritis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEndophthalmitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(0.64)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCataract\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIris neovascularization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMacular\u0026nbsp;hole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(0.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRetinal detachment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eNon-ocular AEs\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated blood pressure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8(9.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4(6.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22(14.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUpper respiratory tract infections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4(6.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30(19.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProteinuria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCoronary artery disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcute coronary syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(0.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArrhythmia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeart failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(0.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiac discomfort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFrom day 0 to month 6, seven patients (4.46%) in the treatment group developed SAEs, one of which was endophthalmitis (n\u0026thinsp;=\u0026thinsp;1), which was related to the study intervention. Previous studies have confirmed that endophthalmitis is a medication risk mainly related to intravitreal injection. In the control group, 7 (8.43%) patients developed SAE. From months 6 to 12, 1 (1.6%) patient in the control group developed SAE that was not related to the study drug. No patients died during the study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eTreatment Exposure\u003c/h2\u003e\u003cp\u003eAt month 12, the mean numbers of injections in the treatment and control groups were 9.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 and 7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8, respectively. In the treatment group, the mean interval between doses achievable with PRN treatment from months 6 to 11 was 84.8\u0026thinsp;\u0026plusmn;\u0026thinsp;63.1 days. No patients underwent laser rescue therapy during the entire study period.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study evaluated the efficacy and safety of intravitreal injection of conbercept in the treatment of CRVO-ME. The findings indicate that the improvements in BCVA letters and CRT achieved with monthly intravitreal injections of conbercept in the first 6 months of treatment were largely maintained during the PRN (as needed) phase of the study. In our study, from day 0 to month 6, ophthalmic injection of conbercept was found to effectively improve the vision of patients with CRVO-ME, while the BCVA of the control treatment with sham injection decreased. At the end of the study (12 months), the mean BCVA letter significantly increased by 0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1 letters compared with the end of month 6 in the treatment group. Conversely, the mean BCVA letters of the control group increased by an average of 5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1 letters after the administration of PRN treatment, this suggested that delayed PRN conbercept injections can also significantly improve BCVA in patients with CRVO-ME who received sham injection for 6 months. In addition to evaluating CRT improvement after intravitreal injection of conbercept in patients with CRVO-ME, the overall macular volume was analyzed, and the improvement in macular volume after conbercept injection was found to be consistent with the improvement in BCVA.\u003c/p\u003e\u003cp\u003eIn this study, it was found that after 6 months of treatment with conbercept injection, the mean BCVA letters of the treatment group significantly increased whereas that of the control group significantly decreased compared with baseline. A statistical difference was observed between the treatment and control groups compared with the mean change at baseline in mean BCVA letter score. The COPERNICUS trial of aflibercept for CRVO showed an increase of 17.3 letters in the mean change from baseline BCVA at 6 months in the treatment group treated at a frequency of one dose per month\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, when PRN treatment to 12 months, the mean BCVA letters in the treatment group keeping stable. After 6 months of sham injection, the mean BCVA letters of