Chinese herbal prescription Qing-Xin-Jie-Yu granule combined with conventional treatment for intermediate coronary lesions: study protocol for a randomized, double-blinded, placebo-controlled trial

doi:10.21203/rs.3.rs-2731010/v1

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Study protocol

Chinese herbal prescription Qing-Xin-Jie-Yu granule combined with conventional treatment for intermediate coronary lesions: study protocol for a randomized, double-blinded, placebo-controlled trial

https://doi.org/10.21203/rs.3.rs-2731010/v1

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Background

Intermediate coronary lesion (ICL) is a critical stage affecting coronary artery disease’s progression and prognosis and may quickly progress to acute coronary syndrome. However, percutaneous coronary intervention therapy and conventional drug therapy have certain limitations. Qing-Xin-Jie-Yu Granules (QXJYG), a Chinese herbal prescription with a pre-research basis, has the potential to be a complementary treatment for ICL. Previous studies have shown that QXJYG combined with conventional drug therapy could alleviate angina symptoms and reduce the incidence of composite ‘hard’ endpoint in treating stable coronary artery disease. However, for ICL, the effect of this prescription on the degree of coronary stenosis, plaque stability, and long-term efficacy remains unclear. Therefore, we designed this study to evaluate the efficacy and safety of QXJYG in patients with ICL.

Methods

This is a multi-center, block-randomized, double-blinded, placebo-controlled trial. One hundred and twenty participants with ICL will be randomly assigned to two groups in a 1:1 ratio. Based on conventional intervention, the participants of the treatment group will receive QXJYG orally, and the participants of the control group will receive placebo for six successive months. The primary outcomes involve the degree of coronary stenosis, including the percentage of diameter stenosis and the percentage of area stenosis measured by coronary CT angiography. The secondary outcomes involve coronary artery calcification score, Gensini score, CT-fractional flow reserve, angina symptom score, traditional Chinese medicine syndrome score, blood lipids, inflammatory factors, carotid artery ultrasound parameters, and major adverse cardiovascular events. Safety will be assessed by adverse events and laboratory examinations. Measurements will be performed at baseline (visit 1), months 2 (visit 2), months 4 (visit 3), months 6 (visit 4), and months 12 (visit 5).

Discussion

The results of this trial will verify the efficacy and safety of QXJYG in treating ICL, thus adding to the existing knowledge for resolving the problem in ICL.

Trial registration:

This trial is registered at the Chinese Clinical Trial Registry (www.chictr.org.cn). Registration number: ChiCTR2200059262. Register date: April 27, 2022.

Coronary artery disease

Intermediate lesions

Chinese herbs

Qing-Xin-Jie-Yu granule

Randomized controlled trial

Protocol

Coronary artery disease (CAD), also known as ischemic heart disease, was the top global cause of death in 2019 (1)and the ten most important driver of increasing burden in older adults (2). Likewise, in China, the morbidity and mortality of CAD were increasing year by year, and up to 2018, the number of cases reached 11.39 million (3). The serious health problems and economic burden caused by CAD have become an important common sanitation question worthy of attention.

Intermediate coronary lesion (ICL), defined as lesions with coronary artery diameter stenosis between 50% and 70% (4), is a key pathological stage that influences the development and prognosis of CAD. Although its stenosis was not severe enough to significantly interfere with blood flow, most myocardial infarctions (MI) developed from previous non-severe lesions(5), which are acute occlusions of blood vessels due to acute thrombosis induced by plaque rupture. Another study showed that approximately 6% of patients with ICL progressing to acute coronary syndrome (ACS) require percutaneous coronary intervention (PCI) within 1-year (6). These follow that plaques in ICL may be unstable and that plaque progression could be the beginning of ACS. Therefore, effective treatments of ICL to stabilize plaque and eventually reduce the incidence of coronary events is worth exploring.

In terms of treatment, there is still some controversy about the superiority of conventional drug therapy and PCI therapy. According to the guidelines (7), for significant anatomic (≥ 50% left main or ≥ 70% non-left main) or physiological (FFR ≤ 0.80) stenosis, revascularization including PCI and coronary artery bypass grafting (CABG) is recommended. Instead, medication is recommended. Most ICLs are in a critical phase for choosing interventional or pharmacological treatment. On one hand, some studies have shown that PCI could reduce the incidence of angina(8, 9). Moreover, with the maturity of PCI technology, some interventional therapists recommend PCI for all lesions suspected of causing myocardial ischemia, including ICL. However, ISCHEMIA and COURAGE studies showed that PCI could not reduce the risk of death and other MACEs compared with medical therapy (10, 11) or even increase the short-term risk of MI(12). Moreover, oxidative stress and inflammatory response are induced after PCI, which may increase plaque vulnerability (13). In addition, there is a risk of restenosis and thrombosis after PCI. On the other hand, the REVERSAL and PARADIGM studies confirmed the efficacy of lipid-lowering drugs in delaying the progression of atherosclerosis (AS) (14, 15). The PROVE-IT and AtoZ studies resulted in a trend toward reducing major cardiovascular events with the use of lipid-lowering agents (16, 17). However, there remains a high risk of cardiovascular events (18). In this case, it is significant to study whether complementary and alternative medicine can delay the progression of ICL.

