Treatment of coronary heart disease (CHD), which poses a significant threat worldwide, has made great progress, including thrombolysis, intervention, and coronary artery bypass grafting. However, according to the COURAGE study, these interventional therapies may not effectively reduce the risk of major adverse cardiac events in patients with stable CHD as compared with conservative treatment [
In addition, diabetes mellitus as an important independent risk factor of cardiovascular disease has been described in the 1999 American Heart Association statement as “a cardiovascular disease” and regarded as a coronary disease equivalent by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III 2001 [
With the publication of the Scandinavian Simvastatin Survival Study, the Cholesterol and Recurrent Events, and other large-scale clinical trials, the relationship between blood lipid levels and cardiovascular atherosclerosis has gradually become clear. Dyslipidemia is closely related to atherosclerosis and is an independent risk factor of CHD. Previous studies showed that lipid lowering can significantly reduce the risk of CHD by 2%, with total cholesterol and low-density lipoprotein cholesterol (LDL-C) both lowered by 1%. Extremely low levels of high-density lipoprotein cholesterol have been shown to increase the risk of CHD by 70% in men and 100% in women. Therefore, controlling abnormalities in serum lipid levels is an important part of the secondary prevention of CHD. The morbidity and mortality of CHD could be significantly reduced by using lipid-lowering drugs, which also could slow down and reverse the progression of atherosclerosis.
Furthermore, dyslipidemia, which is associated with diabetes, is the main cause and one of the major risk factors of diabetes-associated macrovascular complications [
Traditional Chinese medicine (TCM) emphasizes symptomatic treatment and has long-term application in CHD-related diseases. From the view of TCM, patients with CHD and abnormal glucose and lipid metabolism can be divided according to symptoms. A common symptom is the Qi and Yin deficiency syndrome. The effect of Zhenyuan capsules in the treatment of this type of patients has been observed in the clinical setting. The main component of the Zhenyuan capsule is ginseng fruit saponin (GFS), a ginsenoside extract from the mature fruit of the
Therefore, we designed this randomized, double-blind, parallel-controlled, multicenter, phase IV clinical trial to investigate the efficacy of the Zhenyuan capsule in the treatment of CHD accompanied with glucose and lipid metabolic disorders. The outcome measures are focused on symptom reduction and improvement in physiochemical indexes. We will also determine clinical safety.
This study is registered with the Chinese Clinical Trial Registry (registration number
Participants will be recruited from three participating centers, namely, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Guan’anmen Hospital of China Academy of Chinese Medical Sciences, and the Second Affiliated Hospital of Tianjin University of TCM. The leading unit among the three centers is Xiyuan Hospital. In this trial, 200 patients will be recruited and randomly allocated to two groups (treatment group,
Study flowchart.
Inpatients and outpatients will be screened and identified in three participating centers strictly according to the inclusion and exclusion criteria. Written informed consent of each participating patient is required for entry to the study.
Subjects are eligible for study participation if they meet the following criteria: (1) coronary angiography or coronary computed tomographic angiography shows that at least one of the main branches of the coronary artery has stenosis of at least 50%; (2) TG levels between 1.70 and 2.25 mmol/L and HbA1c level between 5.7% and 7%; (3) the TCM syndrome differentiation is Qi and Yin deficiency; (4) age between 45 and 75 years at screening; and (5) providing informed consent form.
Participants will be excluded if they report any of the following criteria: (1) serious cardiovascular diseases, including severe valvular heart disease, heart valve replacement, refractory heart failure, cardiac function grade IV (NYHA), and cardiogenic shock or serious cardiac insufficiency (EF < 35%); (2) mental disease or malignant tumor; (3) renal insufficiency, serum creatinine level of >2.5 mg/dl for men (>220
Participation will be discontinued if the participant has sudden worsening of condition that is not confirmed to be associated with this trial, or serious adverse events, or is unable to cooperate with the trial investigators and/or to complete the follow-up. If the condition continues to worsen, complications or special physiological changes emerge, a participant refuses to continue the trial, or a participant uses medicines that are not permitted in this trial, the patient will be withdrawn from the trial after the researcher’s assessment. The data will be considered invalid but will still be included in the full analysis set (FAS). Information from dropouts will be collected by phone interviews, such as the reason for the trial discontinuation and the status of the final medication received. Participants who withdraw from the trial will receive appropriate treatment for adverse events.
Patients who meet all the inclusion and none of the exclusion criteria will be randomized into two groups as follows: (1) treatment group, 0.5 g of Zhenyuan capsule, 3 times/day, and (2) control group, 0.5 g of placebo, 3 times/day. According to the Guideline for the Diagnosis and Treatment of Chronic Stable Angina, participants can maintain the conventional drug treatments such as antiplatelet agents, statins, nitrates, anticoagulation drugs,
The primary indicators, HbA1c, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2hPBG), and triglyceride (TG) levels, will be tested at T0, T1, T2, T3, and T4. The secondary indicators, ultrasonic cardiography (UCG) finding, coagulation indicator, and P- selectin level, will be assessed at T1 and T4. Cardiac death, nonfatal myocardial infarction, coronary revascularization, Seattle Angina Questionnaire (SAQ) score, and TCM symptom indicators will also be monitored periodically. Adverse events, which include hemorrhage, will be followed up using electrocardiography, routine urinalysis, routine stool test, and liver and kidney function tests (ALT, AST, Cr, and BUN) from T1 to T4. Items to be measured and the time window of data collection are shown in Table
Measurement items and time points for data collection.
