Ignite Creation Date:
2024-05-06 @ 7:41 PM
Last Modification Date:
2024-10-26 @ 3:11 PM
Study NCT ID:
NCT06092736
Status:
RECRUITING
Last Update Posted:
2023-10-23
First Post:
2023-09-24
Brief Title:
Microvascular Angina Intervention With Compound Danshen Dripping Pill MAIDS
Sponsor:
Qilu Hospital of Shandong University
Organization:
Qilu Hospital of Shandong University
Study Overview
Official Title:
Microvascular Angina Intervention With Compound Danshen Dripping Pill MAIDS
Status:
RECRUITING
Status Verified Date:
2023-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MAIDS
Brief Summary:
Coronary microvascular disease MVD refers to exertional angina or myocardial ischemia caused by abnormal structure andor function of precoronary arterioles and arterioles under the action of various pathogenic factors The symptoms of patients with coronary microvascular disease are mainly exertion-related chest pain episodes
The basic and clinical researches of the traditional Chinese medicine compound Danshen dropping pills have found that it can improve vascular endothelial function and relieve angina pectoris and it is widely used in clinical practice
This is a randomized double-blind placebo-controlled multicenter clinical study of Compound Danshen Dropping Pills and blank control in patients with microvascular angina pectoris
The experimental drug and control drug of this clinical trial were selected according to the ratio of 11 patients were enrolled in the pre-experiment
After the selected patients signed the informed consent they were divided into a compound Danshen dripping pill treatment group and a placebo group according to a random double-blind placebo-controlled method Dosage of Compound Danshen Dropping Pills or placebo 20 capsules each time 3 times a day for a total of 6 months Follow-up was performed every 2 months for a total of 6 months
Primary study endpoints is the difference of the left anterior descending coronary flow reserve CFR measured by ultrasound between the two groups compared with the baseline
Secondary study endpoint include the Number of angina attacks per week the time of angina pectoris and the time of ischemic ST segment depression in exercise test
The basic and clinical researches of the traditional Chinese medicine compound Danshen dropping pills have found that it can improve vascular endothelial function and relieve angina pectoris and it is widely used in clinical practice
This is a randomized double-blind placebo-controlled multicenter clinical study of Compound Danshen Dropping Pills and blank control in patients with microvascular angina pectoris
The experimental drug and control drug of this clinical trial were selected according to the ratio of 11 patients were enrolled in the pre-experiment
After the selected patients signed the informed consent they were divided into a compound Danshen dripping pill treatment group and a placebo group according to a random double-blind placebo-controlled method Dosage of Compound Danshen Dropping Pills or placebo 20 capsules each time 3 times a day for a total of 6 months Follow-up was performed every 2 months for a total of 6 months
Primary study endpoints is the difference of the left anterior descending coronary flow reserve CFR measured by ultrasound between the two groups compared with the baseline
Secondary study endpoint include the Number of angina attacks per week the time of angina pectoris and the time of ischemic ST segment depression in exercise test
Detailed Description:
1 Research Background Coronary microvascular disease MVD is a clinical syndrome refers to laboratory evidence of exertional angina or myocardial ischemia caused by structural andor functional abnormalities of precoronary arterioles and arterioles under the influence of multiple pathogenic factors The main symptoms of patients with coronary microvascular disease are exertion-related chest pain attacks It is difficult to distinguish patients with coronary microvascular disease from patients with severe coronary stenosis based on symptoms alone However the following clinical characteristics suggest that patients have coronary microvascular disease It is more likely First of all it is more common in women accounting for about 56-79 of patients with coronary microvascular disease However most female patients with coronary microvascular disease have their first symptoms after menopause which is no different from traditional female coronary heart disease patients Secondly most of the symptoms are induced by exertion but it is not uncommon to have patients with silent chest pain There are fewer patients with coronary microvascular disease who simply present with silent chest pain Impaired coronary dilatation increased sympathetic stimulation and sensitivity and exercise-mediated coronary constriction can lead to the development of coronary microvascular dysfunction and reduced coronary flow reserve Long-term recurrent angina pectoris attacks affect the patients quality of life Patients with significantly reduced coronary blood flow reserve or myocardial perfusion reserve especially female patients may have a higher incidence of adverse cardiovascular events
Regarding drug treatment traditional anti-ischemic treatment methods are currently recommended including β- blockers calcium ion antagonists and nitrates If symptoms persist other drugs include angiotensin-converting enzyme inhibitors statins ivabradine ranolazine and estrogen drugs However there is no specific clinical drug treatment Basic and clinical studies of the traditional Chinese medicine Compound Danshen Dripping Pill have found that it can improve vascular endothelial function and relieve angina pectoris and is widely used in clinical practice However its effect on coronary reserve function and angina pectoris in coronary microvascular disease needs further clinical research to confirm
2 Study drug The main drug studied in this study is Compound Danshen Dripping Pill Compound Danshen Dripping Pills Compound Danshen Dripping Pills produced by Tasly Holding Group Co Ltd is a compound traditional Chinese medicine preparation composed of Salvia miltiorrhiza Panax notoginseng and Borneol In 1994 it was approved as a drug for the treatment of coronary heart disease and angina pectoris It has good clinical efficacy and has It has the characteristics of fast onset low toxicity small adverse reactions and high safety
The active ingredients of compound Danshen dripping pills are water-soluble phenolic acids such as salvia miltiorrhiza and Panax notoginseng saponins During the preparation process borneol and auxiliary materials are added and a highly dispersed solid dispersion is made through a specific process The active ingredients of the drug have high purity are evenly dispersed and can be quickly absorbed through the mucous membrane The dripping pills have good solid dispersion effect The principle is to melt the drug ingredients and matrix into a solid solution and the active ingredients of the drug are in the molecular state or in extremely fine form The crystalline state is highly uniformly dispersed in the matrix with fast drug dissolution and higher bioavailability It can be taken sublingually and can quickly relieve angina pectoris and chest tightness