Chinese herbal medicine, as a complementary therapy, has unique advantages in preventing and treating CAD. In the theory of traditional Chinese medicine (TCM), “blood-stasis” is the main pathological mechanism of CAD, which is related to vascular occlusion or stenosis, thrombosis, circulation disorders, and changes in blood physicochemical properties (19), and the therapeutic principle of “activating blood circulation and removing stasis” is applied to CAD. Qing-Xin-Jie-Yu Granules (QXJYG), an empirical prescription composed of herbs for activating blood circulation and removing stasis, has been used to treat CAD for nearly two decades in China. An experimental study indicated that QXJYG could regulate the serum levels of lipids and alleviate systemic inflammation, thereby alleviating AS (20). Randomized controlled trials showed that QXJYG combined with conventional therapy for stable coronary artery disease (SCAD) could alleviate not only the symptoms of angina pectoris (21) but also reduce the incidence of composite ‘hard’ endpoint (including cardiovascular death, nonfatal MI and ischemic stroke) (22).

However, the efficacy of QXYJYG on the degree of coronary stenosis, plaque stability, and long-term outcome in patients with ICL remains unclear. Therefore, this exploratory study is designed through a multi-center, block-randomized, double-blind, placebo-controlled clinical trial to scientifically confirm the efficacy and safety of QXJYG in the treatment of ICL.

Study objective

This study aims to evaluate the efficacy and safety of QXJYG in patients with ICL.

Study design

This multi-center, block-randomized, double-blinded, placebo-controlled trial is registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059262), and approved by the Ethics Committee of Xiyuan Hospital, China Academy of Chinese Medical Sciences (reference number: 2022XLA038-1). This trial will be carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Patients who meet the eligibility criteria will be recruited from three centers in China and enrolled with a written Informed Consent Form (ICF). Then, 120 participants will be randomly assigned to the QXJYG group (n = 60) and placebo group (n = 60) with six-month treatment and another six-month follow-up. Clinical assessments will be performed at baseline (visit 0), months 2 (visit 1), months 4 (visit 2), months 6 (visit 3), and months 12 (visit 4). Data management and statistical analysis will be independently performed by third-party personnel at Xiyuan hospital. This protocol strictly follows the international recommendations of SPIRIT 2013 statements [see Additional file 1] (23). This trial began in June 2022 and will continue until June 2025. The Consolidated Standards of Reporting Trials (CONSORT 2017) (24) will also be followed when reporting the study results. The study flowchart is briefly shown in Fig. 1.

Participants

Inpatients and outpatients in three research centers (Table 1) will be screened and identified according to the eligibility criteria.

Diagnostic criteria

Diagnostic criteria of ICL: referring to the “ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease” (4).

TCM syndrome differentiation criteria: referring to the “TCM Syndrome Differentiation Criteria for Coronary Heart Disease” (1990 edition) (25).

Quantitative scoring standards for blood-stasis syndrome in CAD: referring to the “Diagnostic Criteria of Blood Stasis Syndrome for Coronary Heart Disease”(26).

Inclusion criteria

Patients meeting the diagnostic criteria for CAD and coronary computed tomographic angiography (CCTA) suggest at least one major coronary artery lumen diameter stenosis between 50% and 70%.

Patients conform to the TCM syndrome differentiation criteria of blood-stasis.

Patients with heart function grading of NYHA grade Ⅰ-Ⅱ.

Patients aged 18–80 years.

Patients sign the ICF informed and voluntarily.

Exclusion criteria

Patients who have previously undergone coronary stent implantation, CABG, or MI within three months.

Patients with diffuse lesions throughout the diseased vessels.

Patients who have previously undergone other cardiac operations, such as valve replacement.

Patients with severe cardiac, hepatic or renal insufficiency that are unsuitable for CAG or CCTA and related examination and treatment.

Patients suffering from mental disorders.

Patients suffering from hepatitis, tuberculosis, AIDS, or other infectious diseases.

Allergic sufferers.

Pregnant and lactating women.

Patients with a life expectancy of less than one year.

Participation in other clinical trials within the last three months.

Elimination criteria

"Violation of legitimacy", meaning that the case selection violates the inclusion or exclusion criteria for cases that should not be randomized to the group.

Patients do not comply with randomization, or do not take any test drugs after randomization, or take very few drugs (< 10%).

Patients in which the efficacy and safety cannot be assessed due to the use of prohibited drugs.

