This study is multicenter, randomized, double-blind, placebo-controlled, clinical trial. A total of 260 eligible participants will be enrolled. The participants will be randomized assigned in an equal ratio to groups receiving either NXT or placebo for 12 weeks. After a 2-week run-in period, they will receive either NXT or placebo (3 pills, 3 times daily) for 12 weeks. Efficacy and safety data will be obtained during the treatment. A flow chart of the trial is illustrated in Figure 1.
Ethics
This trial has been registered in the China Clinical Trial Registry (ChiCTR2000034871). This trial is reported in accordance with the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines[10,11].Ethical approval has been obtained from the Ethics Committee of the Guangdong Provincial Hospital of Traditional Chinese Medicine (BF2020-152-01). Participants who meet all of the inclusion criteria will be asked to sign an informed consent before the trial that will contain the details about the trial such as inclusion criteria, exclusion criteria, therapeutic interventions, scheduling, trial benefits, and possible risks of this trial. Participants have the right to desert throughout the trial.
Participants and recruitment
Participants will be recruited through Internet advertisement and posters in the community and selected hospitals. A total of 240 eligible participants will be recruited in the following six hospitals: (1) Guangdong Provincial Hospital of Traditional Chinese Medicine, (2) The First Affiliated Hospital of Sun Yat-sen University, (3) Zhujiang Hospital, (4) Southern Medical University Hospital, (5) Shenzhen Longgang District Hospital of Traditional Chinese Medicine and (6) Yangjiang People’s Hospital. The first center will recruit 80 patients, with 32 for each of the remaining centers.
Eligibility criteria
Eligible participants are those who fulfill all of the listed inclusion criteria and do not have any of the exclusion criteria.
Diagnostic criteria
The diagnostic criteria for CHD
(1)A history of myocardial infarction, with or without revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting) treatment;
(2) Coronary angiography confirmation or computed tomography coronary angiography confirmation of stenosis greater than 50% of at least 1 major branch of the coronary artery luminal diameter, with or without revascularization;
(3) Noninvasive imaging stress test diagnostic of CHD.
A patient meeting at least one of the above criteria is considered to be diagnosed with CHD.
The diagnostic criteria for CSA
Diagnostic criteria for CSA were determined according to the Chinese Medical Association's 2007 Guidelines for the Diagnosis and Treatment of Chronic Stable Angina[12], 2013 ESC guidelines on the management of stable coronary artery disease[13],The classification of angina referred to the Canadian Cardiovascular Society (CSS) Functional Classification of Angina.
Inclusion criteria
(1)A diagnosis of CHD and the provision of exact imaging information (coronary angiography or computed tomography coronary angiography confirmation of stenosis greater than 50% of at least one major branch of the coronary artery luminal diameter, or nuclear perfusion scan diagnosed as CAD). CCS classification of angina grade II
(2)The onset of angina pectoris ≥3 months previous and the frequency of angina attack≥twice a week
(3)Age between 35 and 75, regardless of gender
(4)Signed informed consent by participants or surrogates
Exclusion criteria
(1)Uncontrolled or mismanaged blood pressure and blood glucose. Severe cardiopulmonary insufficiency, or severe arrhythmia (rapid atrial fibrillation and flutter, paroxysmal ventricular tachycardia second degree and greater than a second degree atrioventricular (AV) block). Acute MI in the past 2 months, or has undergone coronary revascularization in the past 12 months.
(2)Renal dysfunction, male serum creatinine > 2.5 mg/ dl (> 220 μmol/L) or female serum creatinine > 2.0 mg/ dl (> 175 μmol/L). Serious liver disease(expression of aminotransferase (ALT) and aspartate aminotransferase (AST) of 1.5 times higher than the normal upper limit).
(3)Factors that precluded satisfactory interpretation of the electrocardiogram (ECG) (e.g. digoxin therapy, left bundle branch block, implanted with pacemaker, left ventricular hypertrophy, or electrolyte disturbance).
(4)Complications with a serious bone joint disease or other comorbidities that may interfere with ability to perform required ETT.
(5)Patients planning to undergo coronary revascularization during the study period.
(6)Patients who might be allergic or are known to be allergic to ingredients of the study drug.
(7)pregnant, pregnancy planners or lactating women.
(8)Patients who are allergic to NXT capsule.
(9)Substance abuse, alcohol and drug dependence in the last 2 years.
(10)Patients who participated in other clinical drug trials within 1 month.
Withdrawal criteria
The rejection criteria include the following:
(1)Patients who experience serious complications or rapid deterioration of the condition throughout the trial.
(2)Serious adverse events (AEs) occurring, which would result in treatment being stopped according to the doctors’ decision.