Compound Danshen Dripping Pill has achieved a full-process quality control method from medicinal materials intermediates to preparations GAP-GEP-GMP through the multi-factor fingerprint quality control system of compound oral Chinese medicine preparations further improving the full-process quality control system of Compound Danshen Dripping Pill after testing and analyzing nearly 200 batches of Compound Salvia Miltiorrhizae Dropping Pills Extract and Compound Salvia Miltiorrhizae Dropping Pills the similarity is over 90 and the quality of the products is stable between batches It has been confirmed through the toxicology study of Compound Danshen Dripping Pill and the clinical use of hundreds of millions of people it has no toxicity few adverse reactions and is safe and reliable for long-term use
As a Chinese patent medicine for the treatment of stable angina pectoris Compound Danshen Dripping Pill are included in Category A of the 2018 National Essential Drugs Catalog and the 2019 National Basic Medical Insurance Work Injury Insurance and Maternity Insurance Drug Catalogue Under the name of Compound Danshen Dripping Pill it has been written into more than 20 national medical guidelines or consensus 15 of which involve the cardiovascular field including Guidelines for Rational Medication in Coronary Heart Disease 2nd Edition Acute Myocardial Medication Guidelines for the Diagnosis and Treatment of Infarction by Integrated Traditional Chinese and Western Medicine Chinese Expert Recommendations on the Clinical Application of Compound Danshen Dripping Pill Expert Consensus on the Diagnosis and Treatment of Atherosclerosis by Integrated Traditional Chinese and Western Medicine etc
In terms of international evidence-based research large-sample randomized double-blind placebo-controlled RCT studies were used and 1004 patients were included in phase III clinical studies at 127 centers in 9 countriesregions around the world indicating that the US FDA-Phase III The main clinical efficacy indicators significantly increase the patients exercise flat time and improve exercise tolerance Compared with the increase time of exercise oxygen tolerance of similar drugs Compound Danshen Dripping Pill has obvious advantages Secondary efficacy indicators effectively reduce the number of angina attacks per week and significantly reduce the weekly nitroglycerin dosage
In terms of domestic evidence-based research 1011 studies on Compound Danshen Dripping Pill for the treatment of stable angina 16 Meta-analyses with a total enrollment of more than 100000 people 137 studies on the treatment of peri-PCI thrombolysis period the total number of participants exceeds 10000 there are 36 studies on Compound Danshen Dripping Pill improving coronary microcirculation disorders filling the gap in Western medicine treatment
Systematic study of Compound Danshen Dripping Pill combined with Western medicine in the treatment of coronary heart disease angina pectoris 21 articles were included with a total number of cases of 2229 Compound Danshen Dripping Pill combined with Western medicine can benefit patients with coronary heart disease angina pectoris especially in improving clinical symptoms and electrocardiogram It has outstanding effects on ischemic state and regulating cholesterol levels
A meta-analysis based on PubMed EMBASE CNKI and Wanfang databases studied the efficacy of aspirin combined with Compound Danshen Dripping Pill in the treatment of coronary heart disease The analysis included 14 randomized controlled trials with a total of 1367 patients The results showed that the combination Compared with aspirin alone the drug can achieve more significant therapeutic effects in relieving angina pectoris symptoms and lowering blood lipids Lu Yuhong et al randomly divided 128 patients with coronary heart disease into groups The control group took oral aspirin on the basis of conventional treatment and the observation group took Danshen Dropping Pills on the basis of conventional treatment After 2 months the total clinical effective rate of the patients in the observation group was significantly higher than Control group Compared with before treatment the maximum platelet aggregation rate and thromboxane B2 levels of the two groups of patients were significantly reduced and the decrease in the observation group was more obvious than that in the control group The Guidelines for the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine in Acute Myocardial Infarction led by Academicians Chen Keji Academician Ge Junbo and Professor Zhang Minzhou were formulated in conjunction with experts in the fields of traditional Chinese medicine Western medicine integrated traditional Chinese and Western medicine and methodology across the country The guideline clearly states that Compound Danshen Dripping Pill are recommended for the treatment of acute myocardial infarction The recommendation level is the highest in the guideline Compound Danshen Dripping Pill can relieve chest pain reduce the patients risk of cardiac death and improve the patients cardiac function and the role of quality of life
3 Research purpose A randomized double-blind placebo-controlled multi-center clinical study of Compound Danshen Dripping Pill and blank control was conducted in patients with microvascular angina pectoris
4 research design 41 Study title and registration The Chinese name of this project is Microvascular Angina Intervention with Compound Danshen Dripping Pill English name Microvascular Angina Intervention with Compound Danshen Dripping Pill Referred to as MAIDS Study
42 Research design Randomized double-blind placebo parallel-controlled multi-center clinical study
4 3 dosing regimens double-blind single simulation
1 Placebo group Placebo the appearance is the same as Compound Danshen Dripping Pill main ingredient starch Production unit Tianjin Tasly Co Ltd taken orally after meals 3 times a day 20 pills each time
2 Treatment group Compound Danshen Dripping Pill Tianjin Tasly Co Ltd taken orally after meals 3 times a day 20 pills each time
Note The batch number on the drug packaging is unified as 161299 5 Research objects 51 Source of patients patients with chest pain who had no obvious coronary artery stenosis on coronary angiography or coronary CT examination were admitted to the hospital outpatient clinics and wards
52Selection criteria _
1 With typical symptoms of exertional angina
2 Coronary CTA or angiography with normal coronary artery or 50 stenosis or 50 residual coronary stenosis after revascularization
3 Ischemic downward shift of the ST segment is found in the electrocardiogram at rest or during exercise stress horizontal or downsloping downward shift behind the J point 01mv lasting 008s
4 Transthoracic ultrasound before and after intravenous adenosine injection to check the anterior descending coronary artery blood flow reserve test CFR 25
5 The patient agreed to participate in this study 53 Exclusion criteria 1 Aged less than 30 years old or older than 75 years old 2 Have a history of carotid endarterectomy or stent implantation and have a history of stroke 3 Myocarditis pericardial disease valvular disease and cardiomyopathy 4 Difficult-to-control diabetes fasting blood glucose 70 mmolL 5 Uncontrollable hypertension SBP150 mmHg andor DBP90 mmHg 6 Familial hypercholesterolemia 7 Takayasu arteritis 8 Those who are pregnant or lactating or those who intend to have a child within one year or those who have not taken effective contraceptive measures during the childbearing age 9 Abnormal liver function serum GPT level exceeds 30 times the upper limit of normal value or abnormal renal function serum creatinine level exceeds 2 mgdl 10 Other clinically significant respiratory digestive blood infection immune endocrine neuropsychiatric tumor diseases etc which may cause serious danger to patients 11 Take K channel openers and traditional Chinese medicine preparations that activate blood circulation and remove blood stasis to improve microcirculation 12 Those allergic to intra-arterial injection of contrast media blood and blood products 13 Patients who are participating in other clinical studies
