In the current study, PPCP patients with CHD from Guangdong Provincial Hospital of Traditional Chinese Medicine (Guangzhou, China) were randomly assigned to experimental group and control; patients in experimental group received YMOS and standardized medical treatment, while those in control group received the placebo for three times/day for 12 weeks and standardized medical treatment for 12 weeks. Once the patients were assigned to the experimental group, they received laboratory tests and completed Seattle angina questionnaire (SAQ) score (physical limitation (PL), angina stability (AS), angina frequency (AF), treatment satisfaction (TS), and disease perception (DP), Hamilton anxiety rating scale (HAMA), Hamilton rating scale for depression (HRSD), Canadian Cardiovascular Society (CCS) angina score, New York Heart Association (NYHA) classification, visual analogue scale (VAS), and 12-Item short form survey (SF-12), while the frequency of angina-associated symptoms per week and the number of nitroglycerin use were recorded. The results of laboratory tests were used to evaluate the safety of YMOS, including blood routine examination, urine and stool routine examination, hepatic and renal function, fasting blood glucose and blood lipid, coagulation, troponin I (TnI), ECG, and thyroid function test as required. The patients were followed-up for 8 weeks with repeated questionnaires every 4 weeks. At the beginning of the study, all the patients signed the written informed consent forms, in which they were informed about the risks and benefits of the treatment strategy. The study was guided by the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Fig. 1). A flowchart of the trial is shown in Fig. 1.
Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) Male or female patients who aged 18–85 years old; (2) Patients with a confirmed history of PCI of CHD within more than 30 days and less than 180 days, without need of selective coronary revascularization (coronary artery bypass grafting) plan assessed by cardiovascular specialists; (3) Patients with symptoms related to heart, such as chest distress, chest pain, palpitation, shoulder and back pain, shortness of breath, weakness, activity intolerance. Angina attack frequency (AF) dimension score in the SAQ would be < 80; (4) HAMA score would be in the range of 7–21 (mild-to-moderate anxiety); (5) Signing the written informed consent form.
The exclusion criteria were as follows: (1) Women who were pregnant or preparing to be pregnant or nursing; (2) Women who were at child-bearing age, while did not agree to use contraception on medication; (3) Patients with severe anxiety (HAMA score > 21); (4) Patients with major depression (HAMD score ≥ to 24); (5) Patients who were taking anti-anxiety drugs (e.g., selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, benzodiazepines, etc.); (6) Stable angina with grade 4 based on CCS; (7) Uncontrolled hypertension (systolic pressure > 180 mmHg or diastolic pressure > 100 mmHg) despite ongoing antihypertensive treatment; (8) Heart failure with grade III or IV in NYHA; (9) Patients with CHD with atrial fibrillation; (10) Clinically significant complications, including liver dysfunction (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level more than 2 times higher than normal), renal dysfunction (serum creatinine level more than 2 times higher than normal), severe cardiopulmonary dysfunction, pulmonary hypertension, chronic obstructive pulmonary disease, history of cerebral hemorrhage or epilepsy, with need of anticonvulsant drugs; (11) Patients who did not take drug to treat CHD, while disappearance of related symptoms was noted at within 7 days of introduction period; (12) Patients with myocardial infarction or grade IV angina at 3 months before commencing the study; (13) Patients with acute coronary syndrome confirmed by examination and chest pain caused by rheumatic heart disease, cardiomegaly, severe neurosis, climacteric syndrome, hyperthyroidism, cervical spondylosis, choledochocardial syndrome, gastroesophageal reflux, hiatal hernia, aortic dissection, and so on; (14) History of specific bleeding or bleeding from warfarin; (15) Patients with previous hematopoietic diseases; (16) Patients who have undergone surgery within 4 weeks before beginning the study and were prone to bleeding (without PCI); (17) Patients who participated in other clinical studies or took investigational drugs for within 90 days; (18) Patients with known or suspected to be allergic to the drug in this study or allergic constitution; (19) Drug abusers. (patients with a recent history (in the recent 2 years) of alcohol abuse or a known history of drug dependence; (20) Psychopath; (21) Patients who have been judged ineligible by physicians for inclusion in the study; (22) Patients who were medical staff’s family members or relatives.
