Comparative Effectiveness of Di'ao Xin Xue Kang Capsule and Compound Danshen Tablet in Patients With Symptomatic Chronic Stable Angina

A high proportion of patients with stable angina remains symptomatic despite multiple treatment options. Di'ao Xinxuekang (XXK) capsule and Compound Danshen (CDS) tablet have been approved for treating angina pectoris for more than 20 years in China. We compare the anti-anginal effectiveness of XXK capsule and CDS tablet in patients with symptomatic chronic stable angina. A randomized, multicenter, double-blind, parallel-group, superiority trial was conducted in 4 study sites. 733 patients with symptomatic chronic stable angina were included in the full analysis set. The primary outcomes were the proportion of patients who were angina-free and the proportion of patients with normal electrocardiogram (ECG) recordings during 20 weeks treatment. Compared with CDS, XXK significantly increased the proportion of angina-free patients, but no significant difference was noted in the proportion of patients with normal ECG recordings. Weekly angina frequency and nitroglycerin use were significantly reduced with XXK versus CDS at week 20. Moreover, XXK also improved the quality of life of angina patients as measured by the SAQ score and Xueyu Zheng (a type of TCM syndrome) score. We demonstrate that XXK capsule is more effective for attenuating anginal symptoms and improving quality of life in patients with symptomatic chronic stable angina, compared with CDS tablet.


Background and objectives 2a
Scientific background and explanation of rationale 4-6 2b Specific objectives or hypotheses 6

Methods
Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 13 3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons N/A Participants 4a Eligibility criteria for participants 13-14 4b Settings and locations where the data were collected 13 Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were actually administered

14-15
Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed 15-17 6b Any changes to trial outcomes after the trial commenced, with reasons N/A Sample size 7a How sample size was determined 18 7b When applicable, explanation of any interim analyses and stopping guidelines 18 Randomisation: Sequence generation 8a Method used to generate the random allocation sequence 14 8b Type of randomisation; details of any restriction (such as blocking and block size) 14 Allocation concealment mechanism 9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned 14 Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions

14-15
Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how 14 11b If relevant, description of the similarity of interventions 14 Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 18 12b Methods for additional analyses, such as subgroup analyses and adjusted analyses N/A

Results
Participant flow (a diagram is strongly recommended) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome  Table 1  Numbers analysed  16 For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups 6 Outcomes and estimation 17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) 7-9 17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended 7-9 Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory 7 Figure 3 Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) 9

Discussion
Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 12 Generalisability 21 Generalisability (external validity, applicability) of the trial findings 9-12 Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 9-12 Sources of funding and other support (such as supply of drugs), role of funders 26 *We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.  The primary efficacy endpoint of this study is:

Other information
 Proportions of patients who were angina-free.
 Proportion of effective electrocardiogram (ECG) improvement.
Secondary efficacy endpoints are:  Change from baseline in weekly average frequency of self-reported angina episode over the 20-weeks treatment phase.
 Weekly average nitroglycerin consumption rate at week 8 and week 20.  Change from baseline in the blood stasis syndrome and the proportion of patients who had significant syndrome improvement.
 Change from baseline in ECG exercise test (the first 1/3 of patients included at each site)performed at 0 and 8 weeks.
 Change from baseline in serum lipid: total cholesterol, triglyceride, HDL cholesterol, and LDL cholesterol, measured at 0 and 8 weeks.
 Related signs: heart rate, rhythm, murmur, and BP, recorded before and after Treatment.
 Accompanying symptoms after treatment: fatigue, shortness of breath, aversion to cold, cold extremities and etc. (recorded as "yes" or "no").

Safety:
 Vital signs;  Blood, urine and stool routine tests;  Liver function (ALT), kidney function (BUN and Cr);  Any AE that occurs throughout the treatment period.