No data available after randomization.

Withdrawal, dropout and discontinuation

The patients with the following conditions will be withdrawn after the investigator’s assessment: 1) conditions that continue to worsen; 2) comorbidities, complications, or special physiological changes; 3) poor compliance or use of prohibited drugs; 4) adverse events or serious adverse events; 5) leak of blindness.No matter when or why, subjects who do not complete the observation period will be regarded as dropouts. The investigators should maintain contact with the dropouts by phone calls, ask the reasons for withdrawal, record the time of the last medication, and have the dropouts complete as many assessment items as he or she can. The remaining test drugs of the dropouts will be recalled and recorded. Then a case report form (CRF) will be filled out, and the data will be included in the full analysis set (FAS). If someone withdraws from the trial due to allergic reactions, adverse reactions, and ineffective treatment, he/she will receive appropriate treatment and certain financial compensation. Moreover, the clinical trial will be completely discontinued in the following circumstances: 1) serious safety issues; 2) the efficacy of the test drug is poor or even ineffective; 3) major errors in the study protocol or important deviations in its implementation; 4) financial and management reasons.

Recruitment

Inpatients and outpatients will be recruited at three participating centers (Table 1) from June 2022 to June 2024. Patients with coronary stenosis between 50% and 70% will be screened. Then each potentially eligible patient will be assessed by two experienced cardiologists separately to determine whether he/she meets the criteria for recruitment. Prior to final enrolment, the investigators will provide each subject a complete and comprehensive introduction to the purpose, procedures, possible benefits and risks of this trial, and then inform them of the right to withdraw from the trial at any time. Each subject will be required to sign the written ICF voluntarily.

Table 1

The hospitals participating in this study.
Code	Participating Hospitals	Role
01	Xiyuan Hospital of China Academy of Chinese Medical Sciences	Leader and sponsor
02	Guan’anmen Hospital of China Academy of Chinese Medical Sciences	Member
03	Beijing Tongren Hospital Affiliated to Capital Medical University	Member

Interventions

According to the guidelines(27), all enrolled subjects will receive guideline-directed conventional drug therapy such as antiplatelet agents, angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists, nitrates, calcium channel antagonists, β-blockers, statins. Meanwhile, a therapeutic lifestyle will also be recommended like smoking cessation, diet control, proper exercise, etc. (28). Based on the above treatment, subjects will be randomly allocated into the treatment group treated with QXJYG or the control group treated with placebo for six successive months. Subjects will be instructed to dissolve one bag of the granules (5g/bag) in 100 ml of hot water at a time and take it orally twice daily. Then subjects of both groups will only receive guideline-directed conventional therapy for another six-month follow-up. Other Chinese medicines for CAD, atherosclerosis and hyperlipidemia will be prohibited during the trial period. Drugs for other diseases could continue to be taken, and related information (names, dosage, frequency, etc.) will be recorded for final analysis and reporting.

QXJYG consists of five herbal granules (Table 2), including Astragalus Membranaceus (Huangqi), Salvia miltiorrhiza Bunge (Danshen), Ligusticum chuanxiong Hort (Chuanxiong), Agastache rugosus (Huoxiang) 10g, and Coptis Chinensis (Huanglian). The placebo is made up of 5% granule and 95% dextrin with a look, smell and taste similar to the active granule. The test drugs are produced by China Resources Sanjiu Modern Chinese Medicine Pharmaceutical Co., Ltd., and the drug quality should be consistent with the Chinese Medicine Standards of the State Food and Drug Administration. Each subject's drugs are packaged in a large box containing three medium boxes. These boxes all have an identical appearance and are labeled with the corresponding drug code for each subject. Subjects will be given a medium-boxed test drug face-to-face at each visit according to the individual drug code. The drug codes and treatment assignment remain blind. A drug management record card will be established to record drug quantity and verify drug codes at each visit. In addition, to ensure mediation adherence, the investigators will have phone calls with subjects every week to reinforce medication instructions.

Table 2

Components and dose of QXJYG.
Chinese name	Latin or English name	Origin	Pharmacological effects	Weight (%) *
Huang Qi	Astragalus Membranaceus	The dried root of Astragalus membranaceus (Fisch.) Bge.	Protect ischemic and hypoxic myocardium	27.27
Dan Shen	Salvia miltiorrhiza	The dried root or rhizome of Salvia miltiorrhiza Bge.	Anti-atherosclerosis, anti-platelet aggregation and anti-thrombotic, improve microcirculation, dilation of vasculature, anti-inflammatory	27.27
Chuan Xiong	Ligusticum chuanxiong Hort	The dried rhizome of Ligusticum chuanxiong Hort.	Anti-platelet aggregation and anti-thrombotic, improve microcircu-lation, dilation of coronary arteries	18.18
Huo Xiang	Agastache rugosus	The dried above-ground part of Pogostemon cablin (Blanco) Benth	Dilation of microvasculature	18.18
Huang Lian	Coptis Chinensis	The dried rhizome of Coptis chinensis Franch.	Anti-atherosclerosis and lipid regulation, anti-inflammatory	9.09

*The weight of every single herb in one bag of QXJYG (5g).