6 Research methods 61Sample size The experimental drugs and control drugs in this clinical trial will be selected according to the number of cases in a ratio of 11 100 patients were enrolled in the preliminary experiment
62 Random grouping The randomization method adopts the central randomization method The central randomization system uses DAS211 software to generate random numbers 00 1 -100 and drug packaging numbers B ZH001-100 The random numbers and drug packaging numbers are separated in the system The researcher passes the Apply to the system to obtain the drug packaging number for the subject The random number and drug packaging number of the same subject are different but their corresponding treatment plans are consistent within the system
63 Research process After signing the informed consent form the selected patients were divided into the Compound Danshen Dripping Pill treatment group and the placebo group according to a random double-blind placebo-controlled method Dosage of Compound Danshen Dripping Pill or placebo 3 times a day 20 pills each time for a total of 6 months Follow-up visits were conducted every 2 months and the follow-up period was 6 months in total
64 Screening Phase
1 CTA or CAG examination Coronary artery CTA or angiography examination shows that the coronary arteries are normal or stenotic 50 and coronary epicardial vasospasm is excluded
2 Electrocardiogram Resting or exercise stress test shows ischemic downward shift of ST segment horizontal or downward shift behind J point 01mv lasting 008s
3 Laboratory tests Fasting for more than 6 hours blood routine urine routine fasting blood glucose alanine aminotransferase aspartate aminotransferase troponin serum creatine phosphokinase urea nitrogen creatinine plasma total cholesterol triglycerides hypoglycemia The existing data on density lipoprotein cholesterol high-density lipoprotein cholesterol high-sensitivity C-reactive protein and prothrombin time during the screening phase can no longer be reviewed
4 Echocardiogram
After signing the informed consent form the following inspections will be performed See Appendix 1 for inspection methods
1 Routine ultrasound examination two- dimensional dynamic images of left ventricular parasternal long axis apical four-chamber apical two-chamber apical long axis and left ventricular apex level papillary muscle level and mitral valve level short-axis sections At the same time pulse wave Doppler was used to obtain the diastolic mitral valve orifice blood flow spectrum and tissue Doppler was used to obtain the mitral valve annular motion spectrum See Appendix 1 for details
2 Acoustic contrast adenosine test First observe the distal left anterior descending coronary artery under color Doppler guidance measure the blood flow velocity with pulsed Doppler ultrasound and then administer the contrast agent SonoVue add 85ml sterile saline to one bottle bolus injection followed by slowly injecting 5 ml of normal saline over 20 seconds and measuring the blood flow velocity of the distal left anterior descending coronary artery again Finally adenosine 140 µgkg -1 min -1 was given for 6 minutes by continuous intravenous micropump injection During the injection process the coronary blood flow velocity was monitored Pulse Doppler ultrasound measured the maximum coronary blood flow velocity in the distal left anterior descending artery This could be repeated at the same time Acoustic contrast enhances spectral signals
3 The adenosine test simultaneously records a 12-lead electrocardiogram
4 After recording the coronary blood flow in the contrast-enhanced ultrasound examination the two-dimensional short-axis sections of the left ventricular parasternal long axis apical four- chamber heart apical two-chamber heart apical long axis and left ventricular apex level papillary muscle level and mitral valve level were recorded dynamic images
65 Enrollment and follow-up phase
1 Case grouping 100 patients were selected and randomly divided into Compound Danshen Dripping Pill group and control group 50 cases each Compound Danshen Dripping Pill 20 pills three times a day Placebo 20 pills three times a day
2 Follow-up observation Follow-up observations were conducted at 2 months 4 months and 6 months after inclusion including clinical conditions laboratory examinations and ultrasound examinations Safety assessment
7 Efficacy evaluation 71 Main observation indicators Difference in left anterior descending coronary flow reserve CFR measured by ultrasound at 6 months compared with baseline
72 Secondary observation indicators
1 Difference in left anterior descending coronary flow reserve CFR measured by ultrasound at 2 months and 4 months compared with baseline
2 Number of angina attacks per week
3 The time when angina pectoris occurs in exercise test 4 The time when ischemic ST segment depression occurs during exercise testing
8Safety assessment Including clinical adverse reactions laboratory indicators etc 9 Adverse event observation and reporting 91Definition of Adverse Events Adverse events refer to any adverse medical event that occurs to a patient in this clinical trial from the time the patient signs the informed consent form and is selected to participate in the trial to the last follow-up visit regardless of whether this event is causally related to the above-mentioned drugs
NOTE An adverse reaction may be any discomfort and unconscious signs including abnormal laboratory test results symptoms or disease new or worsening related to the medication
Events that meet the definition of adverse events include
Exacerbation of an existing chronic or intermittent disease including increased frequency andor intensity
A disease that is newly detected or diagnosed after taking the investigational drug even though it may have been present before the trial began
Signs symptoms or clinical sequelae suspected of being caused by an interaction
Signs symptoms or clinical sequelae caused by suspected overdose of the investigational drug or concomitant medication overdose itself is not an adverse event serious adverse event
Lack of efficacy or failure to achieve the expected pharmacological effect itself is not reported as an adverse event or serious adverse event However signs symptoms andor clinical sequelae due to lack of efficacy will also be reported as adverse events or serious adverse events if they meet the definition of an adverse event or serious adverse event
Events that do not meet the definition of an adverse event include
Medical or surgical procedure eg endoscopy appendectomy the event leading up to the procedure is an adverse event
Situations in which adverse medical events would not occur social security and or admission facilitation
There was no worsening of pre-existing diseases or conditions that were present or detected at the start of the trial only expected day-to-day fluctuations
disease being studied or the expected progression signs or symptoms of the disease being studied Unless the situation is more serious than expected
Definition of serious adverse event serious adverse event is an adverse event that can occur at any dose and will
cause death
threatening life Note Life-threatening means that the subject is in danger of death when the event occurs not that death could theoretically result if the event were more serious