Criteria For Losing Cases
In the case of quitting the study or losing the follow-up, the investigators should take active measures to complete the final test, in order to analyze efficacy and safety of treatment. All cases who missed the chance of full participation in the study were recorded in a case report form (CRF) and in research conclusion form and the reason of losing the study was noted. Participants who did not complete the research for the following reasons were taken eligible into consideration: Investigators decided to quit: (1) In case of allergic reaction or serious adverse events (AEs), the investigation prohibited the cases from following the study according to physicians’ judgment; (2) Other complications and special physiological changes that occurred during the study, who did not further participate in the study; (3) Poor patients’ compliance; Subjects who left the study by themselves: (1) Regardless of the reason, a patient would be unwilling or impossible to continue the clinical study, or recommended to withdraw the study by physicians; (2) Although a subject did not explicitly withdraw from the study, he/she may not accept the medicine or test, leading to loss of the study.
Exclusion Criteria
Participants who do not complete the research project for the following reasons were excluded: (1) Those who failed to meet the inclusion criteria and were incorrectly included or met any of the exclusion criteria; (2) Those who met the inclusion criteria, while have not used medicine after inclusion, or had no further consultation records; (3) Patients who changed the medicine or used combination therapy different from original prescription in the middle of the course by themselves, especially those who used the combination therapy influencing effectiveness and safety of the therapy regimen.
Discontinuation criteria
The purpose of discontinuation is to protect rights and interests of subjects, ensure quality of study, and avoid unnecessary economic losses. Criteria for discontinuation were as follows: (1) In case of serious safety problems in the study, the study was discontinued in-time; (2) If the medicine was found to have no clinical value in the study, the study was discontinued to avoid ineffective treatment for subjects and unnecessary economic loss; (3) Clinical study regimen has been found with major issues during study, thereby causing difficulty in evaluating the therapeutic effect; or a well-designed regimen with important deviations during implementation, causing difficulty in assessment of the therapeutic effect if continues; (4) The asking discontinuation on behalf of principal investigator’s requests; (5) The China Food and Drug Administration (CFDA) recommended to discontinue the study for some reasons.
Recruitment strategies
In order to recruit patients, advertisements were placed in a broad range of media outlets, including flyers within the hospital, as well as the Chinese Clinical Trial Registry website. Patients who were interested in the trial received information about the study. Each potential participant was informed that the participation is fully voluntary and refusal to participate in the research has no negative effect on their treatment. Those who would like to join the study were further assessed to determine whether they could meet the inclusion criteria or not.
Randomization And Blinding
In the present study, "interactive web-based response system (IWRS)" was employed for randomized allocation. The Department of Medical Statistics in the National Center for Cardiovascular Diseases (Beijing, China) was in charge of preparation and maintenance of the random system. For patients who met the inclusion and exclusion criteria, their medical data were collected, and relevant operation processes were automatically retained. The research team members, except for the clinical research methodology personnel, were blinded to the treatment and the group assignment. Patients were informed about the experimental group and the control group, while they were not informed about group assignment. Both YMOS and placebo were provided by the Qionglai Tianyin Pharmaceutical Co., Ltd. (Qionglai, China), and the preparation of placebo oral solution with the same appearance, similar color, smell and taste, as YMOS package was blinded to investigators, patients, and statistical experts. The study code was not revealed until the end of the study, unless a serious adverse event (AE) was reported.