(3)Participants with vital deviations in the implementation of the study, such as poor compliance and difficulty in evaluating drug effects
(4)Patients who quit this clinical trial voluntarily
Sample size
The sample size was estimated to treat the symptoms of angina pectoris for 12 weeks as the main effect index according to the statistical requirements. According to the literature, the total effective rate of basic treatment + placebo was 67.5%, and the total effective rate of basic treatment + test drug was estimated to be 84.3. %, let α = 0.05, 1-β = 0.2, according to the test group: control group = 1:1 set, after calculation, the minimum sample size that meets the statistical requirements is 98.4 cases per group, considering no more than 20% the shedding rate was 120 cases in each group, a total of 240 cases.
Randomization and blinding
A total of 240 participants will be randomized in a 1:1 ratio assigned to the NXT group and the control group by the method of using 240 opaque envelopes. Half of them are labeled with NXT group, and half of them are control group. After all the envelopes have been sealed, they will be mixed evenly and distributed to each research center. When a sub-center accepts an eligible patient, the baseline information such as the subject’s hospital ID number, name, age and gender will be recorded. All participants, investigators, and attending physicians will be blinded to the treatment assignments until the research is finished. Only drug administrators and dispensing nurses can open the envelope to check the group allocation and perform the interventions according to the instructions of this study, All investigators, outcome assessors and data analysts will be blinded to collect and summarize which is only based on a subject’s baseline information until the completion of the visit and analysis.
Interventions
Eligible patients will be randomly allocated to a treatment group or a control group in an equal ratio. In order to ensure the safety of participants, enrolled patients in both control group and treatment group will receive standard conventional therapies, under the Chinese Guidelines for the Diagnosis and Treatment of CSA (2007) [14]. Routine medications in the trial as follows:
(1)antiplatelet agents: aspirin (75–100 mg, once per day) or clopidogrel;
(2)Lipid-lowering agents (statins): atorvastatin (10–20 mg, once per day) or simvastatin (20–40 mg, once per day).
(3)Anti-angina agents: β-blockers (metoprolol 50–200 mg, once per day, or analogous agents); long-acting nitrates (isosorbide mononitrate 40–60 mg, once per day); or calcium channel blockers (amlodipine 5–20 mg, once per day).
On the basis of conventional western medicine treatment, the experimental group will receive NXT capsule for 12 weeks,3 pills/day, taken orally, after meals; while the control group will receive placebo capsule, the placebo capsule simulator is similar to the NXT capsule, with a comparable appearance, the primary content of the placebo capsule is starch, the control group will receive NXT capsule simulator for 12 weeks,3 pills/day, taken orally, after meals,
Efficacy assessment
Primary outcome: The primary outcomes of this study include changes of curative effect of angina pectoris symptoms: The number of angina attacks, degree of pain, duration, as well as the dosage of nitroglycerin are used as indicators for scoring. Score ranges from 0 to 15, with higher score indicate more severe angina. (Table 2)
Table 2 Measurement items and points of data capture.
Study phase
|
run-in period
|
intervention period
|
|
Time
|
Visit 1
|
Visit 2
|
Visit3
|
Visit4
|
Visit5
|
|
-14±2days
|
-4~0days
|
4weeks±4days
|
8weeks ±4days
|
12weeks±4days
|
Baseline data collection
|
|
|
|
|
|
Informed consent
|
´
|
|
|
|
|
Demographic data
|
´
|
|
|
|
|
Concomitant disease and treatment
|
´
|
´
|
´
|
´
|
´
|
Inclusion/exclusion criteria
|
|
´
|
|
|
|
Screen index
|
|
|
|
|
|
Urinary pregnancy test
|
´
|
|
|
|
|
Safety evaluation
|
|
|
|
|
|
Vital signs
|
´
|
´
|
´
|
´
|
´
|
Blood and urine routine, stool routine+occult blood, fasting blood glucose
|
|
´
|
|
|
´
|
Liver funtion(ALT,AST,TBIL)and renal function test(BUN,Cr)
|
|
´
|
|
|
´
|
Coagulation function test
|
|
´
|
|
|
´
|
Blood lipid level
|
|
´
|
|
|
´
|
ECG
|
´
|
´
|
|
|
´
|
Efficiency evaluation
|
|
|
|
|
|
TCM syndrome score
|
´
|
´
|
|
|
´
|
Scores of angina symptoms
|
´
|
´
|
´
|
´
|
´
|
CCS angina classification
|
´
|
´
|
´
|
´
|
´
|
Number of episodes of AP per week
|
´
|
´
|
´
|
´
|
´
|
Nitroglycerin consumption
|
´
|
´
|
´
|
´
|
´
|
Score of seattle angina scale
|
´
|
´
|
´
|
´
|
´
|
Homocysteine
|
|
´
|
|
|
´
|
Other work
|
|
|
|
|
´
|
Random grouping
|
|
´
|
|
|
|
Dispense drug
|
´
|
´
|
´
|
´
|
|
Recovery drug
|
|
´
|
´
|
´
|
´
|
Aes records
|
|
´
|
´
|
´
|
´
|
Evaluate the clinical efficacy and adherence
|
|
|
|
|
´
|
Secondary outcomes
(1)Therapeutic effect of TCM syndromes: The TCM syndromes scoring system used in this study will follow the guidelines of clinical research on the treatment of coronary heart disease (chest pain) with new Chinese medicine , in which all symptom and sign scores are graded (Table 3). The symptoms of CSA include: chest pain, chest tightness, breathlessness, palpitations, mental fatigue, aversion to cold, and cold limbs, lumbar and knee soreness, spontaneous sweating, and insomnia. The score ranges from 0 to 27. 0 indicate asymptomatic, 1 for mild, 2 for moderate and 3 points for severe. The higher the score, the severe it is.