Requires hospitalization or prolonged hospitalization Note Typically hospitalization refers to a subject staying in the hospital or emergency room usually at least overnight to receive observation andor treatment that cannot be completed in the doctors office or outpatient clinic Complications that occur during hospitalization are considered adverse events An event is classified as a serious adverse event if the complication prolongs hospitalization or meets the criteria for any other serious adverse event When it cannot be determined whether hospitalization occurred or was necessary it will be treated as a serious adverse event
Elective hospitalization that does not worsen a pre-existing condition compared with baseline is not an adverse event
Causes disability or affects the ability to work and live Note Disability refers to a substantial impairment of an individuals ability to carry out normal life It does not include discomforts of little clinical significance such as common headaches nausea vomiting diarrhea influenza and accidental trauma such as sprained ankles which may affect the quality of daily life but will not constitute a substantial disruption
Cause congenital malformations In other cases medical or scientific judgment should determine whether adverse event reporting is appropriate For example some important medical events may not be immediately life-threatening leading to death or hospitalization but may harm subjects or require drug or surgical intervention to avoid the serious adverse events listed above These events should also be considered serious adverse events such as invasive or malignant cancer allergic bronchospasm requiring close monitoring in the emergency room or at home hematologic cachexia or convulsions that do not result in hospitalization drug dependence or drug abuse
92 Adverse drug reactions Definition Refers to harmful reactions that occur under normal usage and dosage of qualified drugs and have nothing to do with the purpose of medication
Causal judgment indicators for adverse reaction judgment
Item 1 Is there a reasonable sequence between the time of starting medication and the time when the suspicion appears Item 2 Whether the suspected adverse reaction conforms to the known adverse reaction type of the drug Item 3 Whether the suspected adverse reaction can be explained by the patients pathological condition concomitant medications concomitant therapies or previous therapies Item 4 After stopping the drug or reducing the dose whether the suspected adverse reactions are reduced or disappeared Item 5 Whether the same reaction reappears after using the suspected drug again
Causality judgment criteria Judgment based on the order of the above five judgment indicators
It is up to the investigator to evaluate possible associations between adverse events trial drugs and concomitant medications according to the table below
Adverse reaction cause and effect judgment table
critical result Judgment index Project 1 Project 2 Project 3 Item 4 Item 5 Definitely related - probably related - may be relevant suspicious - Impossibly related - - -
Explanation Affirmation - Negation Difficult to affirm or deny The situation is unknown
1Based on the table above determine the relationship between the following grade 5 adverse events and the drug
1 Definitely related 2 Probably related 3 Possibly related 4 Suspicious 5 Impossibly related
2 The incidence rate of adverse reactions is calculated using the total number of 1 2 3 4 cases as the numerator and all selected cases that can be evaluated for adverse reactions as the denominator
93Recording of adverse events on the basis of comprehensive consideration of comorbidities and concomitant medications their relevance to the experiment should be evaluated The relevance of the drug and documented in detail by the physician
If an adverse event is discovered the observing physician can decide whether to terminate the observation based on the condition Cases of drug discontinuation due to adverse events should be followed up and investigated and the results should be recorded in detail If any abnormality in safety test indicators blood urine stool routine electrocardiogram liver function kidney function occurs during or after treatment the adverse event form should be filled in in a timely manner reviewed at an appropriate time and communicated with the subject A comprehensive analysis will be conducted on the onset treatment etc to determine whether it is related to the experimental drug
94 Handling of serious adverse events For any serious adverse events that occur during the trial including events requiring hospitalization prolonged hospitalization disability affecting work ability endangering life or death causing congenital malformations etc during the clinical trial the researcher shall immediately respond to the patients request In addition to taking emergency measures the subject must also immediately report to the ethics committee of the National Drug Clinical Trial Institution of Shandong University Qilu Hospital and the main research unit Tianjin Tasly Co Ltd the unit responsible for the research The content of the report of serious adverse events should include patients name random number length of study participation start date and stop date of serious adverse events maximum intensity of serious adverse events possible relationship between serious adverse events and study drugs due to serious Whether the adverse event required a change in the study drug the treatment given to the patient as a result of the serious adverse event concomitant medications if the serious adverse event occurred and the outcome of the serious adverse event
10 Data management and statistical analysis 101Data management
1 Establish database The data administrator establishes an EXCEL database based on the research plan and CRF and sets up logical verification according to the data verification plan DVP Release for use after passing the test
2 Data entry Data entry personnel conduct independent double entries and double checks Inconsistent results will be checked and corrected item by item against the CRF until the results are completely consistent
3 Data questions and answers After data entry is completed the data administrator conducts question screening according to DVPs manual verification plan opens database access to researchers and answers questions remotely The data administrator responds to questions and can issue questions again if necessary until the data is clean
4 Database locking After the main researcher statistical analysts and data managers jointly sign the database lock record the data administrator locks the database
5 Database submission The data administrator submits the database to the statistician
102 Statistical analysis data set
1 Full analysis set FAS a set of all randomly enrolled cases that used the study drug at least once
2 Per-protocol set PPS It is a data set generated by subjects who are fully compliant with the trial protocol Compliance includes the treatment received the availability of primary endpoint measurement and no major impact on the trial protocol Violation etc PPS analysis was used for the primary efficacy outcome measure
3 Safety Data Set SS Actual data that received at least one treatment and had post-treatment safety indicator records The incidence of adverse reactions was based on the number of SS cases as the denominator
103Statistical methods 931 Subject distribution analysis
1 List the number of subjects selected and completed the trial and determine three analysis data sets FAS PPS SS
2 Conduct a classification analysis on the reasons for not entering PPS and calculate the number of subjects in different categories