1．BACKGROUND INFORMATION
Xinxuekang (XXK), an oral capsule, is a pure traditional Chinese medicine (TCM) preparation manufactured by modern scientific techniques. It is indicated for the treatment of angina pectoris associated with coronary heart disease (blood stasis syndrome or "Xueyu zheng"), which has the functions of promoting blood circulation, removing blood stasis, promote qi circulation and relieving pain. It has been approved by the State Food and Drug Administration of China (SFDA) and widely used to treat angina in Chinese medical practice for many years.
Pre-clinical studies of XXK capsule mainly include pharmacokinetic, pharmacodynamic and toxicological (acute and chronic toxicities) studies, which are summarized in separate brochures.

OBJECTIVES
To investigate the clinical pharmacological characteristics of XXK capsule in the treatment of angina associated with coronary heart disease (blood stasis syndrome). to the study drug.

Superiority design
An adaptive design is applied in this clinical trial, which utilizes accumulating data to modify aspects of the study as it continues, without undermining the validity and integrity of the trial. "Validity" refers to deducing correct statistical analysis without comprising the bias that might include protecting the Type I error; and "integrity" refers to preplanning, as much as possible, based on intended adaptations, maintaining confidentiality of data, and providing convincing results to a broader scientific community.
This study aims to evaluate the efficacy and safety of XXK capsule versus CDS tablets in the treatment of angina associated with coronary heart disease (blood stasis syndrome).
Four qualified study sites will be recruited to conduct the trial.
Due to the adaptive design, one interim analyses is planned. If the superiority of the trial group is demonstrated at the time of interim analysis, then the trial should be terminated, which is also satisfies the ethical considerations.

Initial estimation of sample size
Since this trial adopts an adaptive design, we initially estimated the sample size based on one of the primary efficacy endpoints, i.e. the proportions of patients who were angina-free according to findings from other and previous studies [1][2]. We assume that the effective rate in the proportions of patients who were angina-free of the trial group was 30%, while that of the control group was 20%. We chose a significance level of 0

Randomization and case assignment
For the allocation of participants, a computer-generated list of random numbers was used. Randomization sequence was created using SAS 9.1 statistical software and was stratified by study site with a 1:1 allocation using random block sizes of 2, 4, and 4. Study participants will be serially numbered as 001-576 and randomly assigned to receive treatment with XXK capsule or CDS tablets (288 in the trial group and 288 in the control group).

Case assignment in 4 participating sites
Sites

Selection of control group
Based on the comparability principle, Compound Danshen (CDS) tablet is selected as the control group in the trial, whose indications and functions are similar to those of XXK capsule.

Blinding
Since the dosage forms of XXK capsule and CDS tablet are different, dummy preparations in both capsule and tablet forms are prepared to allow for double-blind and double-dummy comparison.
Blinding is conducted in two steps in this trial, i.e. treatment is randomly assigned to patients in the first step, and then A or B is randomly assigned to the treatment in the second step. The randomization lists of the two blinding steps are kept in sealed envelops in duplicate, one stored at the clinical study office of China Academy of Chinese Medical Sciences and the other kept by the sponsor.
Two-step unblinding will be performed after all patients have completed the trial.
Step 1: after all data is locked, personnel who keeps the sealed envelop will assign A or B to either of the treatments for the conduct of statistical analysis and production of statistical reports.
Step 2: after the statistical analysis is finished and the clinical trial report is prepared, the corresponding treatment that A or B refers to will be unblinded.
An emergency envelope will also be provided along with each test drug in its package, which should only be opened in case of emergency unblinding.
A patient's treatment assignment should only be unblinded when knowledge of the treatment is essential for the further management of the patient.
If the identity of the test medication is necessary for patient management (in the case of a serious complication or a serious adverse event), emergency unblinding is permitted.
Investigator, project manager, and clinical study coordinators should participate in the process of emergency unblinding; when, where and why the unblinding occurs as well as each personnel's signature should also be documented. The principal investigators should make every attempt to contact the sponsor after blinding.
At the time of emergency unblinding, it is also necessary to ensure that adequate procedures are in place to ensure the integrity of the data.