Outcomes and measures

Basic data

At baseline, general information and clinical data will be collected. General information includes date of birth, gender, ethnicity, occupation, etc. General clinical data includes current medical history of CAD (angina CCS grading and TCM syndrome differentiation), past medical history, medication history, smoking, drinking and allergy history. The past medical history such as cerebrovascular disease, heart disease, peripheral vascular disease, kidney disease, diabetes, dyslipidemia, family history of premature cardiovascular disease will be focused. A physical examination including vital signs and cardiac examination will also be performed.

Primary outcomes

The primary outcomes are the degree of coronary stenosis including the percentage of diameter stenosis (% DS) and the percentage of area stenosis (% AS) measured by CCTA. % DS is an international common index to determine lumen obstruction in CAD lesions and is also the basis for grading the degree of coronary artery stenosis. Therefore, this trial will use % DS as the primary efficacy indicator to measure the changes in luminal stenosis before and after treatment. Another primary outcome indicator, % AS will also be measured to reflect the changes in plaque area.

Secondary outcomes

The secondary outcomes include the following items. First, CT-FFR, Coronary Artery Calcium (CAC) score and Gensini Score measured by CCTA allow for a comprehensive assessment of both coronary anatomy and physiology, that is CT-FFR to assess coronary artery function, CAC score to identify plaque composition and Gensini Score to assess the severity of coronary stenosis. Second, angina symptom score and TCM symptom score are designed for evaluating patients’ symptom improvement. Third, in the pathogenesis of atherosclerosis (AS), lipid deposition is the main pathological change causing luminal narrowing, and inflammatory response increases plaque instability. Therefore, blood lipids [including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)] and inflammatory factors [including high sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9)] will also be examined. Fourth, carotid intima-media thickness (IMT) (mm), carotid plaque length × thickness (longitudinal section) (mm) and carotid lumen stenosis (%) will be detected by carotid artery ultrasound. Carotid plaque and increased carotid IMT correlate with the severity of CAD detected by CCTA (29). Therefore, carotid ultrasound parameters will be used as an indirect indicator reflecting the efficacy of treating ICL. At the same time, major adverse cardiovascular events (MACEs) including non-fatal MI, cardiovascular death and revascularization therapy will be recorded as endpoints.

Safety outcomes

Safety outcomes including blood, urine and stool routine, liver and renal function, fasting blood glucose (FBG) and electrocardiogram (ECG) will be monitored periodically. Adverse events (AEs) will be recorded all the time during the trial.

Measurements

CCTA as a non-invasive measurement allows for the quantitative evaluation of lumen stenosis and plaque burden, identification of high-risk plaques, and assessment of coronary function (30). Therefore, CCTA will be used in this trial for the detection of coronary stenosis and the identification of plaque composition. The analysis and assessment of CCTA parameters will be conducted in accordance with the Society of Cardiovascular Computed Tomography Guidelines (31). % DS is calculated as [1-(minimum lumen diameter/reference vessel diameter) ×100%]. % AS is calculated as (plaque area/reference vessel area) ×100%. CAC score is a quantitative assessment of plaque burden using Agatston score (32); the calculation is shown in Table 3. The calculation of the Gensini Score follows this guideline (33) and is shown in Table 4. Referring to angina CCS grading and the Seattle Angina Scale, angina symptom score is quantified in terms of the number of episodes, duration, pain level and nitroglycerin dosage. TCM syndrome score, based on the scoring standards(26), is a quantitative score for the severity of clinical symptoms including chest pain, chest tightness, palpitations, and tongue and pulse manifestations. Blood sample collection for laboratory tests will be performed early in the morning before eating at each visit.

In addition, assay indicators will be tested in the same laboratory, with the same instruments and batches of reagents as far as possible. The investigators and inspection operators will undergo uniform training and a kappa test will be used to guarantee the consistency of the measurements and results. Items to be measured and the time points of data collection are shown in Table 5.

