This TXL-CAP Trial is a randomized, double-blind, placebo-controlled, parallel-grouped multicenter clinical study. The trial was registered at the Chinese Clinical Trial Registry and the registration number was ChiCTR1900025842 (the date of first registration was 10/09/2019). The objective is to evaluate the efficacy and safety of TXL capsules in Chinese NSTE-ACS patients with vulnerable coronary atherosclerotic plaques. A total of 18 medical centers (including major locations) will participate in this study. We confirmed that TXL-CAP study was approved by the Medical Ethics Committee of Qilu Hospital of Shandong University and carried out in accordance with the relevant regulations. All the participants will sign the informed consent form before participating in the experiment.
Selection Of Subjects
Patients with diagnosis of NSTE-ACS who meet all the inclusion criteria and not meet any of the exclusion criteria are enrolled in the study. The inclusion criteria and exclusion criteria are shown in Table 1. Patients who are taking TXL capsules before enrollment are excluded. Record the baseline characteristics of the patients and the drugs they are taking. After signing the informed consent forms, the information of eligible patients will be entered into a central randomized system that generates a double-blind random number for each enrolled patient. Then the researchers log in the randomized and experimental drug management system (RTSM) to generate the random patient’s number and the corresponding drug number in the order of the enrolled time. Each follow-up needs to log in the system to apply for a new drug number. The numbers are different, and the drugs are the same.
Interventional Method
Drug
The ingredients of the TXL capsule include ginseng, leech, scorpion, turtle, centipede, cicada slough, red peony, borneol, sandalwood, incense, frankincense, sour jujube kernel. The placebo is the simulator of the TXL capsule, which is completely consistent with TXL capsule in color, specification and packaging. All the above research drugs are provided by Shijiazhuang Yiling Pharmaceutical Co., Ltd.
Intervention
Patients will be randomized to the TXL group or the placebo group at a 1:1 ratio. After random grouping, all patients will be orally administrated a routine dose of the research drug (TXL or placebo) 1.04g (4 capsules) three times a day until 12 months. The use of other traditional patent Chinese medicine in which composition is similar to the TXL capsule should be prohibited during the entire study period. All patients should be given standard medical therapies for ACS based on guideline recommendations, including dual antiplatelet agents (aspirin, clopidogrel or ticagrelor) and statins [11].
The outpatient follow-up time is set at 6th (± 7 days) and 12th months (± 7 days), respectively. During each visit, the patients should return all the remaining drugs and the researcher will deliver the drugs to the patients. At the end of the study, all remaining drugs should be returned to the sponsor and disposed by the person in charge of the applicant.
Design
The study flow diagram is shown in Fig. 1.
Screening period (day-7 ~ day 0)
Patients’ information will be recorded during the screening period which includes medical history, physical examination, laboratory examination, Electrocardiogram (ECG), and ultrasound cardiogram (UCG). Optical coherence tomography (OCT) examination is used to detect the vulnerable plaque with the thickness of the fibrous cap less than 100 µm and the radian of lipid more than 90 °. The patients who meet the inclusion and not meet the exclusion criteria will enter the stage of random treatment.
Random treatment period (day 1 ~ 12 months):
The patient’s medical history and the results of physical examination, laboratory tests, 12-lead ECG, UCG, and OCT are recorded at 0 months (Table 2). The outpatient follow-up time is set at 6th (± 7 days) and 12th months (± 7 days), and telephone follow-up is at 3rd (± 7 days) and 9th months (± 7 days), respectively (Table 2). ECG and laboratory tests are performed at the 6th and 12th months. UCG and OCT examinations are conducted at the 12th month (Table 2). Grading of angina pectoris, Seattle Angina Questionnaire (SAQ) score, and endpoint events are recorded (table2). The method for grading the angina pectoris is according to the Canadian Cardiovascular Society grading of angina pectoris [12]. The SAQ consists of 19 items that quantify 5 clinically relevant domains of coronary artery disease (CAD): physical limitation (question l), angina stability (question 2), anginal frequency (questions 3 and 4), treatment satisfaction (questions 5–8), and disease perception (questions 9–11) [13].
Standard Drug Therapy
All the patients receive the standard drug therapy according to the guidelines [11]. Drugs used for patients according to their condition include angiotensin-converting enzyme inhibitor, angiotensin Ⅱ receptor antagonist, angiotensin-converting enzyme inhibitor, calcium channel blocker (CCB), β-receptor blocker, nitrates, statins, antiplatelet drugs (aspirin tablets, clopidogrel tablets), and hypoglycemic drugs. Drug doses are individually tailored, under the guideline recommendations. Any other traditional Chinese medicine which composition is similar to the TXL capsule should be prohibited during the study period. All the treatments should be recorded.
