This is a randomized, double-blind, placebo-controlled trial. Participants will be randomly allocated into two groups, the test group and the control group. Patients in the test group will receive Mingjing Granule plus Ranibizumab, while those in the control group will receive placebo with Ranibizumab. All of them will be interviewed every 4 weeks. Mingjing Granule and placebo will be dispatched every 4 week until week 24, Ranibizumab will be administered as needed after three consecutive monthly injections until week 48 (Figs.1 and 2). The protocol is designed following the guidelines of the Consolidated Standards of Reporting Trials and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (see Additional file 1 SPIRIT 2013 checklist). The trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2000035990, registered on 21 August 2020).
We will recruit 180 persons with diagnosed nAMD from six hospitals in China.
- Foshan Hospital of Traditional Chinese Medicine,
- Shenzhen Traditional Chinese Medicine Hospital,
- Henan Province Hospital of Traditional Chinese Medicine / The Second Affiliated Hospital of Henan University of Chinese Medicine,
- The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine,
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine / Shandong Province Hospital of Traditional Chinese Medicine,
- The first Teaching Hospital of Tianjin University of Traditional Chinese Medicine.
For the recruitment of possible participants for the study, we will advertise using a information poster placed on notice boards in every participating center and resident communities. The information poster will include a brief description of the subjects that are eligible and details of activities and necessary contributions as participants in the study. For those people who are ineligible or decline to participate, we will record the basic demographic information and reasons for non-participation. The investigator will introduce the protocol as well as the benefits and risks to the enrolled participants and an informed consent form is mandatory before the study.
Randomization and allocation concealment
Random sequence table will be generated by Strategic Applications Software (SAS, version 9.4, SAS Institute, Inc., Cary, USA) and performed by Institute of Clinical Pharmacology, China Academy of Chinese Medical Sciences. Participants will be allocated randomly into one of the two groups with a ratio of 1:1. The identification code and random number is unique for each participant.
All participants, clinical physicians, nurses, data managers, and statisticians and other staff will be blinded to the treatment allocations until the trial is completed. The placebo looks and tastes indistinguishable from Mingjing Granule. The randomization list and blinding codes will be kept strictly confidential. Emergency unblinding process should only be done when the knowledge of intervention allocation is essential to guide the clinical management. The blinding will be broken after obtaining the consent of principle investigator.
- Exudative changes due to active CNV lesions secondary to AMD in one eye or both eyes.
- Aged 50 to 80 years.
- The BCVA between 73 and 34 assessed by ETDRS charts (approximately 20/40-20/200 Snellen equivalent).
- Agree to participate in the trial and provide written informed consent.
- Prior treatment of the study eye with intraocular anti-VEGF agents, verteporfin photodynamic therapy, other laser, corticosteroids, surgery (except cataract surgery at more than 30 days prior to screening) or systemic use of anti-VEGF products within 3 months prior to study entry.
- Ocular condition in the study eye that might impact vision and confound study outcomes.
- Active severe infection / intraocular inflammation in the study eye.
- Unclear dioptric media in the study eye that affecting fundus photography and OCT examination.
- Those with severe cardiovascular diseases, cerebrovascular diseases, impaired hepatic and renal function (AST and/or ALT 2-fold the upper limitation of normal or above, the same for creatinine), hematopoietic diseases, or severe life-threatening primary diseases, mental illness(such as depression disorder, anxiety disorder).
- History of allergy to the study / treatment-related agents.
- Previous (within 3 months) or concomitant participation in another clinical study with investigational medicinal products.
- Patients who the investigators deem to be ineligible for the study.
- In cases of worsening disease or concomitant complications with a necessity of safety evaluation and curative treatment.
- With the forbidden therapy and medication history during the trial, which will lead to bias for efficacy and safety evaluation.
Test group (Mingjing Granule group)
Participants in the test group will be instructed to dissolve Mingjing Granules（5.95g/bag）in 200ml hot water and take the solution orally twice a day for 24 weeks. Mingjing Granule will be manufactured, packaged, and labeled by pharmaceutical factory (Beijing Tcmages Pharmaceutical Co. Ltd.). The main ingredients include Radix Astragali(huangqi), Salvia miltiorrhiza root(danshen), Lycium barbarum(gouqizi), Eclipta alba(mohanlian), Pollen Typhae (puhuang), and Cirsium Japonicum(daji).
Control group (Placebo group)
For the control group, placebo contains 95% bitterant, edible lactose, starch, pigment (such as lemon yellow, caramel pigment, and sunset yellow), and also includes 5% Mingjing Granule to achieve the similar appearance, color, smell, taste, and weight as Mingjing Granule.
Participants in both groups will receive 3 consecutive monthly intravitreal injections of ranibizumab (allowed to be injected at a dose of 0.5mg per time). If necessary they will be reinjected another during the followed-up period. Decision for the reinjection will be guided on the criteria formulated by PrONTO : ①a loss of 5 letters or more. ②An increase in CRT at least 100μm. ③New retinal hemorrhage appears. ④New typical CNV. ⑤Fluid still exists after injection last month. ⑥Any qualitative increase in the amount of fluid.
Participants will be requested not to receive any other treatments for nAMD, such as complementary treatments (e.g.herbal medicine, and acupuncture) or other medications, throughout this study. Participants will be allowed to take western medicine to treat the systematic diseases, such as hypertension or heart disease. The use of all drugs, if any, will be documented in detail in the case report form (CRF).
The mean change of BCVA(from baseline to week 24, 48): We will assess the participants' best-corrected distance visual acuity by ETDRS charts before and after the treatment at week 24 and 48. When necessary, the participants will be examined more than once.