Table 3

Illustration of the steps for calculating the CAC Score*.
Step 1: Quantification of plaque area (mm²) with CCTA
Step 2: Determination of a lesion score in the following manner:
CT value (HU)	Density score
130–199	1
200–299	2
300–399	3
≥ 400	4
Step 3: Calculation of the score for each region: a region score = density score × the area.
Step 4: Sum of all the region scores
*The threshold for a calcified lesion is a plaque with an area ≥ 1mm² and CT value > 130 HU

Table 4

Illustration of the steps for calculating the Gensini Score.
Step 1: calculation of the severity score for each lesion.
Degree of stenosis (%)	Severity Score
1–25	1
26–50	2
51–75	4
76–90	8
91–99	16
100	32
Step 2: determination of the multiplication factor of each lesion based on its location in the coronary tree
Segment	Multiplication factor
RCA proximal	1
RCA mid	1
RCA distal	1
PD	1
PL	0.5
LM	5
LAD proximal	2.5
LAD mid	1.5
LAD apical	1
1st diagonal	1
2nd diagonal	0.5
LCX proximal	2.5(right dominance) or 3.5(left dominance)
LCX apical	1(right dominance) or 2(left dominance)
OM	1
Step 3: sum of all the lesion severity scores.

RCA: right coronary artery; PD: posterior descending branch; PL: posterior branches of left ventricular; LM: left main coronary artery; LAD: left anterior descending branch; LCX: left circumflex branch; OM: obtuse marginal branch.

Table 5

Measurement items and time window of data collection.
	Enrollment	Treatment			Post-treatment
	Before treatment (Visit 1)	Month 2 (Visit 2)	Month 4 (Visit 3)	Month 6 (Visit 4)	Month 12 (Visit 5)
ENROLLMENT
Eligibility screen	X
Informed consent	X
General information	X
Medical history	X
Comorbidities	X
Concomitant medication	X	X	X	X
Symptoms and signs	X	X	X	X
Allocation	X
INTERVENTIONS
QXJYG	X	X	X	X
Placebo	X	X	X	X
ASSESSMENTS
Primary outcomes
% DS	X			X
% AS	X			X
Secondary outcomes
CAC score	X			X
Gensini score	X			X
CT-FFR	X			X
Angina symptom score	X	X	X	X
TCM syndrome score	X	X	X	X
hs-CRP	X			X
MMP-9	X			X
Blood lipids ^a	X			X
Carotid artery ultrasound ^b	X			X
MACE		X	X	X	X
Safety outcomes
Blood routine	X			X
Urine routine	X			X
Stool routine	X			X
Liver function	X			X
Renal function	X			X
FBG	X			X
ECG	X			X
AE		X	X	X	X
Medication adherence		X	X	X

^a Blood lipids include TC, TG, LDL-C and HDL-C. ^b Carotid artery ultrasound parameters include carotid intima-media thickness (IMT) (mm), carotid plaque length × thickness (longitudinal section) (mm) and carotid lumen stenosis (%).

Adverse events

Adverse events (AEs) are defined as all adverse medical events after receiving test drugs, which can be manifested as symptoms, signs, diseases or abnormal laboratory tests. Subjects will be required to report any discomfort symptoms truthfully during the trial. Meanwhile, investigators need to periodically monitor the subjects’ changes in physical examinations, vital signs, laboratory tests, etc. If AEs occur, investigators should perform a symptomatic treatment or discontinue the treatment according to the severity, and then analyze the possible reasons and record related information in the CRF. Furthermore, once serious adverse events (SAEs) occur, investigators must complete the Serious Adverse Event Report Form and immediately report to the National Medical Products Administration, the ethics committee and the sponsor within 24 hours.

Study-specific visits and procedures

The schedule for study procedures is shown in Table 5. Patients who meet the eligibility criteria and sign ICF will be enrolled in the trial followed by a collection of basic data (demographic data, medical history, concomitant medication, physical examination). Enrolled patients will receive a random allocation at baseline (visit 1), a 6-month treatment (visit 2–4) and another 6-month follow-up (visit 5). Baseline measures (visit 1) include efficacy indicators (%DS, %AS, CT-FFR, CAC score, Gensini score, angina symptom score, TCM syndrome score, blood lipids, inflammatory factors, carotid artery ultrasound parameters) and safety indicators (blood, urine and stool routine, liver and renal function, FBG, TNT, ECG). Above baseline measurements will be repeated after 6-month treatment (visit 4). During the treatment period, concomitant medication, physical examination, angina symptom score and TCM syndrome score will be recorded at each visit (visit 1–4). Meanwhile, based on the remaining test drugs, medication adherence will be judged every two months after allocation (visit 2–4). In addition, MACEs and AEs will be observed throughout the trial (visit 2–5). Furthermore, in each procedure, individuals will be assessed by the same investigator whenever possible.