the patients in the control group decreased by 4.0 letters compared with baseline. With the continuation of PRN treatment until 12 months, the mean BCVA letters of patients increased by 7.8 letters compared with that at month 6. In the treatment group, the CRT was significantly altered by \u0026minus;\u0026thinsp;457.2 \u0026micro;m from baseline after 6 months of treatment and was well maintained at 12 months (\u0026minus;\u0026thinsp;413.0 \u0026micro;m). In the CRUISE trial, at 6 months of intraocular injections of 0.5-mg ranibizumab or sham injections, the mean BCVA letters change from baseline was 14.9 letters in the treatment group versus 0.8 letters in the control group compared with baseline\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. After 6 months of PRN treatment, a slight decrease in BCVA letters compared with that at month 6 in the treatment group and an increase of 7.3 letters compared with that at baseline in the control group were observed. Our study was consistent with the overall trend of the above studies. COPERNICUS and CRUISE studies have confirmed the efficacy and safety of ranibizumab/aflibercept in CRVO-ME population. Our study validated the effectiveness and safety of conbercept in the treatment of CRVO-ME in the Chinese population, and the improvement of BCVA in patients was comparable to the results of phase III clinical studies with other anti-VEGF drugs. After receiving continuous monthly administration in loading phase, patients experienced a significant increase in visual acuity. It was also found that PRN treatment could maintain vision and anatomical improvement. Furthermore, the data indicated that delayed antiVEGF treatment compromised the visual benefits. Therefore, patients with CRVO-ME should be given medication immediately after the diagnosis.\u003c/p\u003e\u003cp\u003eIn this study, the interval between doses achievable with PRN treatment from months 6 to 11 was 84.8 days. This suggests that conbercept has a long-lasting therapeutic effect and long treatment interval and that conbercept PRN treatment could exert a stable therapeutic effect on patients with CRVO-ME after an adequate loading phase, as confirmed by the PHOENIX study\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The PHOENIX study explored the efficacy of conbercept (3\u0026thinsp;+\u0026thinsp;Q3M: intravitreal injections of 0.5-mg conbercept once monthly for the first 3 months and then once quarterly until month 12) in treating patients with nAMD, with an average of 5.8 injections at 12 month and a mean improvement of 9.98 letters in visual acuity compared with baseline. Another interesting result was that unlike the patients from the CRUISE study who experienced a sharp decline in visual acuity between months 6 and 7, conbercept had only a minor reduction between months 6 and 7 of treatment, and visual acuity at month 12 improved by 0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1 letters compared with month 6. This suggested that the effect of conbercept can be sustained for a longer period. Therefore, intravitreal injection of conbercept for CRVO-ME is effective and has a longer duration of efficacy.\u003c/p\u003e\u003cp\u003eIn this study, most ocular and non-ocular AEs have been identified in previous conbercept trials. The main ocular AEs observed in the patients were conjunctival hemorrhage (12.7%) and elevated intraocular pressure (10.2%). Their severities were mainly mild to moderate and were related to intravitreal injection. This was consistent with previous AEs reported that were associated with the use of conbercept ophthalmic injection and other antiVEGF drugs. Their severities were mostly mild and mainly associated with intravitreal injection. The SAEs associated with the study intervention were predominantly endophthalmitis and hypertension. Previous studies have confirmed that endophthalmitis is a medication risk.\u003c/p\u003e\u003cp\u003eThis study has some limitations. First, it was conducted on Asian ethnicity. Thus, more in-depth research on other ethnicities is warranted. Second, the follow-up period of this study was not long enough. The 6\u0026thinsp;+\u0026thinsp;PRN regimen is safe and effective in treating CRVO-ME, with a mean injection number of 9.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 during the 12-month period. Future trials should explore the impact of treatment interval extension on further reducing treatment burden.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, patients with CRVO-ME in the treatment group exhibited significantly improved visual acuity, CRT, and total macular volume after receiving continuous monthly administration for 6 months. Furthermore, subsequent PRN treatment was found to maintain the treatment efficacy of conbercept. The control group received PRN treatment after receiving sham injections for 6 months and exhibited significant improvements in visual acuity, CRT, and total MV. The results of the CRAVE study indicated that intravitreal ophthalmic injection of 0.5-mg conbercept showed good efficacy and safety in patients with CRVO-ME.