Committee
To ensure the validity and integrity of the trial, two committees are established by the multi-center study coordination committee, i.e. Data Monitoring Committee (DMC) and Implementation & Decision-making Committee. DMC is responsible for ensuring the integrity and accuracy of data collection; and the latter (consists of leaders of each site and principal investigators) is responsible for monitoring the implementation of the trial and making important decisions related with the trial process.

Interim analysis
One interim analyses will be conducted under blinding conditions after 1/2 of the total number of cases have completed the trial. The statistical results of interim analysis will be reported to the Data and Safety Monitoring Board and Implementation & Decision-making Committee, which will decide the subsequent arrangement and calculate the needed number of cases in the next stage of trial. If one group of treatment is terminated after the interim analysis, patients in this group may choose to crossover to continue with the trial or discontinue treatment and only report their safety information (considered as dropout cases).

WM (Western Medicine) and TCM diagnostic criteria of angina pectoris
According to the "Guiding principle of clinical research on novel TCM preparations in the treatment of angina associated with coronary heart disease" [3], and "Nomenclature and criteria for diagnosis of ischemic heart disease" reported by the

TCM diagnostic criteria of angina pectoris (blood stasis syndrome)[3]
Angina pectoris (blood stasis syndrome) is manifested as fixed and stabbing or gripping chest pain, which radiates to shoulder, back or the medial side of the arm, choking sensation in the chest, palpitation, dark purple lips and tongue, thin and choppy pulse.
 Main symptom: chest pain (stabbing, gripping, fixed, and radiating to shoulder, back or the medial side of the arm);  Accompanying symptoms: chest distress, palpitation, and dark purple lips;  Tongue and pulse: dark purple tongue, thin and choppy pulse.
If the main symptom and at least 2 accompanying symptoms are observed, along with the manifestations of tongue and pulse, the diagnosis of angina (blood stasis syndrome) could be established.
The six phenotypes of angina (blood stasis syndrome), including chest pain, choking sensation in the chest, palpitation, dark purple lips, ecchymosis on the tongue and fine-choppy pulse constitutes the phenotypic group of blood stasis syndrome.

Grading of angina pectoris[5]
According to the "Canadian Cardiovascular Society(CCS)grading of angina pectoris", the severity of angina can be graded as follows: Class I: Ordinary physical activity does not cause angina, such as walking and climbing stairs. Angina with strenuous or rapid or prolonged exertion at work or recreation.
Class II: Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, or in cold, in wind or under emotional stress, or only during the few hours after awakening. Walking more than two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions.
Class III: Marked limitation of ordinary physical activity. Walking one or two blocks on the level and climbing one flight of stairs in normal conditions and at normal pace.
Class IV: Inability to carry out any physical activity without discomfort; angina may be present at rest.

Inclusion criteria
 Patients who fulfill the diagnostic criteria of stable angina pectoris;  Patients who fulfill the diagnostic criteria of CCS grading classⅠ, Ⅱ or Ⅲ ;  Patients who fulfill the diagnostic criteria of blood stasis syndrome;  Patients who have angina attacks ≥2 episodes per week;  Ischemic changes on ECG: ST segment depression ≥ 0.05mv and/or deep T wave inversions > 0.2mv, flat T wave less than 1/10R, or positive exercise stress test.
 Those who are willing to provide a signed informed consent form.

Exclusion criteria
 Those who do not fulfill the inclusion criteria;  Those who have documented acute myocardial infarction or other heart diseases, severe neurosis, menopausal syndrome, hyperthyroidism, cervical spondylosis, gallbladder-heart disease, or gastroesophageal reflux;  Those who are complicated with poorly-controlled hypertension (systolic BP ≥160mmHg, and/or diastolic BP ≥100mmHg), severe cardiac or pulmonary insufficiency, severe arrhythmia (e.g. rapid atrial fibrillation, atrial flutter, paroxysmal ventricular tachycardia), serious primary diseases of liver, kidney or hematopoietic system, or psychosis;  Those who have obtained a complete revascularization after coronary artery bypass grafting or coronary intervention;  Pregnant or lactating women;  Those who are prone to allergies or with known allergy to many drugs;  Those who participated in other clinical trials within 1 month prior to randomization.