Sample size calculation

The number of cases in the treatment group and the control group is arranged in a ratio of 1:1, so c = 1. According to the literature reports (34, 35), it is assumed that the mean percentage of diameter stenosis is decreased by approximately 22% in the treatment group and 12% in the control group; the standard deviation σ = 0.15 for both two groups. Given a type I error rate of α = 0.05 (two-side test), a power of 90% (type II error rate of β = 0.1), so u_α=1.96, u_β=1.28, n₁ = n₂ ≈ 47. Considering the maximum dropout rate of 20%, a total of 113 patients is needed. As a superiority clinical trial design, the sample size can be enlarged appropriately to get a statistically positive result.\(\)Meanwhile, to facilitate randomized and blind grouping, 120 participants will be included in this trial. The calculation formula is as follows:

\({n}_{1}=\left(\frac{1+c}{c}\right){\left[\frac{\left({u}_{\alpha }+{u}_{\beta }\right)\sigma }{{\mu }_{T}-{\mu }_{C}}\right]}^{2}\) , and \({n}_{2}=c{n}_{1}\)

Randomization and blinding

Enrolled patients will be randomized in a ratio of 1:1 and a block of 4 based on a random number table. The computer-coded random number table will be generated by a third-party statistician from Xiyuan Hospital Information Center using SAS statistical software, according to the case distribution number and random proportion of the participating units. The statistician will also code the drug numbers according to the random number table. Then subjects will be allocated to either the treatment or control group based on the drug numbers they are assigned through the central random system. After allocation concealment, subjects will obtain the test drugs corresponding to their drug number at each visit. The test drugs all have the same appearance, odor, taste, etc., and are individually packed in identical large boxes labeled with the drug numbers. Anyone participating in the trial (including subjects, attending physicians, inspection operators, and statisticians) is blinded to treatment assignment. The double unblinding method will be used in this study. The first unblinding will be performed to reveal the group (group A or group B) corresponding to each drug number after the data entry and the database lock. The second unblinding will be performed to reveal the treatments corresponding to group A and group B after statistical analysis. The blind codes recording the drug number, corresponding random number and group will be sealed in duplicate and kept by the Clinical Pharmacology Center, Xiyuan Hospital of China Academy of Chinese Medicine Sciences. In addition, an emergency letter (electronic) recording drug codes and group assignments will be prepared for emergency unblinding, and any of the following situations could call for blind breaking: serious adverse events, serious complications, and deterioration.

Data collection and management

To ensure the accuracy of data collection, all investigators will receive training for filling out the CRF. According to the paper version of CRF [see Additional file 2], eCRF has been designed and created for data collection. Then, using SQL Sever2000, an electronic database will be established for data entry. The data from three participating centers will be imported into the clinical data management system after each visit by means of independent and double entry. Special personnel are responsible for data management and confidentiality. Then data verification will be carried out to guarantee data integrity, validity and authenticity. Data verification content should include the primary and secondary efficacy indicators, key safety indicators, etc. Data verification procedures should be multiple. First, a supervisor will check the consistency of eCRF data with the source data on-site at each participating center. Second, when inputting data, a system automatic logic check will be run to identify simple, logically contradictory, and questionable data through a pre-defined logic program. Third, manual checks will be performed to further identify complex and specific problems. For questionable data, the supervisor can issue a Data Clarification Form (DCF) to the investigator, ask for an answer, and then revise the data after verification according to the investigator’s responses. The DCF should be kept as a source file along with raw data. All error data, queries, and revision results should have audit trials. The above data verification and cleaning will be conducted by a third-party personnel every two months. Moreover, the Data Coordination Center will be in charge of data validation.

Statistical analysis

After blind audit, the data from three participating centers will be combined and an independent statistician from Xiyuan Hospital will conduct the statistical analysis of primary and secondary endpoints, as well as AEs. The analysis of efficacy indicators will adopt a full analysis set (FAS) according to the intention-to-treat principle. Patients who signed the ICF, have taken the test drug at least once, and have efficacy data records will be included in FAS. We will also perform per-protocol set (PPS) analysis for patients who have good compliance with the protocol. We can judge the stability of the results by comparing the results from FAS and PPS. Patients with safety data will be included in the safety analysis set (SAS). If there are key efficacy data missing, we will use the last observation carryover method to supplement the data.

Continuous variables (including %DS, %AS, CAC score, Gensini score, angina symptom score, TCM syndrome score, carotid artery ultrasound parameters and laboratory indicators) will be expressed as the mean ± standard deviation (SD), median or interquartile range (IQR). Categorical variables (such as the occurrence of MACEs and AEs) will be expressed as numbers or percentages (%). For the comparability of characteristics between the two groups, continuous variables will be analyzed by two independent-sample t-test with normal distribution or Wilcoxon rank sum test with non-normal distribution. Categorical variables will be analyzed by chi-square test or the Fisher exact test. For the within-group comparisons, the paired t-test or the Wilcoxon signed-rank test will be applied based on the normality of the data. Moreover, if there is significant differences between groups (such as age, gender, syndrome, etc.) or related factors affecting the efficacy (such as concomitant medication), covariance or logistic regression analysis will be used to reduce the influence of confounding factors. When considering central effects, the Cochran-Mantel-Haenszel test will be used in this multicenter trial.

