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 Table of Contents  
RESEARCH ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 2  |  Page : 71-76

Ranibizumab versus conbercept for wet age-related macular degeneration: Protocol for a prospective cohort study


1 Department of Pharmacy, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province; Chinese Evidence-based Medicine Centre, Sichuan University, Chengdu, Sichuan Province, China
2 Department of Ophthalmology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
3 Department of Pharmacy, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China

Date of Web Publication6-Jul-2018

Correspondence Address:
Juan Xie
Department of Pharmacy, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3975.235152

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  Abstract 

Background and objectives: Conbercept is a novel anti-vascular endothelial growth factor (VEGF) agent for the treatment of wet age-related macular degeneration (wAMD). However, no head-to-head study has compared the effectiveness of conbercept with that of ranibizumab. In this study, we will compare the effectiveness, cost-effectiveness and safety profiles of ranibizumab and conbercept in the treatment of wAMD.
Design: This is a single-center, prospective, cohort study.
Methods: Patients (≥ 50 years old) diagnosed with wAMD will be allocated to the conbercept or ranibizumab group according to their preference. Following a treat-and-extend protocol, patients will receive intravitreal injections of 0.5 mg conbercept or 0.5 mg ranibizumab every month in the first three injections.
Outcome measures: The primary outcome is quality of life, measured with the Chinese version of the Low Vision Quality of Life Questionnaire, from baseline to 48 weeks post-treatment. Secondary outcomes include best corrected visual acuity, central retinal thickness, cost of treatment, intraocular pressure, and adverse events. The follow-up phase will last 1 year. Propensity score matching will be used to deal with differences in baseline between the two groups. A cost-effectiveness analysis will be performed.
Discussion: The results of this study will provide clinicians with a rational basis for choosing the most effective treatment for wAMD patients.
Ethics and dissemination: This study has been approved by the Medical Ethics Committee of Guizhou Provincial People’s Hospital (approval number: 2017113). Patient recruitment was initiated in November 2017. Analysis of primary outcome measures will be completed in October 2020, and the study will be finished in October 2021. Dissemination plans include presentations at scientific conferences and publication in scientific journals.
Trial registration: This study was registered in the Chinese Clinical Trial Registry with registration number of ChiCRT-OPC-17013023, protocol version: 2.0.

Keywords: age-related macular degeneration; ranibizumab; conbercept; cohort study; propensity score


How to cite this article:
Zhang JX, Li D, Hu Q, Xie J, Yan CH, Qian X, Zhao HY. Ranibizumab versus conbercept for wet age-related macular degeneration: Protocol for a prospective cohort study. Clin Trials Degener Dis 2018;3:71-6

How to cite this URL:
Zhang JX, Li D, Hu Q, Xie J, Yan CH, Qian X, Zhao HY. Ranibizumab versus conbercept for wet age-related macular degeneration: Protocol for a prospective cohort study. Clin Trials Degener Dis [serial online] 2018 [cited 2018 Jul 23];3:71-6. Available from: http://www.clinicaltdd.com/text.asp?2018/3/2/71/235152


  Introduction Top


Background

Age-related macular degeneration (AMD), a progressive chronic disease of the central retina (the macula), results primarily in the loss of central vision. The Global Burden of Disease Study, 2010, reported an exponential increase of 160% in years lived with vision-related disability caused by AMD, highlighting the overwhelming social burden of the disease.[1] AMD has become the leading cause of adult blindness in industrialized countries, and the incidence is expected to at least double by 2020.[2]

Clinically, AMD is classified as dry or wet AMD (wAMD). wAMD (neovascular or exudative) accounts for more than 80% of cases, with severe visual loss or legal blindness.[3] According to the guidelines of the American Academy of Ophthalmology (AAO) and the European Society of Retina Specialists (EURETINA), anti-vascular endothelial growth factor (VEGF) agents are the most effective treatments for managing neovascular AMD, and are therefore first-line treatments.[2],[4] Between 2004 and 2006, three anti-VEGF drugs—pegaptanib, ranibizumab and bevacizumab—were introduced for the treatment of AMD. Thereafter, aflibercept and conbercept were approved in the United States and China in 2011 and 2013, respectively.