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSynopsis/Precis:\u003c/strong\u003e Compared with the control group, intravitreal injection of conbercept for 12 months can effectively improve the BCVA and CRT of CRVO-ME patients, and the safety is controllable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e: Presented in part at: World Ophthalmology Congress (WOC), September 9-12, 2022.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinancial Support: This work was supported by Chengdu Kanghong Biotechnology Inc.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinancial Disclosures: Wenbin Wei has nothing to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZunhong Ke, Xiao Ke, Zhili Niu, Xinguo Wang, Xu Han, Zhujun Zhang, Tongxin Diao, Qiang Zheng are employees of Chengdu Kanghong Biotechnology, Company, Ltd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcept and design: Wenbin Wei.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData collection: Wenbin Wei, Xiaorong Li, Xiaoxin Li, Hongquan Han, Xiaodong Sun, Luosheng Tang, Lin Lv, Ming Zhang, Youxin Chen, Xiaoling Liu, Guanfang Su, Jian Ye, Minli Huang, Fei Yuan, Lei Li, Linnong Wang, Hongliang Dou, Tiecheng Liu, Liu Yang, Yanling Wang, Yanping Song, Li Qin, Pei Wang, Shaowei Wang, Xueyi Chen, Zheli Liu, and Yan Shao.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalysis, or interpretation of data, and the draft of the manuscript: Wenbin Wei, Xuehui Shi, Xiao Ke, Zhili Niu, Xinguo Wang, Xu Han, Zhujun Zhang, Tongxin Diao, and Qiang Zheng. Manuscript modification: Wenbin Wei and Xuehui Shi.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOverall responsibility: Wenbin Wei.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInvolved in administrative, technical, and material support: Zunhong Ke.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (each institutional review board or ethics committee (identifier no.\u0026nbsp;NCT03223714)) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u0026nbsp;All patients provided written informed consent to participate in the trial.\u003c/p\u003e\n\u003cp\u003eThe full name of the ethics committee that approved this study and its affiliated institution are as follows:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp;Ethics Committee of Beijing Tongren Hospital (Approval No.: TREC2015-55),\u0026nbsp;Beijing Tongren Hospital;\u003c/p\u003e\n\u003cp\u003e2. Ethics Committee of Tianjin Medical University Eye Hospital (Approval No.:\u0026nbsp;（2016）药2号), Tianjin Medical University Eye Hospital;\u003c/p\u003e\n\u003cp\u003e3. Ethics Committee of Peking University People\u0026apos;s Hospital (Approval No.: 2016PHA004-01), Peking University People\u0026apos;s Hospital;\u003c/p\u003e\n\u003cp\u003e4. Ethics Committee of Tianjin Eye Hospital (Approval No.: TJYYLL-2016-02), Tianjin Eye Hospital;\u003c/p\u003e\n\u003cp\u003e5. Ethics Committee of Shanghai General Hospital (Approval No.:\u0026nbsp;院伦审[2016]06号), Shanghai General Hospital;\u003c/p\u003e\n\u003cp\u003e6. Ethics Committee of Zhongshan Ophthalmic Center, Sun Yat-sen University (Approval No.: 2016YWNL004), Zhongshan Ophthalmic Center, Sun Yat-sen University;\u003c/p\u003e\n\u003cp\u003e7. Ethics Committee of the Second Xiangya Hospital of Central South University (Approval No.:\u0026nbsp;（2016）伦审【药】第（058）号), the Second Xiangya Hospital of Central South University;\u003c/p\u003e\n\u003cp\u003e8. Ethics Committee of Zhongshan Ophthalmic Center, Sun Yat-sen University (Approval No.: 2016YWNL004), Zhongshan Ophthalmic Center, Sun Yat-sen University;\u003c/p\u003e\n\u003cp\u003e9. Ethics Committee of West China Hospital, Sichuan University (Approval No.: 2016年临床试验（西药）审（40）号), West China Hospital, Sichuan University;\u003c/p\u003e\n\u003cp\u003e10. Ethics Committee of Peking Union Medical College Hospital, Peking Union Medical College Hospital;\u003c/p\u003e\n\u003cp\u003e11. Ethics Committee of Eye Hospital, Wenzhou Medical University (Approval No.: 2016-10-Y-5) Eye Hospital, Wenzhou Medical University;\u003c/p\u003e\n\u003cp\u003e12. Ethics Committee of the Second Norman Bethune Hospital of Jilin University (Approval No.:\u0026nbsp;（2016）临会审第（003）号), the Second Norman Bethune Hospital of Jilin University;\u003c/p\u003e\n\u003cp\u003e13. Ethics Committee of Army Medical Center of People\u0026apos;s Liberation Army (Approval No.:\u0026nbsp;伦审批药字（2016）第05号), Army Medical Center of People\u0026apos;s Liberation Army;\u003c/p\u003e\n\u003cp\u003e14. Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (Approval No.:\u0026nbsp;伦审2016第（003）号), the First Affiliated Hospital of Guangxi Medical University;\u003c/p\u003e\n\u003cp\u003e15. Ethics Committee of Eye \u0026amp; ENT Hospital of Fudan University (Approval No.: [2016]伦审字第（2015051-1）号), Eye \u0026amp; ENT Hospital of Fudan University;\u003c/p\u003e\n\u003cp\u003e16. Ethics Committee of Nanjing First Hospital (Approval No.: YW20160907-05), Nanjing First Hospital;\u003c/p\u003e\n\u003cp\u003e17. Ethics Committee of Peking University Third Hospital (Approval No.:\u0026nbsp;（2016）药伦审第（016-02）号), Peking University Third Hospital;\u003c/p\u003e\n\u003cp\u003e18. Ethics Committee of the General Hospital of the People\u0026apos;s Liberation Army (Approval No.: C2016-008-02), the General Hospital of the People\u0026apos;s Liberation Army;\u003c/p\u003e\n\u003cp\u003e19. Ethics Committee of Peking University First Hospital (Approval No.:\u0026nbsp;（2016）药物注册第（03）号), Peking University First Hospital;\u003c/p\u003e\n\u003cp\u003e20. Ethics Committee of Beijing Friendship Hospital, Capital Medical University (Approval No.: 2016-P1-药002-01), Beijing Friendship Hospital;\u003c/p\u003e\n\u003cp\u003e21. Ethics Committee of General Hospital of Central Theater Command (Approval No.: [2016]002-2), General Hospital of Central Theater Command;\u003c/p\u003e\n\u003cp\u003e22. Ethics Committee of the First Affiliated Hospital of Xi\u0026apos;an Jiao Tong University (Approval No.: 2015伦审药临字第（14）号), the First Affiliated Hospital of Xi\u0026apos;an Jiao Tong University;\u003c/p\u003e\n\u003cp\u003e23. Ethics Committee of Jiangxi Provincial People\u0026apos;s Hospital (Approval No.:\u0026nbsp;【2016】临审第（002）号), Jiangxi Provincial People\u0026apos;s Hospital;\u003c/p\u003e\n\u003cp\u003e24. Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (Approval No.: 2016-药（器）-009), the Second Affiliated Hospital of Harbin Medical University;\u003c/p\u003e\n\u003cp\u003e25. Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (Approval No.: D160727-04), the First Affiliated Hospital of Xinjiang Medical University;\u003c/p\u003e\n\u003cp\u003e26. Ethics Committee of the First Hospital of China Medical University (Approval No.: 2016YL013), the First Hospital of China Medical University;\u003c/p\u003e\n\u003cp\u003e27. Ethics Committee of the Second Hospital of Dalian Medical University (Approval No.: 大医二院伦审2016第080号), the Second Hospital of Dalian Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author thanks the researchers and clinical workers who have contributed to the study at each center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. \u003cem\u003eOphthalmology \u003c/em\u003e2010;117(2):313-319 e311.\u003c/li\u003e\n\u003cli\u003eSong P, Xu Y, Zha M, et al. Global epidemiology of retinal vein occlusion: a systematic review and meta-analysis of prevalence, incidence, and risk factors. \u003cem\u003eJ Glob Health \u003c/em\u003e2019;9(1):010427.\u003c/li\u003e\n\u003cli\u003eIijima H. Mechanisms of vision loss in eyes with macular edema associated with retinal vein occlusion. \u003cem\u003eJapanese journal of ophthalmology \u003c/em\u003e2018;62(3):265-273.\u003c/li\u003e\n\u003cli\u003eWong TY, Scott IU. Clinical practice. Retinal-vein occlusion. \u003cem\u003eThe New England journal of medicine \u003c/em\u003e2010;363(22):2135-2144.\u003c/li\u003e\n\u003cli\u003eLiu W, Xu L, Jonas JB. 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Baseline Characteristics and Outcomes After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema in Participants With Hemiretinal Vein Occlusion Compared With Participants With Central Retinal Vein Occlusion: Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) Report 18. \u003cem\u003eJAMA Ophthalmol \u003c/em\u003e2022; 140(5):458-464.\u003c/li\u003e\n\u003cli\u003eNanji K, Sarohia GS, Kennedy K, et al. The 12- and 24-Month Effects of Intravitreal Ranibizumab, Aflibercept, and Bevacizumab on Intraocular Pressure: A Network Meta-Analysis. \u003cem\u003eOphthalmology \u003c/em\u003e2022; 129(5):498-508.\u003c/li\u003e\n\u003cli\u003eArrigo A, Bandello F. Retinal vein occlusion: drug targets and therapeutic implications. \u003cem\u003eExpert Opin Ther Targets \u003c/em\u003e2021;25(10):847-864.\u003c/li\u003e\n\u003cli\u003eZhang M, Yu D, Yang C, et al. The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization. \u003cem\u003ePharm Res \u003c/em\u003e2009;26(1):204-210.\u003c/li\u003e\n\u003cli\u003eLiu K, Song Y, Xu G, et al. Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 PHOENIX Study. \u003cem\u003eAmerican journal of ophthalmology \u003c/em\u003e2019;197:156-167.\u003c/li\u003e\n\u003cli\u003eLiu K, Wang H, He W, et al. Intravitreal conbercept for diabetic macular oedema: 2-year results from a randomised controlled trial and open-label extension study. \u003cem\u003eThe British journal of ophthalmology \u003c/em\u003e2022;106(10):1436-1443.