Intervention
All the subjects included in the current study were randomly divided into experimental group and control group by researcher, received standardized treatment [23] + YMOS and standardized treatment + placebo (10 ml for three times/day for 12 weeks). It was found highly essential to take other medicines at an interval of more than 1 h. According to the status of undergoing standardized treatment in the past, stratified random sampling was carried out. Previously, patients who were treated in accordance with standardization treatment for more than 1 week were directly assigned to the group for screening and randomized distribution. Patients who have not been previously treated in accordance with the standardized treatment plan were treated in accordance with the standardized treatment plan for 1 week (introduction period), and then enrolled for screening and randomized distribution. When a patient had an angina pectoris, one tablet (0.5 mg) of nitroglycerin was taken under the tongue, and the information of the patient's diary card was recorded. One tablet could be repeated every 5 min for each episode until the pain eased. If the pain persists after accumulating 3 tablets for within 15 min, it is essential to seek for medical attention immediately. Both placebo and YMOS may be dispensed by the Central Hospital Pharmacy as a set of boxes at the beginning of each study week. Patients were asked to return the boxes for checking patient compliance. The patients’ treatment prescriptions and conditions were recorded in the CRF. Details of the study procedures are given in Table 1.
Table 1
Study procedures of the trial
|
Study procedures
|
Lead-in period
|
|
Treatment period
|
|
Follow-up period
|
|
Time point
|
-1w±2d
|
0
|
4w±4d
|
8w±4d
|
12w±4d
|
16w±6d
|
20w±6d
|
|
Clinical data
|
√
|
|
|
|
|
|
|
|
Combined use of drugs
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
Medical examination
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
|
Therapeutic evaluation
|
|
|
|
|
|
|
|
|
SAQ
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
CCS
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
NYHA
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
VAS
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
HAMD
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
HAMA
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
Weekly incidence of angina
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
Nitroglycerin stopping rate
|
|
|
√
|
√
|
√
|
√
|
√
|
|
SF-12
|
√
|
|
√
|
√
|
√
|
√
|
√
|
|
Safety indicators
|
|
|
|
|
|
|
|
|
Blood routine examination
|
√
|
|
|
|
√
|
|
|
|
Urine and stool routine examination
|
√
|
|
|
|
√
|
|
|
|
Hepatic and renal function
|
√
|
|
|
|
√
|
|
|
|
Fasting blood glucose and blood lipid
|
√
|
|
|
|
√
|
|
|
|
Coagulation
|
√
|
|
|
|
√
|
|
|
|
Troponin TnI
|
√
|
|
|
|
√
|
|
|
|
Electrocardiogram examination
|
√
|
|
|
|
√
|
|
|
|
Thyroid function examination (when necessary)
|
√
|
|
|
|
√
|
|
|
|
Adverse events records
|
|
|
√
|
√
|
√
|
√
|
√
|
|
Other procedures
|
|
|
|
|
|
|
|
|
Random grouping
|
|
√
|
|
|
|
|
|
|
Distribute research drugs
|
|
√
|
√
|
√
|
|
|
|
|
Distribute nitroglycerin
|
√
|
√
|
√
|
√
|
√
|
√
|
|
|
Issue patient diary card
|
√
|
√
|
√
|
√
|
√
|
√
|
|
|
Recycling of remaining research drugs and kit packaging
|
|
|
√
|
√
|
√
|
√
|
√
|
|
Recovery of remaining nitroglycerin
|
|
√
|
√
|
√
|
√
|
√
|
√
|
|
Recovery of patient diary card
|
|
√
|
√
|
√
|
√
|
√
|
√
|
|
Clinical efficacy judgment
|
|
|
|
|
√
|
|
√
|
|
Note: SAQ Seattle angina questionnaire, HAMA Hamilton anxiety scale, HAMD Hamilton depression scale, CCS Canadian Cardiovascular Society, NYHA New York Heart Association classification, VAS visual analogue scale.