At present, ranibizumab and conbercept are the most prescribed anti-VEGF agents for AMD in China, with more than 80% of the market. However, these two drugs differ in price and effectiveness, probably because of differences in the mechanisms of action.[5],[6] Cui et al.[7] found a statistically significant difference between conbercept and ranibizumab in the number of treatments (7.4 vs. 8.7, P = 0.001). Zhao et al.[8] conducted a cost-effectiveness analysis based on a Markov model, and concluded that conbercept was a more cost-effective option for the treatment of AMD in China, compared with ranibizumab. Given the limitation of the model and the lack of data on the quality of life of wAMD patients, this conclusion needs to be verified, especially in a real-world population. As a post-marketing evaluation study, it is impossible to conduct a randomized controlled trial (RCT).

Objectives

We will conduct a prospective observational study of wAMD patients to evaluate and compare the effectiveness, cost-effectiveness and safety profiles of conbercept and ranibizumab in China.


  Methods/Design Top


Study design and setting

This is a single-center, prospective cohort study conducted in Guizhou Provincial People’s Hospital in China. Guizhou Provincial People’s Hospital is one of the largest tertiary hospitals in Guizhou province in China. As the medical center of Guizhou region, the hospital has 3000 beds (about 50 beds for the ophthalmology department) and 65 clinical departments. Outpatients in the ophthalmology department number nearly 100 per day, which will provide sufficient wAMD patients for this study. A flow chart of this trial is given in [Figure 1].
Figure 1: Flowchart of the study protocol.

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The study will include a cohort of wAMD patients who will be treated with ranibizumab or conbercept. We will compare the effectiveness, cost-effectiveness and safety profiles of ranibizumab and conbercept in the treatment of wAMD. The results will be made available in a registry database.

Study population

Patients admitted to the outpatient clinic of the Department of Ophthalmology, Guizhou Provincial People’s Hospital in China will be consecutively enrolled in our study from 1 November, 2017 to 31 October, 2020.



Inclusion criteria

The inclusion criteria are as follows: (1) diagnosed with wAMD according to the Clinical Pathway of AMD in China[9]; (2) over 50 years of age; (3) scheduled to receive the anti-VEGF agent ranibizumab or conbercept; (4) signed informed consent and willing to participate in the study.

Exclusion criteria

Patients with glaucoma, cataracts or retinopathy caused by diabetes or hypertension will be excluded.

Assignment and blinding

The physicians will provide the patients with the detailed characteristics of the two anti-VEGF agents before patients make their selection. Eligible patients will be treated with ranibizumab or conbercept depending on their preference, which will not be influenced by the physician [Figure 1]. The investigators assessing outcome will be blinded to patient allocation.

Anti-VEGF drug treatment and management

Following a treat-and-extend (TREX) protocol,[10] patients will receive intravitreal injection of 0.5 mg conbercept (Lumitin; Chengdu Kanghong Biotech, Ltd., Chengdu, Sichuan Province, China) or 0.5 mg ranibizumab (Lucentis; Roche Group/Novartis Pharma Stein AG, South San Francisco, CA, USA) every month in the first three injections. In the first 3 months, the patients will receive injection once a month. All intravitreal injections will be performed by senior ophthalmologists.

After the 3-month loading phase, patients will be examined monthly for best corrected visual acuity (BCVA) and central retinal thickness (CRT), and will be given as-needed treatments with the same drug given during the loading phase. During each visit, concomitant medication and adverse events will be recorded. If the initial anti-VEGF drug fails to achieve the therapeutic goal, the other drug will be prescribed. The decision to switch drugs will be made by both the clinician and the patient, and the reason will be recorded. During the study, the patients will be allowed to continue taking medications for comorbidities (e.g., hypertension, diabetes, hyperlipidemia, etc.), and the type and dose of co-administered drugs will be recorded.