The mean change of CRT (from baseline to week 24, 48): The participants' eyes will be fully dilated, the examiner will take the macular fovea as the center, and perform a multi-directional, 6mm-long, radial linear scan of the most prominent macular lesions and take linear scans in the same direction after the treatment. Central retinal thickness (CRT) is defined as the distance between internal limiting membrane and external limiting membrane, excluding the fluid under RPE. When necessary, the participants will be examined more than once.
Retinal hemorrhage and exudation (from baseline to week 24, 48): The participants' eyes will be fully dilated, the examiner will take the fundus photography, and calculate the area of retinal hemorrhage and exudation through Image Pro Plus software. Participants' optic disc area (PA) will be used as a record before and after the treatment at week 24 and 48. When necessary, the participants will be examined more than once.
TCM syndrome score (from baseline to week 24, 48): Evaluation of TCM syndrome refers to clinical research guidance of new investigational drug in TCM. TCM syndrome score from baseline to weeks 24 and 48 will be calculated. The scores and details of TCM syndrome are given in Table 1.
The mean number of intravitreal ranibizumab injections: We will calculate the mean number of intravitreal ranibizumab injections at week 48.
Total cost of the treatment:We will calculate the total cost of the participants' treatment at week 48.
We will monitor blood regular test, urine regular test, liver function test (AST、ALT、ALP、γ-GT、TBIL) , renal function test (Cr、Urea) and ECG to certify whether Mingjing Granule could be safe. Patients will be asked to report to the researchers any abnormal reactions occurring in the trial. All details of related and unexpected adverse events, such as time of occurrence, degree and duration, suspected causes and the effective measures and outcomes will be recorded on CRF. Any ocular or systemic adverse events will be treated suitably and recorded accurately and completely as well.
Ethics and dissemination
Patient consent and dissemination policy
This trial will be complied with the Declaration of Helsinki and Ethical Guidelines for Clinical Research. We will rigorously follow the latest Consolidated Standards of Reporting Trials (CONSORT 2017) . The protocol has been permitted by the Research Ethical Committee of Eye Hospital, China Academy of Chinese Medical Sciences, Foshan Hospital of Traditional Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Henan Province Hospital of Traditional Chinese Medicine/The Second Affiliated Hospital of Henan University of Chinese Medicine, The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine / Shandong Province Hospital of Traditional Chinese Medicine, and The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine. The results of this study will be disseminated to the public through academic conferences and peer-reviewed journals.
Access to data and confidentiality
Privacy of participants will be highly respected in the conduct of the study. The personal information about the potential and enrolled participants will be collected to be used only in this trial. All data will be kept strictly confidential at the study site. Only research team members will have access to the research data. All local databases will be secured with password-protected access systems. Forms, lists, appointment books and any other listings that link participant ID numbers to other identifying information will be stored securely with limited access. The information of participants will not be released and shared without the written permission of the participant.
We design a superiority trial with a ratio of 1: 1. The primary outcome is the mean change of BCVA at week 48 as compared to the baseline. After reviewing some literature, the mean change of BCVA in the test group is expected to increase by 10.1 letters. Which in the control group is expected to increase by 8.2 letters [39-40]. ncis the participants' number in each group. σ(standard deviation of the two groups)＝4. Z1-α=1.96, when α=0.025; Z1-β=0.84, when β=0.2. Δ＝0, K＝1, μT＝10.1, μC＝8.2. We calculate it by PASS software, there are 71 cases in each group. Considering a 20% drop-out rate, there are 89 cases in each group, and a total of 178 cases in both groups. Thus, we plan to recruit 180 participants in total (30 cases in every center, 15 cases in each group). The sample size calculation formula is as follows :
All the efficacy and safety analyses will be conducted within the full analysis set (FAS) according to the intention-to-treat principle, with all randomly assigned participants included. Last-observation-carried-forward method will be applied in the missing values. We will conduct the per-protocol set (PPS) analysis to compare the results from FAS and PPS, and safety set (SS) will be used for the safety evaluation. Data from the six centers will be combined for statistical analysis of the primary and secondary outcomes as well as adverse events. Demographic, eye examination and laboratory characteristics will be calculated at baseline, intervention and follow-up period. The mean±standard deviation will be chosen for continuous variables and the comparison between the two groups will be analyzed by t-tests with normal diatribution. Non-parametric Mann-Whitney-Wilcoxon test will be used for the comparison of data with non-normal distribution. Categorical variables will be compared using X2 statistics, while the Fisher exact test will be used when the theoretical frequency is less than 5 in more than 25% of the cells. In order to control the center and baseline effects, covariance analysis will be applied for the intergroup comparison with continuous variables and Cochran-Mantel-Haenszel test for categorical variables. All statistical tests are unilateral test, P<0.05 means statistically significant. All statistical analyses will be performed by using SPSS V.19.0.
Quality supervision and management
Request for researchers: Researchers or physicians will receive pre-clinical systematic training, get a full understanding of the protocol details, and they should possess the qualifications and ability to carry the study on and not be changed constantly.
Quality control of laboratory: Every center should offer researchers suitable medical equipment and emergency facilities. Laboratory, Medical Examination Center and other related departments will be established quality control and uniform standard operating processes. Certain item will be in charged by a special person.
Measures for study/treatment agents and compliance of participants: Mingjing Granule and placebo will be manufactured by the same pharmaceutical factory and distributed by a trained staff in each center. Compliance of participants will be inspected by the method of drugs notation, and they will be asked to bring drugs last time in order to calculate the number. The formula is as follows:
Compliance= [(dispensing-remaining)/dispensing ]×100%
Monitoring and inspection: A trial coordinating group will be established, which is responsible for the implementation of the trial and they will visit each center regularly to check the progress of the trial, examine CRF, verify the storage of investigational agents and record of data.