Above the analysis, a two-sided test will be generally performed, and P < 0.05 will be considered statistically significant. The SAS version 9.3 (SAS Institute, Cary, NC, USA) will be used for all the analyses.

Generally, it is believed that atherosclerosis (AS) formed by lipid deposition resulting in lumen stenosis is the main pathological change in stable coronary artery disease. A meta-analysis indicated that LDL-C lowering was associated with a reduced risk of total and cardiovascular mortality (36). For that reason, statin therapy is widely studied and applied. However, a residual risk of cardiovascular events remains despite highly effective lipid-lowering interventions, which may be related to the inflammatory response. A study showed that anti-inflammatory therapy could lower the rate of recurrent cardiovascular events than lipid-lowering therapy alone (37). Nevertheless, anti-inflammatory drugs are not widely used in treating CAD due to the high price and serious side effects.

The Chinese herbal prescription, Qing-Xin-Jie-Yu Granules (QXJYG), consisting of five herbs (Table 2), has multiple effects and better economic benefits than single-ingredient compound drugs. A network pharmacology study showed that the components of QXJYG played a role in the treatment of CAD by anti-platelet, regulating glucose and lipid metabolism, inhibiting the inflammatory response, etc. (38).

In terms of principal active components, for example, Astragaloside IV can attenuate myocardial ischemia injury (39); Tanshinone IIA exerts anti-atherosclerotic effects through anti-LDL oxidation, protection of endothelial function, anti-platelet aggregation, etc. (40); Tetramethylpyrazine has cardioprotective and plaque stabilizing effects associated with its anti-LDL oxidation, anti-inflammatory, and inhibition of platelet activation (41); Berberine inhibits the development of atherosclerotic plaques through LDL-lowering activity and suppressing atherogenic functions of related cells (42). Overall, QXJYG has multicomponent, multitarget, and multi-pathway effects in the treatment of CAD. The combination of QXJYG and conventional therapy has the potential to be a new approach for achieving better effectiveness in treating ICL.

Some clinical studies of QXJYG combined with conventional therapy are also available here, but their results are not entirely consistent. For patients with SCAD, the serum level of hs-CRP and lipid profiles were not significantly reduced (22), while for SCAD patients with elevated inflammatory reactions, QXJYG could improve angina symptoms and reduce the hs-CRP level (21). In addition, the above studies do not study for patients with ICL and do not have specific indicators to visually reflect plaque stability. Therefore, for this specific population of ICL, this protocol uses the degree of coronary stenosis, CAC score, CT-FFR as the main efficacy indicators to evaluate the improvement of coronary anatomy and physiological function objectively.

As for the measurements of the ICL, various detection techniques are available. CAG is the “gold standard” for detecting the degree of coronary artery stenosis, but it cannot observe the plaque characteristics. The PROSPECT study showed that MACEs were attributable to recurrence at the site of culprit lesions and to non-culprit lesions, most of which were thin-cap fibroatheromas determined by intravascular ultrasound (IVUS) (43). Most plaques in ICL are thin-cap fibroatheromas, also called vulnerable plaques. Therefore, IVUS is widely used to evaluate plaque stability by analyzing plaque composition and structure. Besides anatomical assessment, the coronary function should also be considered. Fractional Flow Reserve (FFR) is the “gold standard” for evaluating myocardial ischemia and is of great significance in guiding whether borderline lesions require interventional therapy (44). Although FFR and IVUS make up for the lack of CAG in coronary plaque assessment, these methods are expensive and invasive. In recent years, there has been a trend for non-invasive CCTA with high accuracy and low economic cost to replace invasive examinations (45). In anatomic measurement, CCTA is an alternative to quantitatively assess both coronary stenosis and plaque. CCTA demonstrated high concordance with invasive CAG for identifying anatomically significant stenosis (≥ 50% luminal narrowing) (46, 47), and has an agreement with the treatment decision-making derived from conventional CAG (48, 49). It also showed a high correlation with IVUS in characterizing and quantifying atherosclerotic plaque (50, 51). Moreover, the low-attenuation plaque burden detected by CCTA could be a stronger predictor for myocardial infarction (52). In functional measurement, CT-derived FFR possessing high diagnostic performance could be an alternative to invasive FFR for detecting coronary ischemic lesions (53), and it showed improved identification of hemodynamically significant coronary lesions compared with CCTA alone (54, 55). With technological advancements in temporal and spatial resolution, CCTA can provide a one-stop evaluation in terms of coronary anatomy, function, and plaque composition, which has become extremely beneficial and cost-effective in clinical practice.