Table 3 Symptom and sign scores
Symptom or sign
|
score
|
|
Asymptomatic(0)
|
Mild(1)
|
Moderate(2)
|
Severe(3)
|
Chest pain(angina)
|
none
|
Occasionally,
self-medication
|
Frequently
obvious when moving
|
Sustained,
can’t insist on work
|
Breathless
|
|
|
|
|
Palpitations
|
|
|
|
|
Chest tightness
|
|
|
|
|
Mental fatigue
|
|
|
|
|
Aversion to cold and cold limbs
|
|
|
Frequently
Need to add clothes
|
Severe
Can not ease when adding clothes
|
Lumber and knee soreness
|
|
|
|
|
Spontaneous sweating
|
|
Occasionally,
Aggravation when moving
|
Frequently
When a little activity
|
Severe,
When no movement
|
insomnia
|
|
Mild
Difficult to sleep, but hardly affected
|
Moderate
Cannot sleep for hours
|
Severe,
cannot sleep all night
|
(2)Grading changes of severity of angina pectoris: According to CCS Angina Severity Classification Standard. I: General physical activity does not cause angina pectoris, angina with strenuous, rapid, or prolonged exertion. II: Slight limitation of ordinary activity, angina when walking upstairs briskly, or walking on a cold or windy day. III: marked limitation, angina when walking at anormal pace up flight of stairs, or walking 1-2 blocks distance. IV: Angina on minimal exertion or even at rest.
(3) Frequency of angina pectoris episodes per week.
(4) The dosage of Nitroglycerin;
(5) Seattle Angina Questionnaire (SAQ): The SAQ quantifies patients’ physical limitations caused by angina, the frequency of and recent changes in their symptoms, their satisfaction with treatment, and the degree to which they perceive their disease to affect their quality of life. Each scale is transformed to a score of 0 to 100, where higher scores indicate better function (eg, less physical limitation, less angina, and better quality of life).
(6) Incidence of cardiovascular event during the 12 weeks such as developing into unstable angina, acute myocardial infarction and even death.
Safety outcomes
Safety outcomes includes vital signs (temperature, heart rate, breathing, and blood pressure after 10 min of rest), coagulation function test, liver and renal function, routine blood tests, urine and stool tests, and electrocardiograph (ECG)
Management and statistical analysis
Statistical analysis will be performed by the Drug Clinical Research Center of Guangzhou University of TCM, 2 independent trained data administrators will read the CRFs and record the data on the EpiData 3.1 software, the study monitor will cross-check the electronic case report forms against the data administrators’ records on the purpose of ensuring the accuracy and reliability of the data. The database will be locked after blinding state data review and the statistical analysis can be performed only with the main investigator, sponsor, and statistical analyst.
Statistical analysis will be performed by a statistician blinded to the whole trial process using SAS 9.3 statistical software packages. The full analysis set (FAS) is the primary analysis set, in which one group receive NXT capsule treatment and the other placebo treatment. For the evaluation of curative effect in this trial, the per-protocol set (PPS) was used. Efficacy assessment will be performed through FAS and PPS. Safety evaluation will also be conducted. Continuous variables will be described using means and standard deviations and tested with Student’s t tests. Categorical variables are expressed in frequency counts and percentages and tested with chi-squared tests. More details will be described in a formal statistical analysis plan. Baseline balance between groups will be performed by a chi-square test or analysis of covariance (ANOVA). All collected data will be processed by professional statisticians using SAS 9.3 software; a two-sided P value of < 0.05 is considered statistically significant.