|
The standardized treatment plan must include the following 3 types of drugs (the use of drugs was recorded in the combination mode of medical records): (1) Anti-platelet aggregation drugs: aspirin (75–100 mg, QD), patients, who could not tolerate aspirin, could receive clopidogrel as an alternative therapy. Patients with a previous history of PCI surgery simultaneously received both drugs. (2) Lipid-lowering drugs: statins, such as Attovastatin (10–20 mg, QD) and simvastatin (20–40 mg, QD). (3) Anti-ischemic medications: ①ß-receptor blockers: metoprolol sustained-release tablets (50–200 mg QD) were recommended; ②Similar stable dose of receptor blockers; ③Long-acting nitrates, involving isosorbide mononitrate sustained-release tablets (40–60 mg QD); Calcium antagonists (e.g., amlodipine tablets (5–10 mg QD). In addition, patients with diabetes or hypertension were recommended to take angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) as secondary prophylaxis drugs for stable angina pectoris, including lisinopril (10–20 mg QD) or losartan (50mg QD). Drugs necessary for other diseases could be additionally used, while the record form of combined therapy was filled out. During the trial, it was prohibited to use Western medicines for the treatment of chronic stable angina pectoris except for standardized treatment and nitroglycerin. The combined use of other proprietary Chinese medicines and traditional Chinese medicine was also prohibited during the trial.
Outcome Measures
At baseline (prior to starting either intervention), every 4 weeks after the intervention and every 4 weeks in the follow-up, all the patients were asked to complete SAQ, HAMA, HAMD, CCS, NYHA, VAS, and SF-12, while the frequency of angina-related symptoms per week and the number of nitroglycerin use were recorded in the patient diary card. Besides, all the patients underwent laboratory examinations at baseline and at the 4th week after the intervention. During the follow-up, any registered participants who could not continue the study during the treatment period remained in their randomized group for intention-to-treat (ITT) analysis.
Primary outcomes
The AF in SAQ for 12 weeks was taken as the primary outcome.
Key Secondary Outcome
Changes in HAMA score compared with baseline during 12-week follow-up were noted.
Secondary outcomes
Secondary outcomes were as follows: (1) Reduction rate of HAMA scale score at the 12th week (reduction rate of HAMA score = [(pre-treatment score - post-treatment score)/pre-treatment score] x 100%). A reduction rate of HAMA score > 75% is clinically cure; a reduction rate of 50–75% is markedly effective; a reduction rate of 25–49% is effective; a reduction rate of < 25% is invalid; (2) CCS and NYHA grades; (3) VAS score; (4) HAMD score; (5) AF of weekly angina; (6) Dosage of nitroglycerin; (7) SF-12 score. (8) PL, AS, TS, and DP scores in SAQ.
Safety examination indices
Safety examination indices were as follows: (1) New vascular events; (2) All-cause mortality events; (3) Severe bleeding events (as defined by Global Strategies for Opening Occluded Coronary Arteries (GUSTO) classification); (4) Moderate bleeding events (as defined by GUSTO); (5) Hepatic and renal functions; (6) AEs/serious AEs reported by investigators: any possible adverse reactions/AEs that were observed during clinical study, and recorded truthfully, such as fever, blush, rash, pruritus, diarrhea, dizziness, headache, etc. Pay special attention to the observation and record drug allergy and local irritation (Table 2).
Table 2
Primary outcomes, secondary outcomes and safety examination indices
|
Primary outcomes
|
(1) SAQ Score
(2) HAMA score changes relative to baseline at 12 weeks of follow-up
|
|
Secondary outcomes
|
(1) HAMA scale at the 12th week Score reduction rate
(2) CCS and NYHA grades
(3) Visual analogue scale
(4) HAMD
(5) Attack frequency of weekly angina
(6) Dosage of nitroglycerin
(7) SF-12 Quality of Life Scale
|
|
Safety
examination indices
|
(1) New vascular events
(2) All-cause mortality events
(3) Severe bleeding events (as defined by GUSTO)
(4) Moderate bleeding events (as defined by GUSTO)
(5) Hepatic and renal function evaluation
(6) Adverse events/serious adverse events reported by investigators: any possible adverse reactions/adverse events are closely observed during clinical study, and recorded truthfully, such as fever, blush, rash, pruritus, diarrhea, dizziness, headache, etc. Pay special attention to the observation and record drug allergy and local irritation.
|
| Note: SAQ Seattle angina questionnaire, HAMA Hamilton anxiety scale, HAMD Hamilton depression scale, CCS Canadian Cardiovascular Society, NYHA New York Heart Association classification, VAS visual analogue scale. |
Follow-up protocol
The patients were followed-up at the 4th and 8th weeks after the treatment, and they had to complete the above-mentioned questionnaire and records. Researchers assessed patients’ health condition by inspecting the medical records, which acquired completing the CRF.