Outcome measures

Primary outcome

The primary outcome is the quality of life, as assessed with the Chinese version of the Low Vision Quality of Life Questionnaire(CLVQOL), from baseline to 48 weeks post-treatment. The scale, containing 25 items, consists of four scales: (1) general vision and lighting; (2) mobility; (3) psychological adjustment; and (4) reading and fine work and activities of daily living. Each item is scored from 0 (worst) to 5 (best). The highest possible score is 125, and a higher score indicates a better quality of life.[11],[12]

Secondary outcome

  • BCVA. BCVA is the gold standard for assessing vision. A standard logarithmic visual acuity chart will be used to evaluate BCVA at each visit.
  • CRT. CRT is a key indicator of macular thickness. Optical coherence tomography (OCT) imaging will be performed to assess CRT at each visit.
  • Cost of treatment. The investigators will record the cost of treatment, including medical and other expenses, by referring to the hospital payment system and consulting patients at each follow-up visit.
  • Intraocular pressure (IOP). A Goldman ophthalmotonom eter will be used to measure IOP within 24 hours after each injection.
  • Adverse events (AEs). The incidence and the reason for AEs will be recorded at each follow-up visit.


The time frame and measures are listed in [Table 1].
Table 1: Measures and time frame

Click here to view


Adverse events

Adverse events will be closely monitored and recorded in detail until resolution. The chief investigator will be informed immediately and will be responsible for reporting to the Scientific Research Department and Medical Ethics Committee of Guizhou Provincial People’s Hospital. To ensure that all adverse events are identified and addressed appropriately, regular monitoring will be conducted.

Sample size

Referring to the outcome (change in CLVQOL score), we used the following formula to calculate the sample size:



In the absence of data on the change in CLVQOL score in the ranibizumab and conbercept groups, we estimate that 244 participants will provide 90% power to detect a change of 5 points in the CLVQOL score, with a standard deviation of 12, using a two-tailed alpha of 0.05. Considering a drop-out rate of 20%, the total calculated sample size is 300.

Data collection

wAMD patients will be enrolled according to the inclusion criteria. After signing informed consent, they will fill out the questionnaires with the help of trained clinicians. The following information will be collected from wAMD patients: gender, age, nationality, height, weight, body mass index, detailed contact information, residential address information, history of smoking or passive smoking, alcohol consumption, dietary habits, co-administered healthcare products, education, health insurance, occupation, and financial information. The duration of eye disease, family history of AMD, previous treatment for AMD, anamnesis, health condition, comorbidity (e.g. hyperlipidemia, hypertension, diabetes, atherosclerosis, etc.), laboratory results, and outcome (CLVQOL score, BCVA, CRT and IOP) will be recorded. All information will be entered into the database and numbered. The wAMD patients will be followed up at 2, 6, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 weeks after the first injection of the anti-VEGF drug [Figure 1]. Clinical data, including treatment, prognosis (CLVQOL score, BCVA, CRT, IOP), cost of treatment and AEs, will be collected. A medical database for all 300 wAMD patients will be established. Outcome measurements will be checked by a clinical expert. These data will be written in the case report form (CRF) by a specialized investigator.

Statistical analysis

Microsoft Access database software will be used for double entry of the data and to establish a database. SPSS statistical software will be used for data analysis. Propensity score matching will be used to deal with differences in baseline. We will develop a multivariate logistic regression model including baseline information (e.g., demographic information, comorbid conditions, anamnesis, etc.) to estimate the probability (propensity) of being treated with conbercept or ranibizumab, conditional on the included covariates. We will exclude 5% of patients at each end of the propensity score distribution. We will match conbercept users with ranibizumab users according to age at cohort entry date, sex, cohort entry date, and the propensity score. We will assess the balance in the covariates between the conbercept and ranibizumab groups before and after matching using the standardized mean difference (expressed as a percentage), whereby an absolute standardized mean difference below 10% implies acceptable balance.[13] The mean changes in CLVQOL score, BCVA, CRT and IOP from baseline until 48 weeks will be assessed using the Mann-Whitney U test or independent t-test or rank-sum test. The incidence of AEs will be summarized for each group and compared using the chi-square test or Fisher’s exact test. A P-value less than 0.05 will be considered statistically significant.

