A Real World Efficacy And Safety Study Of Conbercept Versus Ranibizumab

Background: With the change of people’s lifestyle and the popularization of electronic products,the prevalence of neovascular fundus disease is increasing year by year.On June 5,2020,the National Health and Medical Commission released the first .The white paper pointed out that metabolic eye diseases and age-related fundus diseases have become the main blinding eye diseases in our country.This type of disease is mainly characterized by fundus vascular hyperplasia,and the main treatment methods are early drug intervention and middle and advanced surgery to control the disease progression,still no radical cure.Drug treatment is mainly through intravitreal injection of anti-vascular endothelial growth factor（VEGF）receptor drugs.However,clinical trials supporting the listing of such drugs have strict exclusion criteria,and the actual drug population is not limited to the test population,especially the lack of real world data on the domestic innovative drug Conbercept ophthalmic injection to demonstrate its effectiveness and safety.Objective: Taking Ranibizumab as a control,the safety status of Conbercept since its launch was analyzed.Combined with real world research methods,the clinical efficacy and safety of Conbercept and Ranibizumab were compared,and the serious adverse reports（SAE）were discussed.The risk factors of adverse events can provide reference for clinical rational drug use.Methods: Bibliometrics method was used to retrospectively analyze the relevant literature published by Conbercept at home and abroad,focusing on the occurrence of adverse events（AE）,involving system organs and frequency,and observing the research trend of Conbercept;For Ranibizumab,the U.S.Food and Drug Administration Adverse Event Reporting System（FAERS）was selected for signal mining,and the reported AE status and suspected potential AE signals were detected.The clinical data of IVR were compared and analyzed by cohort study method in the treatment of neovascular age-related macular degeneration（nAMD）.Prospectively observe the drug safety of IVC and IVR in the whole population,compare with the results of bibliometric and signal mining,and explore the risk factors of SAE in patients after drug use,so as to provide reference for clinical safe drug use.（1）Bibliometric analysis of adverse events.Using "Conbercept",’KH902’ and’Conbercept’ as search terms,the scientific citation index database Web of Science,biomedical database Pub Med,Embase,Wanfang Academic Journal Full-text Database,VIP Journal Full-text Database and CNKI As search platform,the retrieval time is up to October 17,2020.Professional retrieval of the literature on the clinical application of Conbercept is carried out,and adverse events reported in the literature are screened by reading the full text.The International Medical Dictionary for Regulatory Activities（Med DRA 23.1）was used to name the Preferred Term（PT）and the system organ class（SOC）was used as the standard to summarize and analyze the occurrence characteristics of AEs in its related studies.（2）Mining of adverse event signals.The AEs of Ranibizumab reported in FAERS were selected for signal mining,and the reporting odds ratio（ROR）and proportional reporting ratio（PRR）were used for signal mining of Ranibizumab,focusing on rare The delayed AE signal is compared with the bibliometric results of Conbercept to provide data reference for real world research.（3）Effectiveness evaluation.A single-center,ambispective cohort real world study,selected nAMD patients who received intraocular injection of Conbercept and Ranibizumab in Yantai Yuhuangding Hospital from January 1,2016 to December 31,2021,and screened from baseline registration For cases with at least six months of in-hospital follow-up,Propensity Score Matching（PSM）was used to balance patient differences between groups.The primary endpoints were the changes in Best Corrected Visual Acuity（BCVA）and Central Retinal Thickness（CRT）within 6months after treatment,and secondary endpoints were the average number of medications and patients lost to follow-up.If the data conform to the normal distribution,one-way analysis of variance or comparison of differences between groups before and after treatment is used,and paired t-test is used to compare differences within groups before and after treatment;if the data does not conform to normality,Kruskal Wallis test and rank sum test are used to compare between groups and within-group differences.（4）Safety evaluation.Patients treated with Ranibizumab and Conbercept in Yantai Yuhuangding Hospital from January 1,2016 to December 31,2021 were retrospectively and prospectively enrolled,and the occurrence of AEs within 12 months after their use was observed and recorded.To judge the correlation between AEs and adverse reactions,AEs were rated using the American Common Adverse Events Rating Criteria（CTCAE）,and the incidence of SAEs was calculated;for SAEs with higher frequency,Lasso regression and univariate Cox regression were used to screen covariates,to construct a Cox proportional hazards regression model to analyze the risk factors for the occurrence of SAE.Results:（1）The relevant studies were all published by domestic researchers.There were 27 English literatures and 453 Chinese literatures reporting AEs.A total of 9 AEs were collected under the SOC classification.Among them,there were 835 eye reports at most.In addition to some adverse events,there were serious adverse events of the nervous system（7 cases）and cardiac organs（1 case）,but there were very few reports,and most of the papers did not observe AEs.