This is a multi-center clinical trial, targeting the special population of ICL, to evaluate the efficacy and safety of QXJYG. QXJYG, an herbal compound, has been proven to have lipid-regulating, anti-inflammatory, and anti-platelet aggregation effects in preliminary basic research. This makes QXJYG the potential to become an innovative complementary treatment for ICL. For the efficacy evaluation, we made some adjustments to the protocol, there differing somewhat from the online clinical registry. In order to reflect the change of ICL more visually, we reselected % DS and % AS as the primary efficacy indicators and combined Gensini score, CAC score and CT-FFR to assess the degree of coronary artery stenosis, plaque compositions and coronary function. Besides, inflammatory factors are used as the secondary outcomes in response to plaque stability. On the measurement of coronary imaging, we will utilize non-invasive quantitative CCTA to perform a comprehensive evaluation of ICL, which is easy for investigators to perform and has higher safety, making it more acceptable to participants. As for the study implementation, a central randomization system will be used to generate random sequences and perform random allocation at a ratio of 1:1. Blinding will be implemented for patients, investigators and statisticians. CRF and the electronic database will be set up for data collection and management. These designs can control the risk of bias so as to obtain reliable study results.

In conclusion, this exploratory study will provide new clinical evidence of TCM for the prevention and treatment of ICL and explore possible mechanisms.

Trial status

The trial was initiated in June 2022 and is currently open for enrolment. However, no analysis has been conducted and no AEs have occurred to the data.

ACS

Acute coronary syndrome

Adverse event

Atherosclerosis

CAG

Coronary angiography

CAD

Coronary artery disease

CCTA

Coronary computed tomography angioplasty

ICL

Intermediate coronary lesion

CRF

Case report form

DCF

Data clarification form

ECG

Electrocardiogram

FAS

Full analysis set

FBG

Fasting blood glucose

FFR

Fractional flow reserve

HDL-C

High-density lipoprotein cholesterol

hs-CRP

high sensitivity C-reactive protein

ICF

Inform consent form

IVUS

Intravascular ultrasound

LDL-C

Low-density lipoprotein cholesterol

MACE

Major adverse cardiovascular events

Myocardial infarction

MMP-9

Metalloproteinase-9

PCI

Percutaneous coronary intervention

PPS

Per-protocol set

QXJYG

Qing-Xin-Jie-Yu Granules

TCM

Traditional Chinese medicine

Total cholesterol

Triglycerides

% AS

Percentage of area stenosis

% DS

Percentage of diameter stenosis.

Ethics approval and consent to participate

This study is in compliance with the Declaration of Helsinki (Edinburgh 2000 version) and Good Clinical Practice guidelines. The study was registered at www.chictr.org.cn(ChiCTR2200059262). The study protocol (version number: XYYY-V-1.0, version date: December 26, 2021) has been reviewed and approved by the Ethics Committee of Xiyuan Hospital of China Academy of Chinese Medical Sciences (No. 2022XLA038-1). If there is any change to the protocol, approval must be sought from the Ethics Committee again. Each subject will be required to sign a written ICF before enrolment.

Consent for publication

Not applicable

Confidentiality

All subjects will be fully anonymous, and the identity of the subjects can only be determined by the patient numbers of the clinical research. Any trial data collected from these subjects will be filled in the CRF corresponding to the patient number and entered into the database. CRFs and the database will be kept confidential by special personnel.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author.

Competing Interests

The authors declare that they have no competing interests.

Funding

This trial was supported financially by the China Academy of Chinese Medical Sciences Innovation Fund (no. CI2021A00908). The funders have no role in study implementation, data analysis and interpretation, or decision to submit results.

Ancillary and post-trial care

After the trial, subjects will receive certain financial compensation. Those who discontinue the trial due to adverse events will be followed-up and treated accordingly.

Dissemination policy

The research results will be shared with society through the publication of papers, the training of graduate students and advanced doctors, business training, conference exchanges and academic lectures.

Authors’ contributions

JYR designed and supervised the study and revised the manuscript. ZFF provided methodological advice to improve the study design and revised the manuscript. CLY conceptualized the study design, drafted the manuscript, established the CRF, and participated in the recruitment of patients. DLL and XJW participated in the indicators detection and data management. DL and HXX participated in the coordination of the study and recruitment of patients. ZLF and ZL participated in the indicators detection. SLB participated in the case management and blood sample collection. All authors read and approved the final manuscript.

Acknowledgments

We thank the Clinical Pharmacology Center, Xiyuan Hospital of China Academy of Chinese Medicine Sciences for its technological support with data management and statistical analysis. We appreciate the efforts and assistance of all participating centers and researchers in the design of the protocol.

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No competing interests reported.

Addtionalfile1SPIRITchecklist.pdf
Additional file 1: SPIRIT Checklist.
Addtionalfile2CaseReportForm.pdf
Additional file 2: Case Report Form

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Chinese herbal prescription Qing-Xin-Jie-Yu granule combined with conventional treatment for intermediate coronary lesions: study protocol for a randomized, double-blinded, placebo-controlled trial

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