Economic evaluation

If non-inferiority of conbercept to ranibizumab is demonstrated, economic evaluation will be performed as a cost-minimization analysis from the patients’ perspective.[14] If conbercept turns out to be inferior to ranibizumab, a cost–utility analysis will be performed with cost per quality-adjusted life-year, which is based on (i) the observed cost and visual acuity data, and (ii) available and upcoming literature on health utility associated with different levels of visual acuity.[15],[16] Then, the cost-effectiveness ratio (CER) and incremental cost-effectiveness ratio (ICER) of the two drugs will be calculated.

Quality control

Data entry and management

The questionnaires were designed based on extensive reviews of the literature and advice from ophthalmologists and methodologists. A combination of hard copy questionnaires and computer database entries will be used for data collection. All personnel involved in data entry will be trained beforehand. Concurrent validity data will be collected for quality control. Training will be provided beforehand. Two specialized personnel will be responsible for the second round of quality control assessments every month and monitoring research progress.

The data monitoring center is in the Department of Pharmacy of Guizhou Provincial People’s Hospital. The participants may drop out of the trial at any time for any reason. The physician will assess each patient and provide any needed assistance. Incidences of loss to follow-up will be reported to the chief investigator of this trial monthly.

Investigator training

CRF tables will be prepared to standardize the investigation and survey techniques and to improve the working ability and responsibility of the investigators.

Questionnaire verification

Every visit will be recorded using digital voice recorder, especially for assessment of the quality of life. After every survey, clinicians will check the questionnaires for logical errors and missed information, and additional surveys will be conducted within 72 hours to supplement the data.

Amendments to the protocol

Amendments to the protocol will only be made by the academic committee and research group and will be approved by the Medical Ethics Committee of Guizhou Provincial People’s Hospital. All modifications will be recorded and applied to all participants, and the registration record will be updated.

Ethics and dissemination

This study protocol acquired written approval from the Medical Ethics Committee of Guizhou Provincial People’s Hospital (approval No. 2017113) (Additional file 1 [Additional file 1]), and will be performed in accordance with the Declaration of Helsinki developed by the World Medical Association. Written informed consent will be obtained from each patient (Additional file 2 [Additional file 2]).

We will publish the findings in national and international journals, and present them at national and international conferences. The protocol adheres to the recommendations of SPIRIT 2013[17](Additional file 3 [Additional file 3]).


  Discussion Top


Our study is a single-center, prospective cohort study aiming to test the hypothesis that conbercept will outperform ranibizumab in cost effectiveness for wAMD in China. In the absence of evidence about the effect of conbercept on the quality of life, our study will pay more attention to this outcome. In our study, the quality of life will be evaluated using the CLVQOL. This questionnaire was translated from the English-version LVQOL by Zou et al.[18] and has proven to be a culturally-specific vision-related quality of life measurement instrument for the Chinese. Zou et al.[18],[19] also used the CLVQOL on patients with AMD and found that it could provide comprehensive information on their vision-related quality of life. Furthermore, we will collect cost information during the follow-up phase and calculate the cost-effectiveness ratios of the two anti-VEGF agents. Compared with the pharmacoeconomic research model,[8] our study conducted on a real-world population will provide a better assessment of these drugs.

Although several randomized trials[20],[21],[22],[23],[24],[25],[26] have investigated the efficacy and safety of conbercept vs. ranibizumab in the treatment of wAMD, our previous systematic review found that the methodological quality of these trials was poor, especially as they lacked description of allocation concealment, blinding methods and registration information. In addition, the sample size of these trials was small, and the follow-up duration was generally short, except for one small RCT.[20] Therefore, prospective RCTs with larger sample size and better methodological design are urgently needed. However, given that patients are paying for the treatment, it is unethical to perform random allocation and not inform the patients and clinicians of the drug allocated. A prospective cohort study design is therefore a better option.