（2）57,680 adverse event reports of Ranibizumab were retrieved from the FAERS database,656 signals were identified by ROR method,1,053 signals were detected by PRR,and a total of 652 repeated signals were included in the two methods.Adverse events involved 22 systems/organs under the SOC classification;most of the signals（48.2%）were ocular complications,followed by cardiovascular system（5.5%）and nervous system adverse event reports（9.5%）and the majority of signals and signals were also seen Such as ear and labyrinth AEs such as deafness,hearing loss,and renal and urinary system AEs such as renal failure.（3）Effectiveness evaluation A total of 35 nAMD patients were included in the IVC group,112 in the IVR group,and 35 patients in the IVR group with similar baseline characteristics to the IVC group.Compared with the baseline visual acuity,the BCVA at the end of the study was improved in both groups of patients,and the BVCA in the Conbercept group was significantly improved compared with the baseline visual acuity in the 2nd and 4th months;one-way analysis of variance showed that the two groups of patients were significantly higher than the baseline visual acuity.There was no statistical difference in BCVA changes between the two groups after treatment;CMT decreased significantly in the two groups after treatment,and Ranibizumab showed a significant monthly change.One-way analysis of variance showed that there was no statistical difference in the monthly CMT changes between the two groups after treatment.learning differences.（4）In the safety study,a total of 177 patients were included in the IVC group,and the average number of injections was 2.42 times per person.A total of 204 AEs were observed in 93 patients,involving 17 system organs,of which 56 were SAEs,accounting for 27.5 percent of all AEs;A total of 780 patients were included in the IVR group,the average number of injections was 2.16,and a total of 388 patients had767 AEs involving 22 system organs,of which 183 were SAEs,accounting for 23.9percent;after PSM matching between groups,177 were matched in the IVR group.86 of them had 194 AEs,and the incidence of AEs in each system was lower than that in the IVC group.Except for ocular events,both groups had more AEs in cardiac organs and various nervous systems.After establishing a multivariate Cox proportional hazards regression model for cardiac and nervous system SAEs,it was found that patients with hypertension underwent IVC and IVR.The risk of later cardiac SAE was 2.2 times higher than that of patients without hypertension（p<0.05,95%CI 1.2～3.9）;patients with a previous neurological history had a higher risk of neurological SAE than those without a neurological history 4 times（p<0.001,95%CI1.8～8.8）.Conclusion:（1）Bibliometric results show that the studies on Conbercept are all efficacy validation or randomized controlled trials,and there is no safety study.After statistical adverse events,it is found that most of the literatures do not report adverse events,and there are few systematic adverse events,it is necessary to conduct safety monitoring;（2）The results of signal mining show that Ranibizumab can lead to systematic adverse events,and the signals of cardiac and nervous system adverse events are more concentrated,and this type of AE should be focused on.The number of reports was also high,possibly of the type of potential adverse reaction.（3）Conbercept and Ranibizumab have similar efficacy in the treatment of nAMD in the real world setting,and they are comparable to Ranibizumab in terms of visual gain and foveal thickness reduction,but the actual visual benefits of the two groups are not as good as RCT.Research.（4）Under real world conditions,Conbercept will produce systematic serious adverse events similar to Ranibizumab,and the trend of adverse events is similar to that of Ranibizumab,in which patients with a history of hypertension and heart disease at baseline are treated with the drug The risk of cardiac SAE increases significantly after treatment,and patients with previous neurological diseases have a significant increase in the recurrence and new incidence of neurological diseases after taking the drug,suggesting that before treating such patients,comprehensive analysis of the patient’s symptoms should be carried out.benefit,change the treatment regimen or prevent the occurrence of related SAEs.Innovation:（1）Using real world research methods,retrospectively analyze the classic drug Ranibizumab and the domestic innovative drug Conbercept,observe the relevant research trends,summarize the occurrence of AEs,and provide data reference for the next research,and then use the real world research method conducts a comprehensive observation of the actual medication patients,analyzes the risk factors of SAE after medication combined with the clinical prediction model,and provides data support for the clinical selection of treatment plans for patients with different characteristics.（2）At present,there is no research report on the safety of ocular anti-VEGF drugs in China,and there is controversy about the clinical benefits of anti-VEGF drugs in foreign countries.The domestic drug Conbercept was compared with the classic drug Ranibizumab to verify the effectiveness of such drugs in the Chinese population,to observe the safety of patients after taking the drug from multiple perspectives,and to explore the risk factors for SAE.