3 Make a detailed list of group classifications including the reasons for not being included in PPSFASSS
4 Draw a flow chart of subject distribution 1032 Demographic data and baseline analysis
Descriptive statistics Demographic information and other baseline characteristic values
1 Calculate the number of cases mean standard deviation 95CI minimum and maximum values for continuous variables
2 Count and grade data calculation frequency and composition ratio
3 Inferential statistical results P values are listed as descriptive results 1033 Medication compliance and concomitant medication analysis
-- --
1 Calculate the percentage of subjects with medication compliance in the range of 80-120 and use the χ2 test or Fishers exact probability method to compare differences between groups
2 Medication exposure use t test to compare differences between groups
3 Calculate the percentage of subjects with combined medications and use the χ2 test or Fishers exact probability method to compare differences between groups
1034 Efficacy analysis 1 Analysis of main efficacy indicators FR measured by ultrasound at 6 months and the baseline between the two groups was compared using t test
2 Analysis of secondary efficacy indicators FR measured by ultrasound at 2 months and 4 months and the baseline was compared between the two groups using t test
For the number of angina attacks per week t test was used to compare the differences between groups
For the time of occurrence of angina pectoris in exercise test t test was used to compare the differences between groups
The time when ischemic ST segment downward shift occurs in exercise test and the t test is used to compare the differences between groups 1035 Security analysis 1 Calculate the incidence of adverse eventsreactions serious adverse eventsreactions and adverse eventsreactions leading to dropout
2 List a detailed list of cases of various adverse eventsreactions serious adverse eventsreactions and adverse eventsreactions leading to dropout
3 List the crosstabs of laboratory tests and electrocardiograms before and after medication
4 Descriptive statistics of changes from baseline in laboratory examinations electrocardiograms and vital signs and actual measured values
5 Make a detailed list of abnormal values in laboratory tests electrocardiograms and physical examinations
1036Statistical software
1 Analysis using S PSS software
2 All statistical tests adopt two-sided tests and a P value less than or equal to 005 will be considered as statistically significant
3 Detailed statistical methods will be provided in the statistical analysis plan
Regarding drug treatment traditional anti-ischemic treatment methods are currently recommended including β- blockers calcium ion antagonists and nitrates If symptoms persist other drugs include angiotensin-converting enzyme inhibitors statins ivabradine ranolazine and estrogen drugs However there is no specific clinical drug treatment Basic and clinical studies of the traditional Chinese medicine Compound Danshen Dripping Pill have found that it can improve vascular endothelial function and relieve angina pectoris and is widely used in clinical practice However its effect on coronary reserve function and angina pectoris in coronary microvascular disease needs further clinical research to confirm
2 Study drug The main drug studied in this study is Compound Danshen Dripping Pill Compound Danshen Dripping Pills Compound Danshen Dripping Pills produced by Tasly Holding Group Co Ltd is a compound traditional Chinese medicine preparation composed of Salvia miltiorrhiza Panax notoginseng and Borneol In 1994 it was approved as a drug for the treatment of coronary heart disease and angina pectoris It has good clinical efficacy and has It has the characteristics of fast onset low toxicity small adverse reactions and high safety
The active ingredients of compound Danshen dripping pills are water-soluble phenolic acids such as salvia miltiorrhiza and Panax notoginseng saponins During the preparation process borneol and auxiliary materials are added and a highly dispersed solid dispersion is made through a specific process The active ingredients of the drug have high purity are evenly dispersed and can be quickly absorbed through the mucous membrane The dripping pills have good solid dispersion effect The principle is to melt the drug ingredients and matrix into a solid solution and the active ingredients of the drug are in the molecular state or in extremely fine form The crystalline state is highly uniformly dispersed in the matrix with fast drug dissolution and higher bioavailability It can be taken sublingually and can quickly relieve angina pectoris and chest tightness
Compound Danshen Dripping Pill has achieved a full-process quality control method from medicinal materials intermediates to preparations GAP-GEP-GMP through the multi-factor fingerprint quality control system of compound oral Chinese medicine preparations further improving the full-process quality control system of Compound Danshen Dripping Pill after testing and analyzing nearly 200 batches of Compound Salvia Miltiorrhizae Dropping Pills Extract and Compound Salvia Miltiorrhizae Dropping Pills the similarity is over 90 and the quality of the products is stable between batches It has been confirmed through the toxicology study of Compound Danshen Dripping Pill and the clinical use of hundreds of millions of people it has no toxicity few adverse reactions and is safe and reliable for long-term use
As a Chinese patent medicine for the treatment of stable angina pectoris Compound Danshen Dripping Pill are included in Category A of the 2018 National Essential Drugs Catalog and the 2019 National Basic Medical Insurance Work Injury Insurance and Maternity Insurance Drug Catalogue Under the name of Compound Danshen Dripping Pill it has been written into more than 20 national medical guidelines or consensus 15 of which involve the cardiovascular field including Guidelines for Rational Medication in Coronary Heart Disease 2nd Edition Acute Myocardial Medication Guidelines for the Diagnosis and Treatment of Infarction by Integrated Traditional Chinese and Western Medicine Chinese Expert Recommendations on the Clinical Application of Compound Danshen Dripping Pill Expert Consensus on the Diagnosis and Treatment of Atherosclerosis by Integrated Traditional Chinese and Western Medicine etc
In terms of international evidence-based research large-sample randomized double-blind placebo-controlled RCT studies were used and 1004 patients were included in phase III clinical studies at 127 centers in 9 countriesregions around the world indicating that the US FDA-Phase III The main clinical efficacy indicators significantly increase the patients exercise flat time and improve exercise tolerance Compared with the increase time of exercise oxygen tolerance of similar drugs Compound Danshen Dripping Pill has obvious advantages Secondary efficacy indicators effectively reduce the number of angina attacks per week and significantly reduce the weekly nitroglycerin dosage
In terms of domestic evidence-based research 1011 studies on Compound Danshen Dripping Pill for the treatment of stable angina 16 Meta-analyses with a total enrollment of more than 100000 people 137 studies on the treatment of peri-PCI thrombolysis period the total number of participants exceeds 10000 there are 36 studies on Compound Danshen Dripping Pill improving coronary microcirculation disorders filling the gap in Western medicine treatment
