Xuesaitong Capsule For Patients After Percutaneous Coronary Intervention For Unstable Angina: Study Protocol For a Randomized Controlled Trial


 • Background: This study was designed to investigate the effect of Xuesaitong (XST) capsule added to conventional treatment in patients after percutaneous coronary intervention (PCI) for unstable angina (UA).• Methods: This is a 12-week, randomized, multi-center, double-blinded, placebo-controlled clinical trial. A total of 120 patients with UA will be recruited and randomly allocated in a 1:1 ratio to receive XST or placebo (2 capsules twice per day) on the background of conventional treatment. The changed level of high-sensitivity C-reactive protein from baseline to week 12 is the primary outcome. Secondary outcomes include tumor necrosis factor-α, interleukin-6, platelet aggregation, blood lipid, angina symptoms and ST segment deviation in electrocardiogram. The safety of XST will be monitored during the trial.• Discussion: This study will provide an evidence regarding the efficacy and safety of XST on the background of conventional medical treatment in patients after PCI for UA.• Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032152. Registered on 14 January 2020.


Introduction Background and rationale {6a}
Unstable angina (UA) is a common type of coronary artery disease (CAD). Previous studies showed that 1-year mortality rate of patients with UA is about 10% 1,2 . Percutaneous coronary intervention (PCI) alleviates the angina, shortens the duration of hospitalization 1,3 , but does not reduce the longer-term motality due to multiple factors such as stent thrombosis, in ammation, increased cytokine secretion, and stent-related endothelial damage 4,5 . Although dual anti-platelet therapy prevents ischemic events 4,5 , the risk of bleeding increases, even counters the bene ts of revascularization. Therefore, there is an urgent need to explore treatment regimen that has a further favor impact on UA patients without the increase in bleeding risk.
The Xuesaitong (XST), derived from traditional Chinese medicine, Panax notoginseng (Burk.) F.H. Chen, is a widely prescribed Chinese patent medicine for CAD 6 . Previous evidence showed that the XST relieves anginal symptoms, inhibits in ammation and platelet aggregation 7,8 . In addition, there is an evidence showing that XST is not associated with increased risk of bleeding 9 . Here, we hypothesize that, compared with conventional therapy alone, XST plus conventional therapy might be an optional treatment strategy for patients after PCI for UA.

Objectives {7}
This trial was designed to test whether XST in addition to conventional therapy has bene cial effects in patients after PCI for UA.

Trial design {8}
This study is designed to be a 12-week, randomized, multi-center, double-blinded, placebo-controlled clinical trial. The trial outline, including measurements at every 4 weeks and collection of biological samples at 0 and 12 weeks is illustrated in Fig. 1 and Table 1.
The study design is conducted in accordance with the principles of the Declaration of Helsinki (2013 version) and Good Clinical Practice guidelines following the theory that guides the appropriate use of TCM in clinical application. The study will follow the Recommendations for Intervention Trials guidelines and the completed checklist can be accessed in Additional le 1. All visits will be documented in Case Report Forms (CRFs), and the reports will be guided by the Consolidated Standards of Reporting Trials. (2) Patients diagnosed with UAP and have undergone PCI within 3 days.
(3) Patients with a history of heart failure, pulmonary heart disease, rheumatic heart disease, myocarditis, cardiomyopathy, aortic dissection, pulmonary embolism.
(5) Patients with active rheumatic immune or tuberculosis or severe blood system diseases or malignant tumors.
(6) Patients with serum alanine aminotransferase or serum creatinine> 2 times the upper limit of the normal reference value.
(7) Pregnant and/or lactating women and/or women of childbearing age who require childbirth.
(8) Patients allergic to the test drugs.
(9) Those who have participated in other clinical trials within 1 month.
Who will take informed consent? {26a} Strategies for achieving adequate participants are as follows. We will publicize our trial in the community, hospitals, and through the media. We will select from patients who meet the criteria for PCI who go to each branch for PCI surgery. For eligible subjects, researchers will give explanation to them, issuing informed consent to patients who are interested and agree to participate in the trial. Written informed consent, as is shown in Additional File 2, will be obtained from all participants prior to enrollment.

Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable. There is no plan for additional analysis.

Interventions
Explanation for the choice of comparators {6b} See 6a.

Intervention description {11a}
The patients will be allocated to receive placebo (2 capsules twice per day) or XST (2 capsules twice per day), for 12 consecutive weeks. The appearance and smell of the placebo resembles the experimental drug, thus could not be differentiated. Both the XST soft capsule and the placebo will be provided by Kunming Shenghuo Pharmaceutical Co., Ltd. (Kunming, China).

Criteria for discontinuing or modifying allocated interventions {11b}
We fully respect the wishes of the participants that they can withdraw from the trial at any time. Once withdrawn, the researcher will record information including time, reason, whether adverse events (AEs) have occurred in the CRF.

Strategies to improve adherence to interventions {11c}
Patient compliance, which is calculated by the sum of the reclaimed boxes, will be recorded at week 4, 8 and 12. Medication compliance = (prescription volume-missed dose) / prescription volume × 100%. A medication compliance of ≥80% will be considered as good, but less than 80% will indicate poor compliance. Since we provide free laboratory tests, patients can undergo a follow-up check after PCI while participating this trial, thus the patient compliance presents to be good.

Relevant concomitant care permitted or prohibited during the trial {11d}
Based on the guideline issued by ESC in 2020, patients in both groups will receive the conventional cardiovascular medications (such as antiplatelet drugs, statins, nitrates, β-blockers, calcium antagonists, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers). The routine drugs used for chronic diseases will not be changed unless necessary. The usage, dosage and frequency of combined drugs during follow-up will be collected in detail in the CRF. Any other Chinese herbal decoction or Chinese patent medicine for the treatment of coronary heart disease is forbidden during the trial.

Provisions for post-trial care {30}
Currently we don't have further plan for post-trial care, but if the participants are interested, we will be willing to provide traditional Chinese medicine prescription.

Primary outcome
The primary outcome, the change in high-sensitivity C-reactive protein (hs-CRP) from baseline to week 12, will be tested at baseline and week 12.

Secondary outcome
The secondary outcome will be as follows: 1. Reduction in tumor necrosis factor-α(TNF-α) and Interleukin-6 (IL-6) at week 12 compared with baseline.
2. Change in blood lipids assessed by the total cholesterol (TC), high-density lipoprotein cholesterol (HDL), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) from baseline to week 12.
3. Angina symptom score, including the intensity, frequency, duration of the chest pain and the amount of nitroglycerin, will be tested at week 0,4,8,12.
4. Change in platelet aggregation rate from baseline to week 12.

Change in ST segment
and T-wave of electrocardiogram (ECG) will be followed at week 0,4,8,12.
Safety outcome 1.Coagulation function (such as prothrombin time, activated partial thromboplastin time, thrombin time or brinogen), blood, urine or stool routine as well as liver and renal function will be tested at week 0 and 12.
2.AEs such as cerebral or gastrointestinal hemorrhage and thrombocytopenia, will be monitored at every visit and recorded in the CRF.

Other outcomes
The other outcomes are as follows: 1.demographic data (age, gender, height, weight, ethnicity, occupation or complicated diseases) 2. in uencing factors (risk factors, history of allergy and medication history) 3. combined medication 4. physical examination (body temperature, heart rate, heart rhythm and blood pressure) Demographic data and the factors affecting the e cacy will be systematically recorded after enrollment while the general physical examination and the combined medication will be tested and recorded at week 0, 4, 8, and 12 of follow-up.

