Study objectives
The purpose of the experiment is to evaluate the efficacy and safety of HTDJ plus western medicine in the treatment of AF, provide medicine evidence of short-term and medium-term clinical efficacy for the treatment of AF with integrated traditional and western medicine on the basis of TCM syndrome differentiation and lay the foundation for further clinical development and application.
Study design and settings
The study will be conducted in the Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, to achieve the goal of 76 participants with AF(palpitation of Qi deficiency-caused phlegm stagnation) in total. Each participant can only be grouped once. The study will include five phases: screening/enrollment, allocation, treatment/intervention, end of intervention, and follow-up. During enrollment, all participants will undergo physical examination and assessment of eligibility in the cardiology clinics and wards before being recruited. The maximum time allowed between the assessment and the intervention is 1 week (week 0). If more than a week has passed since the assessment, the participant will have to undergo repeat assessment before being allowed to start the intervention. Eligible participants will be invited to sign the written informed consent regarding participation in the trial (procedures, risks, options for dropping out), regarding the use of laboratory data, and regarding the collection, storage, and use of biological specimens. A study investigator or medical staff member that has received adequate training will provide the participant with extensive explanations. Upon agreeing to provide consent, the participant will be invited to sign and date the informed consent form, at which time a participant identification (PID) number will be assigned to facilitate PID throughout the study.
The participants will be randomly assigned to the experimental or control group and undergo the corresponding intervention for a total of two treatment cycles. Participants in the experimental group will receive HTDJ, whereas those in the control group will receive placebo granules . The participants will continue to receive systemic therapy, as judged by their treating physician. All changes in symptoms, prescriptions, relevant scores, and macroscopic characteristics (based on photographic evidence), along with any adverse events( AEs), will be recorded. The experimental design is shown in Figure 1.
Diagnostic criteria
The diagnosis of atrial fibrillation can be confirmed based on clinical manifestations, physical examination and electrocardiographic characteristics as follows: (1) Clinical manifestations: palpitation, chest tightness, decreased exercise tolerance. (2) Physical
examination:heart auscultation varies in heart rate, heart sounds vary in strength,
rhythm is absolutely irregular, and pulse is short. (3) Electrocardiogram: P wave disappear, the f wave replaces it, the frequency is about 350-600 times, and the QRS complex rhythm is absolutely irregular.
Inclusion Criteria
The inclusion criteria are as follows: (1) Patient’s age is 18–85 years. (2) Paroxysmal atrial fibrillation, seizure frequency >=2 times a month or persistent atrial fibrillation (at least one ECG diagnosis). (3) The main syndrome of TCM syndrome differentiation was Qi deficiency-caused phlegm stagnation. (4) Have a correct understanding of the significance of the study, have good compliance with the observation and evaluation of the researcher, voluntarily accept the clinical trial and fill in the clinical consent form.
Exclusion Criteria
The exclusion criteria are as follows: (1) Patients with primary diseases such as severe lung, liver, renal insufficiency and hematopoietic system or severe cardiac dysfunction (NYHA IV grade). (2) Atrial fibrillation caused by obvious incentives such as fatigue, mental stress, mood swings, drug poisoning, and electrolyte disturbance. (3) Mental illness and poor control of the condition. (4) Patients whose heart rate is less than 50 beats per minute (such as sick sinus syndrome, atrioventricular or intraventricular block, etc.,who intend to install a pacemaker). (5) Pregnant or lactating women. (6) Cachexia in the terminal stage of malignant tumor. (7) For various reasons, the efficacy cannot be determined or the data is incomplete.
Termination of test cases
Patients who are enrolling but have not completed clinical observations:(1) In case of serious adverse events, the clinical experimenter should be stopped according to the doctor's judgment.(2) If the disease worsens in the course of the disease, or there are other conditions affecting the observation of the study, the clinical experimenter should be stopped and invalid cases should be treated according to the doctor's judgment.(3) Important deviations occurred in the implementation of clinical trial protocols, such as poor compliance, making it difficult to evaluate drug effects. (4) The subject is unwilling to continue the clinical trial during the clinical trial, and proposes to the doctor in charge to withdraw from the clinical trial.
Suspension criteria
The trial will be suspended in case of the following: (1) Those who have not used research drugs or combined with other Traditional Chinese medicines or proprietary Chinese medicines.(2) Misdiagnosis.(3) Those without any test records.
Case drop and treatment
The enrolled cases with incomplete clinical protocols due to the following reasons shall be deemed as shedding, with the shedding rate not exceeding 20% :(1) Patients withdraw spontaneously (unsatisfactory efficacy, adverse reactions, etc.).(2) Loss of follow-up.(3) The researcher ordered to withdraw (did not take medicine as prescribed;Severe comorbidities and complications occur;Serious adverse events).
For abscission cases, the reasons for abscission shall be recorded in detail. If there is a review, the results of the last major efficacy test shall be taken as the final results for statistical analysis, and the CRF table shall be kept for future reference.