OCT Image Acquisition and Analysis
OCT is one of the modalities which uses infrared radiation for intracoronary imaging. The resolution of OCT is 10 ~ 20 µm and it has been widely used to detect plaque fibrous cap, intraluminal thrombus, stent edge peeling and thrombus [14]. OCT C7-XR System is used in our study and images are acquired as previously reported [15]. All images are qualitatively screened by two independent, experienced observers. Select high-quality images for analysis, excluding images of poor quality or artifacts. The OCT images were digitally stored for offline analysis. All consecutive frames are screened and the minimum fibrous cap thickness of the target lesions are measured. The plaques with the thickness of fibrous cap less than 100mm and lipid Radian less than 90 degrees are selected into the group. If the patient has multiple vulnerable plaques at the same time that meet the inclusion criteria, the plaque with the minimum fibrous cap thickness is selected as the target lesion. The change of the target plaque fibrous cap thickness measured by OCT is used as the primary endpoint of the study.
Binding
This trial is carried out by the biostatistics experts who have nothing to do with the statistical analysis of the data management with the SAS statistical software package. The random code is generated by the block randomization method according to the ratio of 1:1 between the test group and the control group. The selected block length and the initial seed parameters of random numbers are sealed in the blind bottom as secret data. According to this random number, the drug is encoded by a statistician who has nothing to do with this test, and then the blind bottom used for the coding needs to be sealed and preserved. The second uncovering blind method is used in this study. After blind verification, the data is locked, and the blindness is revealed for the first time by the main researchers, medical statisticians, data managers and representatives of the bidding units. When the statistical analysis is finished and the summary report is completed, the second blindness is revealed.
Primary endpoint
The change of the thickness of the fibrous cap of the target coronary artery plaque evaluated by OCT (Table 3).
Secondary endpoints
(i) incidence of MACE, including all-cause death, sudden cardiac death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for angina pectoris or heart failure, PCI or CABG surgery cause by ACS recurring; (ii) proportion of patients with angina grading improving at least one class (According to Canadian Cardiovascular Society grading of angina pectoris); (iii) SAQ score; (iv) serum inflammatory cytokines (IL-1 β, IL-18, TNF- α) levels (Table 3).
The Clinical-events committee for the determination of clinical endpoint events consists of a Chairman and five members. Endpoint events should be independently reviewed by two members. If there is a disagreement between the two members, the whole committee members will review the event. The researchers record the events and submit the related documents to the committee.
Security determination
The Security determination will be recorded at 0 months, 6 months and 12 months (study flow chart). The items include blood and urine routine, biochemical indicators, 12-lead ECG and adverse events. Blood and urine samples are collected as required and sent to laboratories in each center. Any medical events occurring during the whole trial period will be assessed, no matter whether there is a causal relationship with the study drug or not.
Serious Adverse Events (SAEs): SAEs refer to any adverse events (AEs) when they meet one or more of the following criteria: (i) death; (ii) life-threatening situation; (iii) prolonged hospitalization or hospitalization; (iv) temporary or permanent disabilities.
All the AEs will be evaluated for their relationship with the study drug and recorded in the Case Report Form (CRF). The patients will be followed up until they recover. Any SAEs that occur during the study should be immediately rescued by and reported to sponsors, clinical research organizations (CRO), ethics committee, China Food and Drug Administration (CFDA), and health administration within 24 hours.
Quality control
The researcher will provide necessary training to all staff participating in the clinical trial so as to make ensure that all the data will be accurately and timely recorded in the CRF. The inspectors should follow the standard operating procedures, supervise the implementation of the program, confirm all CRF reports are correct and consistent with the original information. The data analysis must adopt standard statistical methods.
The trial was registered at Chinese Clinical Trial Registration on September 10, 2019 (Registration No.: ChiCTR1900025842). The first patient of the TXL-CAP trial was randomized on October 30, 2019 and the registration number was 001. A total of 30 patients have been enrolled up to the time of this submission. The entire enrollment is scheduled to be completed by March 2021. Follow-up visits are planned to be completed by March 2022. The main results will be reported by June 2022.
Data Analysis
In this study, a statistician evaluates the study and calculates the sample size. It is assumed that the average increase of the thickness of the plaque fiber cap will be 0.19mm in the TXL group and 0.16mm in the placebo group (α = 0.05, β = 0.80). Based on these, an estimated sample size of 87 patients in each group would give 80% (two-sided α = 0.05 and β = 0.20) statistical power to detect a significant difference. Considering a 20% drop-out rate, a total of 220 cases will be enrolled and randomly assigned to the TXL group and the placebo group at 1:1. PASS11 software is used to calculate the sample size.
The baseline characteristics and the data at the end of trial of each group will be compared. Quantitative data were represented as mean ± SD (standard deviation). The non-normal distribution data are described by a median, 25th, and 75th quantile. Qualitative data were expressed as number (%). The two-sample t-test was used for normally distributed continuous variables and Wilcoxon rank-sum test for non-normally distributed continuous variables. one-way ANOVA was used for multiple comparisons. The chi-square test or Fisher exact test was used for comparing categorical data. All analyses will be performed using SAS 9.4 (or higher version, SAS Institute, Cary, NC, USA). P < 0.05 was considered statistically significant.