\u003c/li\u003e\n\u003cli\u003eNie X, Wang Y, Yi H, et al. Intravitreal conbercept for choroidal neovascularisation secondary to pathological myopia in a real-world setting in China : Intravitreal conbercept was safe and effective in treating myopic choroidal neovascularization. \u003cem\u003eBMC ophthalmology \u003c/em\u003e2021;21(1):116.\u003c/li\u003e\n\u003cli\u003eSun Z, Zhou H, Lin B, et al. EFFICACY AND SAFETY OF INTRAVITREAL CONBERCEPT INJECTIONS IN MACULAR EDEMA SECONDARY TO RETINAL VEIN OCCLUSION. \u003cem\u003eRetina (Philadelphia, Pa) \u003c/em\u003e2017;37(9):1723-1730.\u003c/li\u003e\n\u003cli\u003eChengdu Kanghong Biotech Co. L. A Study Assessing the Safety and Efficacy of Multiple Intravitreal KH902 in Patients With CNV Due to AMD (HOPE) (NCT01242254). \u003cem\u003ehttps://clinicaltrialsgov/study/NCT01242254\u003c/em\u003e\u003cem\u003e (to be published) \u003c/em\u003e2014.\u003c/li\u003e\n\u003cli\u003eBrown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. \u003cem\u003eAm J Ophthalmol \u003c/em\u003e2013;155(3):429-437 e427.\u003c/li\u003e\n\u003cli\u003eCampochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. \u003cem\u003eOphthalmology \u003c/em\u003e2011;118(10):2041-2049.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"conbercept, central retinal vein occlusion, best-corrected visual acuity, central retinal thickness, macular edema","lastPublishedDoi":"10.21203/rs.3.rs-7270611/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7270611/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTo evaluate the efficacy and safety of intravitreal injection of conbercept for the treatment of macular edema secondary to central retinal vein occlusion (CRVO-ME).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003ePatients with CRVO were randomly divided into the treatment (conbercept injection) and control groups (sham injection) at a ratio of 2:1. The primary endpoint was the mean changes in best-corrected visual acuity (BCVA) from baseline to month 6.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFrom baseline to month 6, the mean change in BCVA letters were 13.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and \u0026minus;\u0026thinsp;2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2188) in the treatment and control groups. From baseline to month 12, the mean change in BCVA letters were 14.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and 3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;17.6 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The mean reduction of CRT from baseline to month 6 were 138.4\u0026thinsp;\u0026plusmn;\u0026thinsp;99.4 \u0026micro;m (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and 35.1\u0026thinsp;\u0026plusmn;\u0026thinsp;98.8 \u0026micro;m (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0018). From baseline to month 12, the mean reduction values of CRT were 145.1\u0026thinsp;\u0026plusmn;\u0026thinsp;105.1 \u0026micro;m (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and 81.7\u0026thinsp;\u0026plusmn;\u0026thinsp;107.9 \u0026micro;m (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). No new safety events were identified.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIntravitreal injection of conbercept has definite efficacy and expected controllable safety in patients with CRVO-ME, providing a more flexible strategy for conbercept in the clinical treatment of CRVO-ME.\u003c/p\u003e\u003ch2\u003eTrial Registration:\u003c/h2\u003e\u003cp\u003eClinicalTrials.gov Identifier: NCT03223714, Date: July 21, 2017.\u003c/p\u003e","manuscriptTitle":"2-Month Outcomes of Conbercept in Macular Edema Secondary to Central Retinal Vein Occlusion from a randomized, multicenter, double-blind, sham-controlled phase III study: CRAVE Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 09:28:41","doi":"10.21203/rs.3.rs-7270611/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-09-06T10:37:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"206536385049890452356627144860441568070","date":"2025-08-21T02:52:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"172870676108022319684062380747620968504","date":"2025-08-20T17:30:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-20T08:23:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-14T06:52:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-13T23:47:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-08-13T23:45:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"368c7ce4-0588-4f3f-93bd-1965954001cd","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T09:28:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-01 09:28:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7270611","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7270611","identity":"rs-7270611","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}