In our previous meta-analysis, conbercept was equivalent to ranibizumab in terms of improvement in the BCVA; however, one RCT[20] reported a better therapeutic effect of conbercept. In addition, conbercept seemed to significantly reduce the CRT compared with ranibizumab. However, this finding is inconsistent with another retrospective case-controlled study.[7] To better compare these drugs, our study will focus on the change in CRT over a 12-month period and adjust for confounding factors with the propensity score. Because of small sample sizes and lack of long-term follow-up, previous studies were unable to identify rare AEs. In comparison, our study will systematically evaluate the safety profiles of the two anti-VEGF agents.

In summary, our study is a single-center, parallel-group prospective cohort study that aims to test if conbercept will outperform ranibizumab in cost-effectiveness for wAMD. The results of this study will provide a rational basis for clinicians to optimize treatment for patients with wAMD.


  Trial Status Top


We are currently recruiting participants.

Additional files

Additional file 1: Ethical Approval Documentation.

Additional file 2: Model consent form (Chinese).

Additional file 3: SPIRIT checklist.

Acknowledgments

The authors would like to thank Professor Hai-Dong Zou of Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine. He provided the Chinese-version questionnaire of low vision quality of life (CLVQOL) for our study. We would like to thank all subjects who have agreed to participate in the study and the staff at the Guizhou Provincial People’s Hospital.

Author contributions

JXZ is the chief investigator of this study. DL, QH, JX, CHY, XQ, and HYZ are coinvestigators. DL, QH, and JX assisted in designing the study and defining the objectives and methods of the study. JXZ drafted the manuscript, and JX and DL were responsible for supervision of the study and revision of the manuscript. QH was involved in the recruitment of patients. QH and CHY were responsible for the collection of clinical data for wAMD patients. XQ and HYZ were responsible for follow-up. All authors have contributed to the composition of the study protocol and have approved the final version of this manuscript.

Conflicts of interest

The authors declare no conflicts of interest.

Financial support

No current funding sources for this study.

Institutional review board statement

The protocol has been approved by the Medical Ethics Committee of Guizhou Provincial People’s Hospital of China (approval No. 2017113). Written informed consent was obtained from all study participants prior to enrolment in the study.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the form the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study protocol was reported in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of the Guizhou Provincial People’s Hospital in China.

Copyright transfer agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

The individual participant data is available. Individual participant data that underlie the results reported in this article, after deidentification will be shared. Study Protocol, Informed Consent Form, and Clinical Study Report will be available. Data will be available beginning 9 months and ending 36 months following article publication. Investigations whose proposed use of the data has been approved by an independent review committee (“learned intermediary”) identified for this purpose. The shared data will be used for individual participant data meta-analysis. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University’s data warehourse but without investigator support other than deposited metadata. Information regarding submitting proposals and accessing data may be found at http://www.chictr.org.cn/showproj.aspx?proj=22257.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

 
  References Top

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Wolffson JS, Cochrane AL. Design of the low vision quality-of-life questionnaire (LVQOL) and measuring the outcome of low-vision rehabilitation. Am J Ophthalmol. 2000;130:793-802.  Back to cited text no. 11
    
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Brown GC, Sharma S, Brown MM, Kistler J. Utility values and age-related macular degeneration. Arch Ophthalmol. 2000;118:47-51.  Back to cited text no. 15
    
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Liu R, Liu CM, Li N, Zhou Z, Wei XD, Cui LL. Effect of conbercept ophthalmic injection on peripheral blood vascular endothelial growth factor, intraocular pressure and visual acuity in patients with age related macular degeneration. Zhongguo Shenghua Yaowu Zazhi. 2015;35:104-106.  Back to cited text no. 22
    
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