Adverse events (AEs)
Although no research has still reported AEs of YMOS, all drugs may have side effects or allergic reactions. Any discomfort or unexpected conditions that occurred during the experiment were taken as AEs into consideration, regardless of whether they were related to research interventions. All the AEs were recorded in detail in the CRF. Serious AEs were immediately reported to the principal investigator, including death, life-threatening or severe or permanent disability. The Ethics Committee assessed whether the AEs were associated with the experimental drugs.
Data management
To ensure strict adherence to the research protocol and familiarity with the trial management process, the main research members attempted to establish an independent committee in the beginning of the study. Data management personnel of the committee were qualified, received effective training, and were familiar with the functions of data management. The data management of this clinical trial, including the confirmation of all subjects (being able to effectively check different records, such as medical records and hospital records), all the signed written informed consent forms, all medical records, detailed records related to drug distribution, was conducted. When the patients were recruited into research project, researchers collected their demographic and baseline characteristics by using standard CRF. Data were first processed. The results of questionnaires, clinical outcomes, AEs, and the reasons for the patients’ withdrawal from the study were detailed in the CRFs. To reduce errors, CRF data were assessed independently by two researchers. They checked each other's input values, and only consistent data were stored in the database. Paper files were kept in a locked file cabinet in the hospital, while electronic files, laboratory test results, were stored on a password-protected computer and could only be reached by the principal investigator.
Determination of the sample size
The present study was designed as a prospective, multicenter, randomized, double-blind, placebo-controlled trial to verify the therapeutic effects of YMOS on patients with chest pain. The calculation of sample size firstly aimed to main evaluation outcomes, including actual SAQ scores at follow-up (for 12-week). Based on the results of previous research and related literature, it was assumed that SAQ score in the experimental group was increased by at least 10 points compared with that in the control group, and the standard deviation (SD) of SAQ score was conservatively estimated to be ± 25. Besides, 320 patients were scheduled to be included in the trial on the premise that the sample size was 5% on both sides of the statistical significance level and 10% off rate was taken into account. Additionally, 90% assurance was provided to prove that the effects in the experimental group were superior than those in the control group.
Moreover, according to the literature and clinical experience, it was estimated that the difference between the experimental group and the control group in HAMA score was equal to 1 (the average HAMA score in the experimental group was 1 point lower than that in the control group), and the SD of changing the score point was conservatively estimated to be ± 3. The significance level of the study test was 5% on both sides. Considering 10% drop off rate, 80% assurance rate was provided to prove that the experimental group outperformed the control group in the reduction of HAMA score.
Overall, to meet the evaluation needs of both the main outcomes and the key secondary outcomes, the enrollment size of the study was finally set to 320 cases, who were randomly assigned to two groups at ratio of 1:1 (n = 160 patients for each group).
Statistical analysis
The statistical analysis was conducted in accordance with the principle of ITT. All randomized patients were included in the final analysis (whether against the protocol or not), and the key efficacy outcomes were simultaneously assessed on the basis of the population’s compliance with the therapeutic plan.
For descriptive analysis, quantitative indices were expressed as mean ± SD, and qualitative indices were presented as frequency and/or percentage. For making inter-group comparison, a parametric or a non-parametric method was employed for analysis of the quantitative indices according to their normality status, while chi-square or the Fisher’s exact test was used for qualitative indices based on the expected frequency.
For the analysis of ou, the analysis of covariance (ANCOVA) model adjusted for baseline and central effects was utilized to calculate the difference in the score between the two groups (or change in the score relative to baseline), and corresponding 95% confidence interval (95% CI) was given. The secondary outcomes were analyzed by using the same statistical analysis method. Significance level for all statistical tests was 5%, and statistical analysis was undertaken by using SAS 9.4 software (SAS Institute, Cary, NC, USA).