Systematic study of Compound Danshen Dripping Pill combined with Western medicine in the treatment of coronary heart disease angina pectoris 21 articles were included with a total number of cases of 2229 Compound Danshen Dripping Pill combined with Western medicine can benefit patients with coronary heart disease angina pectoris especially in improving clinical symptoms and electrocardiogram It has outstanding effects on ischemic state and regulating cholesterol levels
A meta-analysis based on PubMed EMBASE CNKI and Wanfang databases studied the efficacy of aspirin combined with Compound Danshen Dripping Pill in the treatment of coronary heart disease The analysis included 14 randomized controlled trials with a total of 1367 patients The results showed that the combination Compared with aspirin alone the drug can achieve more significant therapeutic effects in relieving angina pectoris symptoms and lowering blood lipids Lu Yuhong et al randomly divided 128 patients with coronary heart disease into groups The control group took oral aspirin on the basis of conventional treatment and the observation group took Danshen Dropping Pills on the basis of conventional treatment After 2 months the total clinical effective rate of the patients in the observation group was significantly higher than Control group Compared with before treatment the maximum platelet aggregation rate and thromboxane B2 levels of the two groups of patients were significantly reduced and the decrease in the observation group was more obvious than that in the control group The Guidelines for the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine in Acute Myocardial Infarction led by Academicians Chen Keji Academician Ge Junbo and Professor Zhang Minzhou were formulated in conjunction with experts in the fields of traditional Chinese medicine Western medicine integrated traditional Chinese and Western medicine and methodology across the country The guideline clearly states that Compound Danshen Dripping Pill are recommended for the treatment of acute myocardial infarction The recommendation level is the highest in the guideline Compound Danshen Dripping Pill can relieve chest pain reduce the patients risk of cardiac death and improve the patients cardiac function and the role of quality of life
3 Research purpose A randomized double-blind placebo-controlled multi-center clinical study of Compound Danshen Dripping Pill and blank control was conducted in patients with microvascular angina pectoris
4 research design 41 Study title and registration The Chinese name of this project is Microvascular Angina Intervention with Compound Danshen Dripping Pill English name Microvascular Angina Intervention with Compound Danshen Dripping Pill Referred to as MAIDS Study
42 Research design Randomized double-blind placebo parallel-controlled multi-center clinical study
4 3 dosing regimens double-blind single simulation
1 Placebo group Placebo the appearance is the same as Compound Danshen Dripping Pill main ingredient starch Production unit Tianjin Tasly Co Ltd taken orally after meals 3 times a day 20 pills each time
2 Treatment group Compound Danshen Dripping Pill Tianjin Tasly Co Ltd taken orally after meals 3 times a day 20 pills each time
Note The batch number on the drug packaging is unified as 161299 5 Research objects 51 Source of patients patients with chest pain who had no obvious coronary artery stenosis on coronary angiography or coronary CT examination were admitted to the hospital outpatient clinics and wards
52Selection criteria _
1 With typical symptoms of exertional angina
2 Coronary CTA or angiography with normal coronary artery or 50 stenosis or 50 residual coronary stenosis after revascularization
3 Ischemic downward shift of the ST segment is found in the electrocardiogram at rest or during exercise stress horizontal or downsloping downward shift behind the J point 01mv lasting 008s
4 Transthoracic ultrasound before and after intravenous adenosine injection to check the anterior descending coronary artery blood flow reserve test CFR 25
5 The patient agreed to participate in this study 53 Exclusion criteria 1 Aged less than 30 years old or older than 75 years old 2 Have a history of carotid endarterectomy or stent implantation and have a history of stroke 3 Myocarditis pericardial disease valvular disease and cardiomyopathy 4 Difficult-to-control diabetes fasting blood glucose 70 mmolL 5 Uncontrollable hypertension SBP150 mmHg andor DBP90 mmHg 6 Familial hypercholesterolemia 7 Takayasu arteritis 8 Those who are pregnant or lactating or those who intend to have a child within one year or those who have not taken effective contraceptive measures during the childbearing age 9 Abnormal liver function serum GPT level exceeds 30 times the upper limit of normal value or abnormal renal function serum creatinine level exceeds 2 mgdl 10 Other clinically significant respiratory digestive blood infection immune endocrine neuropsychiatric tumor diseases etc which may cause serious danger to patients 11 Take K channel openers and traditional Chinese medicine preparations that activate blood circulation and remove blood stasis to improve microcirculation 12 Those allergic to intra-arterial injection of contrast media blood and blood products 13 Patients who are participating in other clinical studies
6 Research methods 61Sample size The experimental drugs and control drugs in this clinical trial will be selected according to the number of cases in a ratio of 11 100 patients were enrolled in the preliminary experiment
62 Random grouping The randomization method adopts the central randomization method The central randomization system uses DAS211 software to generate random numbers 00 1 -100 and drug packaging numbers B ZH001-100 The random numbers and drug packaging numbers are separated in the system The researcher passes the Apply to the system to obtain the drug packaging number for the subject The random number and drug packaging number of the same subject are different but their corresponding treatment plans are consistent within the system
63 Research process After signing the informed consent form the selected patients were divided into the Compound Danshen Dripping Pill treatment group and the placebo group according to a random double-blind placebo-controlled method Dosage of Compound Danshen Dripping Pill or placebo 3 times a day 20 pills each time for a total of 6 months Follow-up visits were conducted every 2 months and the follow-up period was 6 months in total
64 Screening Phase
1 CTA or CAG examination Coronary artery CTA or angiography examination shows that the coronary arteries are normal or stenotic 50 and coronary epicardial vasospasm is excluded
2 Electrocardiogram Resting or exercise stress test shows ischemic downward shift of ST segment horizontal or downward shift behind J point 01mv lasting 008s
3 Laboratory tests Fasting for more than 6 hours blood routine urine routine fasting blood glucose alanine aminotransferase aspartate aminotransferase troponin serum creatine phosphokinase urea nitrogen creatinine plasma total cholesterol triglycerides hypoglycemia The existing data on density lipoprotein cholesterol high-density lipoprotein cholesterol high-sensitivity C-reactive protein and prothrombin time during the screening phase can no longer be reviewed
4 Echocardiogram
After signing the informed consent form the following inspections will be performed See Appendix 1 for inspection methods
1 Routine ultrasound examination two- dimensional dynamic images of left ventricular parasternal long axis apical four-chamber apical two-chamber apical long axis and left ventricular apex level papillary muscle level and mitral valve level short-axis sections At the same time pulse wave Doppler was used to obtain the diastolic mitral valve orifice blood flow spectrum and tissue Doppler was used to obtain the mitral valve annular motion spectrum See Appendix 1 for details