Participant timeline {13}
Sample size {14} The sample size will be calculated on the basis of the change of hs-CRP. Based on the previous studies 10 , we hypothesize that, as compared with the conventional medical treatment, the level of hs-CRP will be 20% lower in the XST group after 12 weeks. Supposing type I error α or type II error of the hypothesis test is 0.05 or β=0.1 respectively, the sample size of the intervention group and the control group, which is calculated by PASS 11 software, is 48 cases. Assuming that 20% of the participants drop-out, the sample size should be 120 cases. Ultimately, each of the two groups would include 60 cases.

Recruitment {15}
Strategies for achieving adequate participants are as follows. We will publicize our trial in the community, hospitals, and through the media. We will select from patients who meet the criteria for PCI who go to each branch for PCI surgery. For UA patients who come to each branch for PCI and meet our criteria, researchers will give explanation to them, issuing informed consent to patients who are interested and agree to participate in the trial.

Sequence generation {16a}
Eligible participants will be randomly assigned to either the XST or the placebo group, in a 1:1 ratio based on the randomization system of the Institute of Clinical Pharmacology of China Academy in Chinese Medical Sciences. The allocation sequence will be managed by people who are not involved in the trial and concealed from both participants and researchers. Not until the end of the trial will the allocation sequence be revealed.

Assignment of interventions: Blinding
Who will be blinded {17a} All of the trial subjects, outcome assessors, analysts and the researchers will be blinded to the allocation.

Plans for assessment and collection of outcomes {18a}
Before the start of the trial, all personnel participating in the study will be trained to strictly follow the clinical trial protocol and adopt standard operating procedures. This will ensure quality control of the clinical trial and the implementation of the quality assurance system.

Plans to promote participant retention and complete follow-up {18b}
Throughout the follow-up period, the researchers will contact patients for completion of their follow-up and collect the outcome data.

Data management {19}
After using a uni ed research medical record for data collection, the researchers will use the drug clinical trial data management system of the Xiyuan Hospital of Chinese Academy of Chinese Medical Sciences (http://www.xyedc.com/) for data entry and management. The data entry will be carried out by double entry veri cation method. We will take the following measures to ensure the safety of the data: the research medical records will be kept in the designated place and the data will be managed by a dedicated person and only accessible by research-related staff. Besides, the privacy and con dentiality of the subjects will be protected. In addition, the les will be archived in chronological order with the latest le at the top and identi ed by the version number and date. In addition, a search directory will be set. If a le is archived separately, the location of the le will be recorded. All project les will be kept for 5 years after the end of the clinical study. Only after the whole trial has completed will the entire research-related staff have access to the nal trial dataset.

Con dentiality {27}
The detail personal information will not be published.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable. There are no biological samples collected.

Statistical methods
Statistical methods for primary and secondary outcomes {20a} SPSS 23.0 will be used to analyze the data. The measurement data will be tested for normality by the Kolmogorov-Sminov method. Those that conform to the normal distribution will be described by mean ± standard deviation, while those that do not conform to the normal distribution will be described by the median (25% digits, 75% digits). Description: the count data will be described by the number of cases (percentage). For measurement data, the paired t-test will be used for intra-group comparison; for intergroup comparison, if the two groups meet normality and the variances between the two groups are equal, the independent sample t-test will be used; otherwise, the non-parametric Wilcoxon rank sum test will be employed. On the other hand, for categorical data, the chi-square test will be used for disordered outcomes, while the nonparametric Wilcoxon rank sum test will be used for ordinal data. A two-sided P < 0.05 will be used to evaluate the signi cance of the difference.

Interim analyses {21b}
We fully respect the wishes of the participants that they can withdraw from the trial at any time. Once withdrawn, the researcher will record information including time, reason, whether AEs have occurred in the CRF.

Methods for additional analyses (e.g. subgroup analyses) {20b}
Not applicable. There will not be additional analyses.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} We will try our best to avoid withdrawals, drop-out and loss of participants. For cases that are lost to follow-up, we will conduct multiple imputation and sensitivity analysis. For withdrawal cases, we will use intentional analysis.
The trial protocol and clinical trial report will be made available by the major researchers. Reasonable requests for the concrete trial protocol should be directed to shidazhuo@126.com. Datasets during the current study will not be available due to data privacy.

Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d} At the end of each natural year, we will make a summary to Beijing Administration of Traditional Chinese Medicine. Beijing Administration of Traditional Chinese Medicine will provide organizational support for us if necessary.
Composition of the data monitoring committee, its role and reporting structure {21a} The Research Ethical Committee of Xiyuan Hospital will audit the trial, conducting every three months independently of investigators and the sponsor. The Research Ethical Committee will decide on any premature closure of the study.

Adverse event reporting and harms {22}
After the main investigator's consent, participants who are deemed to have had a serious adverse reaction will terminate the study, receiving free and reasonable corresponding medication. Subsequently, his or her speci c intervention treatment will be unblinded by an individual that is independent of the trial.

Frequency and plans for auditing trial conduct {23}
Upon enrollment of initial 30 patients, personnel who are not directly involved in the clinical trial will conduct a systematic inspection of the trial-related activities and documents. They will evaluate standard operating procedures, relevant regulatory requirements and whether the trial is conducted in accordance with the trial protocol, at a frequency of every three months. The authenticity, timeliness, accuracy and completeness of the trial data will also be evaluated.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} If it is necessary to modify the research protocol during the trial, we will report to the ethical committee of each center and then the registration center.

Dissemination plans {31a}
Trial ndings will be published through peer-reviewed international journals and conference presentations.

Discussion
We design this randomized, placebo-controlled, double-blind trial to explore a potential effective treatment for patients after PCI for UA.
Coronary stents damage the endothelium and activate the release of in ammatory cytokines, which accelerate the rupture of unstable plaques. The level of in ammatory cytokines is also a predictor of the occurrence of adverse cardiovascular events [11][12][13] . Previous studies showed that PNS regulated the in ammation process by accelerating the release of anti-in ammatory cytokines and inhibiting the production of pro-in ammatory cytokines such as Hs-CRP, TNF-α and IL-6 14 . Here, we chose Hs-CRP as the primary outcome because it is not only a biomarker of in ammation, but also an independent predictor of major adverse cardiovascular events 15,16 . The change level of other in ammatory cytokines like TNF-α and IL-6 were measured as the secondary outcomes.
Platelet and blood lipids play crucial roles in CAD 17,18 . PNS has been demonstrated to promote lipolysis and reduce lipid synthesis, thereby improve the metabolism of serum lipids in multiple ways 19 . Aside from that, PNS inhibits platelet activation 20,21 . Therefore, the blood lipid and the platelet aggregation rate will be assessed to test the effect of the XST.
The follow-up frequency was designed as once per month, for the reason that we can monitor patients for adverse reactions in a timely manner. In addition, we chose to draw blood at the time of enrollment and week 12 to reduce invasive testing and at the same time, ensure patient compliance to the greatest extent.
Previous studies have demonstrated better e cacy with the use of XST plus conventional drugs in UAP patients without PCI 9,22 , but data on patients after PCI for UA is limited. Our study, therefore, will be the rst to con rm the potential role of XST in such kind of patients.
The results might be underpowered to extrapolate to other races as the trial is only conducted in Beijing, China. In addition, the follow-up period will only last for 12 weeks, thus the long-term outcomes may not be veri ed.
The information obtained from this exploratory study will inform the decision to conduct a large-scale randomized controlled trial to test the e cacy of XST, which will add to the current high-quality evidence that is available for the management of UA.

Trial Status
The trial was initiated in November 2020 and is scheduled to be completed in December 2021. Currently, it is open for enrollment. The data will be available in mid-or late-2022.  Figure 1 Flow chart of the trial. UA: unstable angina; XST: Xuesaitong; hs-CRP: high-sensitivity C-reactive protein; TNF-α: tumor necrosis factor-α; IL-6: Interleukin-6.