Screening | Treatment period | ||||
---|---|---|---|---|---|
T0 | Run-in period | Week 4 | Week 8 | Week 12 | |
| |||||
Informed consent | × | ||||
Inclusion/exclusion criteria | × | ||||
Demographic data | × | ||||
Medical and treatment history recording | × | ||||
Complication and symptom recording | × | ||||
Concomitant medication | × | × | × | × | |
Vital signs | × | × | × | × | |
| |||||
TG, FBG, 2hPBG, and HbA1c levels | × | × | × | × | × |
TCM symptom indicators | × | × | × | × | |
Seattle Angina Questionnaire score | × | × | × | × | |
Coagulation indicator | × | × | × | × | |
P-selectin level | × | × | × | × | |
Angina pectoris scores and end-point event | × | × | × | × | |
ECG | × | × | |||
UCG | × | × | |||
| |||||
Liver and renal function tests | × | × | × | × | × |
Hemorrhage | × | × | × | × | |
Routine blood and urine tests | × | × | |||
Routine stool and occult blood tests | × | × | |||
| |||||
Randomization and allocation | × | ||||
Drug distribution | × | × | × | ||
Medicine recycling and drug quantity statistics | × | × | × |
Participants are required to honestly report any changes in their symptoms. Any adverse events or unexpected toxic side effects that develop during the trial will be analyzed to determine the cause. These will be recorded and treated appropriately by the intervention administrators. In cases of severe adverse events, the participating patients are asked to take immediate measures to protect their safety and report the events to the Drug Supervision Bureau, the trial applicant, and the ethics committee within 24 hours.
Table
Eligible patients are randomly allocated to the treatment or control group in a 1 : 1 ratio. The randomization sequence will be recorded by staff at the sponsor unit. The researchers and outcome assessors participating in this study have no knowledge of the randomization sequence details. In addition, the results are kept in sealed, opaque, and stapled envelopes. They will be unsealed at the end of the outcome assessment. Emergency letters, including random codes and group assignments, are prepared by a statistician. If the blind code is exposed, patients will be excluded accordingly. Any of the following situations could call for a blind breaking and urgent measure: a serious adverse event, serious complication, or a deterioration in the patient’s condition.
The data of the participants collected according to the Case Report Forms will be imported into the clinical data management system (http://www.xyedc.com/). To keep the data consistency, the supervisor will compare the electronic database with the source documents and correct any identified errors. In addition, computer logic checks will be run after data entry. Manual checks and the Data Coordination Center will also help to identify more complicated and less common errors. All these measures are used to ensure the accuracy and integrity of information.
The sample size was determined with a type I error rate of
Statistical analyses will be conducted by an independent statistician from Xiyuan Hospital. In the FAS, patients will be dosed with the study drugs at least one time and one clinical observation will be recorded. Participants with good compliance and without any protocol deviations will be included in the per-protocol set (PPS). Subjects with safety data who have completed at least one study visit will be included in the safety analysis. The mean ± SD will be used in continuous variables. The characteristic comparability between the two groups will be evaluated by a two-sample Student
Recently, many studies have used the Zhenyuan capsule as treatment for CHD, heart failure [
This study first applies the Zhenyuan capsule for blood lipid research. This may reveal new uses for old drugs in TCM. In addition, this is the first study to address the efficacy and safety of the Zhenyuan capsule for CHD with abnormal glucose and lipid metabolism in a double-blind and parallel-controlled trial. We assume that this design, which is in line with the TCM theory, will contribute to more convincing results and robust evidence for the efficacy of study medications.
This study has some limitations. Owing to the complexity of the disease, many potential influencing factors may exist. Therefore, to minimize possible errors, participants will have a 2-week run-in period. During this period, any TCM medications for improving blood lipids or glucose will not be permitted. In addition, participants will not be permitted to use other treatments for angina pectoris in CHD and diabetes mellitus, including TCM herbs and Chinese patent medicines at any time during the study.
In summary, by rigorous design, the results of this study will provide clinical evidence regarding the efficacy and safety of Zhenyuan capsules for CHD with abnormal glucose and lipid metabolism.
Alanine transferase
Blood urine nitrogen
Coronary heart disease
The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation
Serum creatinine
Case report form
Computed tomographic angiography
Electrocardiography
Full analysis set
Fasting blood glucose
Ginseng fruit saponin
Glycosylated hemoglobin
Low-density lipoprotein cholesterol
National Cholesterol Education Program
Per-protocol set
Seattle Angina Questionnaire
Total cholesterol
Traditional Chinese medicine
Ultrasonic cardiography
2-hour postprandial blood glucose.
The study is conducted in compliance with the Declaration of Helsinki (Edinburgh 2000 version). The study protocol was reviewed and approved by the institutional review boards of the three participating hospitals.
Written informed consent will be signed before participation in the trial.
Neither the funding agency nor any outside organization participated in the study design.
The authors declare that they have no conflicts of interest.
Jingchun Zhang and Dazhuo Shi conceptualized and designed the study. Jingchun Zhang and Yue Liu drafted the manuscript, participated in data collection, and analyzed the data. Yu Qiao and Yue Liu reviewed the protocol for important intellectual content. Zhiqi Liang, Yuhua Wang, and Wei Zheng helped to revise the manuscript. All authors read and approved the final manuscript.
The authors appreciate the help and efforts of all research staff for participating in this trial and recruiting and treating the patients. The study is financially supported by Jilin Jian Yisheng Pharmaceutical Limited Company, Jilin, China.