2 Acoustic contrast adenosine test First observe the distal left anterior descending coronary artery under color Doppler guidance measure the blood flow velocity with pulsed Doppler ultrasound and then administer the contrast agent SonoVue add 85ml sterile saline to one bottle bolus injection followed by slowly injecting 5 ml of normal saline over 20 seconds and measuring the blood flow velocity of the distal left anterior descending coronary artery again Finally adenosine 140 µgkg -1 min -1 was given for 6 minutes by continuous intravenous micropump injection During the injection process the coronary blood flow velocity was monitored Pulse Doppler ultrasound measured the maximum coronary blood flow velocity in the distal left anterior descending artery This could be repeated at the same time Acoustic contrast enhances spectral signals
3 The adenosine test simultaneously records a 12-lead electrocardiogram
4 After recording the coronary blood flow in the contrast-enhanced ultrasound examination the two-dimensional short-axis sections of the left ventricular parasternal long axis apical four- chamber heart apical two-chamber heart apical long axis and left ventricular apex level papillary muscle level and mitral valve level were recorded dynamic images
65 Enrollment and follow-up phase
1 Case grouping 100 patients were selected and randomly divided into Compound Danshen Dripping Pill group and control group 50 cases each Compound Danshen Dripping Pill 20 pills three times a day Placebo 20 pills three times a day
2 Follow-up observation Follow-up observations were conducted at 2 months 4 months and 6 months after inclusion including clinical conditions laboratory examinations and ultrasound examinations Safety assessment
7 Efficacy evaluation 71 Main observation indicators Difference in left anterior descending coronary flow reserve CFR measured by ultrasound at 6 months compared with baseline
72 Secondary observation indicators
1 Difference in left anterior descending coronary flow reserve CFR measured by ultrasound at 2 months and 4 months compared with baseline
2 Number of angina attacks per week
3 The time when angina pectoris occurs in exercise test 4 The time when ischemic ST segment depression occurs during exercise testing
8Safety assessment Including clinical adverse reactions laboratory indicators etc 9 Adverse event observation and reporting 91Definition of Adverse Events Adverse events refer to any adverse medical event that occurs to a patient in this clinical trial from the time the patient signs the informed consent form and is selected to participate in the trial to the last follow-up visit regardless of whether this event is causally related to the above-mentioned drugs
NOTE An adverse reaction may be any discomfort and unconscious signs including abnormal laboratory test results symptoms or disease new or worsening related to the medication
Events that meet the definition of adverse events include
Exacerbation of an existing chronic or intermittent disease including increased frequency andor intensity
A disease that is newly detected or diagnosed after taking the investigational drug even though it may have been present before the trial began
Signs symptoms or clinical sequelae suspected of being caused by an interaction
Signs symptoms or clinical sequelae caused by suspected overdose of the investigational drug or concomitant medication overdose itself is not an adverse event serious adverse event
Lack of efficacy or failure to achieve the expected pharmacological effect itself is not reported as an adverse event or serious adverse event However signs symptoms andor clinical sequelae due to lack of efficacy will also be reported as adverse events or serious adverse events if they meet the definition of an adverse event or serious adverse event
Events that do not meet the definition of an adverse event include
Medical or surgical procedure eg endoscopy appendectomy the event leading up to the procedure is an adverse event
Situations in which adverse medical events would not occur social security and or admission facilitation
There was no worsening of pre-existing diseases or conditions that were present or detected at the start of the trial only expected day-to-day fluctuations
disease being studied or the expected progression signs or symptoms of the disease being studied Unless the situation is more serious than expected
Definition of serious adverse event serious adverse event is an adverse event that can occur at any dose and will
cause death
threatening life Note Life-threatening means that the subject is in danger of death when the event occurs not that death could theoretically result if the event were more serious
Requires hospitalization or prolonged hospitalization Note Typically hospitalization refers to a subject staying in the hospital or emergency room usually at least overnight to receive observation andor treatment that cannot be completed in the doctors office or outpatient clinic Complications that occur during hospitalization are considered adverse events An event is classified as a serious adverse event if the complication prolongs hospitalization or meets the criteria for any other serious adverse event When it cannot be determined whether hospitalization occurred or was necessary it will be treated as a serious adverse event
Elective hospitalization that does not worsen a pre-existing condition compared with baseline is not an adverse event
Causes disability or affects the ability to work and live Note Disability refers to a substantial impairment of an individuals ability to carry out normal life It does not include discomforts of little clinical significance such as common headaches nausea vomiting diarrhea influenza and accidental trauma such as sprained ankles which may affect the quality of daily life but will not constitute a substantial disruption
Cause congenital malformations In other cases medical or scientific judgment should determine whether adverse event reporting is appropriate For example some important medical events may not be immediately life-threatening leading to death or hospitalization but may harm subjects or require drug or surgical intervention to avoid the serious adverse events listed above These events should also be considered serious adverse events such as invasive or malignant cancer allergic bronchospasm requiring close monitoring in the emergency room or at home hematologic cachexia or convulsions that do not result in hospitalization drug dependence or drug abuse
92 Adverse drug reactions Definition Refers to harmful reactions that occur under normal usage and dosage of qualified drugs and have nothing to do with the purpose of medication
Causal judgment indicators for adverse reaction judgment
Item 1 Is there a reasonable sequence between the time of starting medication and the time when the suspicion appears Item 2 Whether the suspected adverse reaction conforms to the known adverse reaction type of the drug Item 3 Whether the suspected adverse reaction can be explained by the patients pathological condition concomitant medications concomitant therapies or previous therapies Item 4 After stopping the drug or reducing the dose whether the suspected adverse reactions are reduced or disappeared Item 5 Whether the same reaction reappears after using the suspected drug again
Causality judgment criteria Judgment based on the order of the above five judgment indicators