Interventions
This subject adopts randomized, double-blind, single-simulated,placebo-controlled research method. 72 cases with AF(palpitation of Qi deficiency-caused phlegm stagnation)were randomly divided into two groups according to the 1:1 distribution principle. The first group was treated with HTDJ plus western medicine. The second group was treated with placebo granules plus western medicine. Western medicine includes cardioversion drugs and heart rate control drugs, as well as myocardial energy metabolism drugs, must be in keeping with “the 2015 Atrial Fibrillation: Current Understanding and Treatment Recommendations''. The HTDJ and placebo were produced and packed in a single batch(production batch number: HTDJ: 1070649; Placebo: 1070649) by Shanghai Wan Shicheng Pharmaceutical Co.,Ltd, which has no conflicts of interest relevant to this study. The test results of drug quality were consistent with the Chinese Medicine Standards of the State Food and Drug Administration. The placebo is composed of 10% crude HTDJ and 90% starch, which have the same appearance and scent as the active treatment drugs. Participants will take one bag twice a day for 4 weeks, while avoiding oral administration of other traditional Chinese medicine for efficacy evaluation. Then do not accept traditional Chinese medicine, only western medicine treatment, followed up for 8 weeks, another clinical evaluation.
Outcomes
1. General information: gender, age, weight, heart rate, heart rhythm, blood pressure, etc.
2. Clinical symptoms: The number and duration of atrial fibrillation episodes were recorded using a scoring method before and after treatment.
3. TCM syndromes: The changes in heart palpitations, shortness of breath, fatigue, coughing, spitting, salivation, body condition, tongue condition, and pulse condition were recorded before and after treatment.
4. The weekly cumulative number and duration of palpitations.
5. Electrocardiogram: trace the changes of resting ECG before and after treatment.
6. Holter ECG: Use Holter ECG to record the dynamic changes of the patient's cardiac electrical activity, record the number of ectopic beats, and evaluate the patient's arrhythmia.
7. Cardiac ultrasound: Ejection fraction (EF), stroke volume (SV), left ventricular end diastolic diameter (LVEDD), etc. before and after treatment in each group were detected by echocardiography.
8. Heart function: proBNP
9. The rate of increase or decrease of western medicines to transfer to the law and to control the room law.
10. Evaluation of Hamilton Anxiety and Depression Scale.The Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) are used to evaluate the emotional state of patients. HAMA is mainly used to assess the severity of the patient's anxiety symptoms, and is generally considered to be greater than 14 points Meaningful. HAMD is currently one of the most commonly used clinical scales to assess depression, and 20 points or more are considered meaningful.
11.SF-36 EVALUATION
Use the MOS item short from health survey (SF-36) to assess changes in the quality of life of patients.
12. Safety indicators: detect changes in blood routine, urine routine, liver and kidney function before and after treatment.
During the experiment, closely observe any adverse reactions/events that may occur and record them in detail and truthfully.
Observation records of adverse events
During the trial period, the adverse event record form should be filled in truthfully. The occurrence, severity, duration, measures taken and outcome of the adverse event should be recorded. Adverse events should be recorded in the designated clinical case observation form (CRF) adverse event form. The person uses mild, moderate, and severe to describe the intensity of the adverse event,and evaluates the possible association between the adverse event and the study drug and combination drug to determine whether it is an adverse reaction.
Research process record points
The subject content and data at each time point, according to the patient’s hospitalization period, will be recorded as shown in Table.1. Specifically, the screening period (-3~0 days) will be 0 to 3 days before recruitment .The 4-week treatment period was planned in two cycles of 2 weeks, with a return visit between cycles to check for AEs and monitor compliance. All interventions will be stopped after 4 weeks. Follow- up will be conducted on weeks 4 and 12.
Sample size
In order to study the efficacy and safety of HTDJ in the treatment of atrial fibrillation , we collected cases from outpatient and inpatient atrial fibrillation in Longhua
Table 1 Research flowchart
Hospital, 30 cases in the test group and 30 cases in the control group, a total of two groups, considering 20% clinical shedding rate, a total of 76 patients are planned to be included.
Randomization
This study uses a center-based stratification and block randomization method. The randomization sequence will be generated by study investigators who are statisticians. Patients will be allocated in a 1:1 ratio, aiming to balance baseline characteristics between the groups. Participants will be assigned a PID number, which will be used for subject identification throughout the study. Information regarding the random-number block will be delivered to the participating centers along with the intervention drugs.
Double-blind
The study is designed as a double-blind investigation. The participants, study monitors, and study investigators will be blinded throughout the duration of the study. The PID will be the only information linked to group allocation.Random codes will be maintained by Cui Xuejun, associate researcher, and director of the Office of National Traditional Chinese Medicine Clinical Research Base of Longhua Hospital to ensure concealment.
Statistical analysis
All data are entered using excel worksheets, and SPSS22.0 statistical software is used for statistical analysis. For measurement data, t-tests are performed for those that conform to the normal distribution, and the data are represented by the mean ± standard deviation; the row-rank conversion that does not conform to the normal distribution For non-parametric test, the data are represented by M (QR). The constituent ratio data uses the χ2 test. The one-way ordered data uses the rank sum test. P>0.05 is not statistically significant, P<0.05 is statistically significant, two-sided test .
Data management and monitoring
In this study, the CRF will be filled out by the researchers in a timely manner, and by a third party is responsible for checking and checking, patient data confidentiality and
through the ethics committee, the ethics committee reviews drug clinical trial scheme
is scientific and ethical rationality, audit and supervision of drug clinical trials researchers qualification, supervision of drugs in clinical trials, ensure the independent, objective, fair and ethical review process.