It is up to the investigator to evaluate possible associations between adverse events trial drugs and concomitant medications according to the table below
Adverse reaction cause and effect judgment table
critical result Judgment index Project 1 Project 2 Project 3 Item 4 Item 5 Definitely related - probably related - may be relevant suspicious - Impossibly related - - -
Explanation Affirmation - Negation Difficult to affirm or deny The situation is unknown
1Based on the table above determine the relationship between the following grade 5 adverse events and the drug
1 Definitely related 2 Probably related 3 Possibly related 4 Suspicious 5 Impossibly related
2 The incidence rate of adverse reactions is calculated using the total number of 1 2 3 4 cases as the numerator and all selected cases that can be evaluated for adverse reactions as the denominator
93Recording of adverse events on the basis of comprehensive consideration of comorbidities and concomitant medications their relevance to the experiment should be evaluated The relevance of the drug and documented in detail by the physician
If an adverse event is discovered the observing physician can decide whether to terminate the observation based on the condition Cases of drug discontinuation due to adverse events should be followed up and investigated and the results should be recorded in detail If any abnormality in safety test indicators blood urine stool routine electrocardiogram liver function kidney function occurs during or after treatment the adverse event form should be filled in in a timely manner reviewed at an appropriate time and communicated with the subject A comprehensive analysis will be conducted on the onset treatment etc to determine whether it is related to the experimental drug
94 Handling of serious adverse events For any serious adverse events that occur during the trial including events requiring hospitalization prolonged hospitalization disability affecting work ability endangering life or death causing congenital malformations etc during the clinical trial the researcher shall immediately respond to the patients request In addition to taking emergency measures the subject must also immediately report to the ethics committee of the National Drug Clinical Trial Institution of Shandong University Qilu Hospital and the main research unit Tianjin Tasly Co Ltd the unit responsible for the research The content of the report of serious adverse events should include patients name random number length of study participation start date and stop date of serious adverse events maximum intensity of serious adverse events possible relationship between serious adverse events and study drugs due to serious Whether the adverse event required a change in the study drug the treatment given to the patient as a result of the serious adverse event concomitant medications if the serious adverse event occurred and the outcome of the serious adverse event
10 Data management and statistical analysis 101Data management
1 Establish database The data administrator establishes an EXCEL database based on the research plan and CRF and sets up logical verification according to the data verification plan DVP Release for use after passing the test
2 Data entry Data entry personnel conduct independent double entries and double checks Inconsistent results will be checked and corrected item by item against the CRF until the results are completely consistent
3 Data questions and answers After data entry is completed the data administrator conducts question screening according to DVPs manual verification plan opens database access to researchers and answers questions remotely The data administrator responds to questions and can issue questions again if necessary until the data is clean
4 Database locking After the main researcher statistical analysts and data managers jointly sign the database lock record the data administrator locks the database
5 Database submission The data administrator submits the database to the statistician
102 Statistical analysis data set
1 Full analysis set FAS a set of all randomly enrolled cases that used the study drug at least once
2 Per-protocol set PPS It is a data set generated by subjects who are fully compliant with the trial protocol Compliance includes the treatment received the availability of primary endpoint measurement and no major impact on the trial protocol Violation etc PPS analysis was used for the primary efficacy outcome measure
3 Safety Data Set SS Actual data that received at least one treatment and had post-treatment safety indicator records The incidence of adverse reactions was based on the number of SS cases as the denominator
103Statistical methods 931 Subject distribution analysis
1 List the number of subjects selected and completed the trial and determine three analysis data sets FAS PPS SS
2 Conduct a classification analysis on the reasons for not entering PPS and calculate the number of subjects in different categories
3 Make a detailed list of group classifications including the reasons for not being included in PPSFASSS
4 Draw a flow chart of subject distribution 1032 Demographic data and baseline analysis
Descriptive statistics Demographic information and other baseline characteristic values
1 Calculate the number of cases mean standard deviation 95CI minimum and maximum values for continuous variables
2 Count and grade data calculation frequency and composition ratio
3 Inferential statistical results P values are listed as descriptive results 1033 Medication compliance and concomitant medication analysis
-- --
1 Calculate the percentage of subjects with medication compliance in the range of 80-120 and use the χ2 test or Fishers exact probability method to compare differences between groups
2 Medication exposure use t test to compare differences between groups
3 Calculate the percentage of subjects with combined medications and use the χ2 test or Fishers exact probability method to compare differences between groups
1034 Efficacy analysis 1 Analysis of main efficacy indicators FR measured by ultrasound at 6 months and the baseline between the two groups was compared using t test
2 Analysis of secondary efficacy indicators FR measured by ultrasound at 2 months and 4 months and the baseline was compared between the two groups using t test
For the number of angina attacks per week t test was used to compare the differences between groups
For the time of occurrence of angina pectoris in exercise test t test was used to compare the differences between groups
The time when ischemic ST segment downward shift occurs in exercise test and the t test is used to compare the differences between groups 1035 Security analysis 1 Calculate the incidence of adverse eventsreactions serious adverse eventsreactions and adverse eventsreactions leading to dropout
2 List a detailed list of cases of various adverse eventsreactions serious adverse eventsreactions and adverse eventsreactions leading to dropout
3 List the crosstabs of laboratory tests and electrocardiograms before and after medication
4 Descriptive statistics of changes from baseline in laboratory examinations electrocardiograms and vital signs and actual measured values
5 Make a detailed list of abnormal values in laboratory tests electrocardiograms and physical examinations
1036Statistical software
1 Analysis using S PSS software
2 All statistical tests adopt two-sided tests and a P value less than or equal to 005 will be considered as statistically significant
3 Detailed statistical methods will be provided in the statistical analysis plan
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None