Withdrawal/dropout criteria
 Those who did not fulfill the eligibility criteria but were included by mistake;  Those who fulfilled the eligibility criteria but did not take any study drug after randomization;  Those with poor compliance that might interfere with the efficacy and safety evaluation;  Those who experienced serious AEs, complications or special physiological changes, making it inappropriate to continue with the trial;  Individual cases that were unblinded prematurely;  Those who discontinued the trial voluntarily;  Those who used any disallowed concomitant medication, especially those that had an obvious effect on the study drug and might interfere with the efficacy and safety evaluation;  Those who discontinued or lost to follow-up for any other reasons or died during the trial;  Those with incomplete data that might interfere with the efficacy and safety evaluation.
For all withdrawal/dropout cases, the potential reasons must be recorded. Patients who experienced any AE during the trial must be included in the statistical analysis of adverse drug reactions. Those who have taken the study drug for at least 1 week should be included in the statistical analysis of drug efficacy.

Criteria for study termination
Circumstances that may warrant termination include, but are not limited to:  Identification of unexpected, significant, or unacceptable risk to subjects;  Poor efficacy or no efficacy of the study drug;  Major mistakes in the trial protocol;  Insufficient adherence to protocol requirements;  Upon sponsor's request (e.g. economic or administrative reasons).

Criteria for subject discontinuation
 Any allergic reaction or AE occurs such that continued participation in the study would not be in the best interest of the subject at the discretion of the treating physician;  Worsening of clinical conditions occurs such that continued participation in the study would not be in the best interest of the subject at the discretion of the treating physician; considered as ineffective cases;  Subjects are free to withdraw from participation in the study at any time upon request.
In any case, every effort must be made to determine why patients discontinued the study treatment prematurely, which may include but are not limited to poor confidence in efficacy, occurrence of AEs, SAEs, or other serious complications, worsening of symptoms such that emergent intervention is required. As for those who withdrew from participation in the study or lost to follow-up, it is essential to investigate the potential reasons via telephone or mail. Investigators should record in detail when and how the last dose was administered, the efficacy and safety parameters at and after discontinuation, the relationship between discontinuation or withdrawal and the study drug, and the potential impact of discontinuation cases on the final conclusion of the study. Moreover, case report form (CRF) of withdrawal/dropout cases should also be completed and their original data should also be documented and stored in a secure manner.

Packaging of study drugs
All drugs used in the study are packaged and supplied by the sponsor in a randomized and blinded manner.

Accountability procedures for study drugs
Upon receipt of the study drugs from the sponsor, investigator or designated individual at each study site should sign a "Receipt form of study drugs" to ensure that the information on the packing slip matches exactly with what has been sent to the site, including the amount, lot numbers and quantity. When an eligible subject is included, investigator or designated individual will dispense the proper drugs in strict accordance with the randomization list. Each time a study drug is dispensed, there should be a "Drug dispensing form" as to the amount dispensed, to whom it is dispensed, and the date and signature of the person dispensing the drug.
Subjects should be advised to return all unused drugs at each study visit. Study personnel should record the amount (number of capsules) and date of return. Study drug will be properly accounted for and tracked with adequate documentation so as to assess subject's compliance.
The study drugs should be stored in a dry and ventilated place at room temperature. (1) trial group: XXK capsule + placebo of CDS tablet, oral, 2 capsules + 2 tablets a time, 3 times a day;

Drug administration
(2) control group: CDS tablet + placebo of XXK capsule, oral, 2 tablets + 2 capsules a time, 3 times a day.  Any AE that occurs throughout the treatment period.
The first 3 items will be observed or evaluated before and after treatment.

Efficacy parameters
The primary efficacy endpoint of this study is: The SAQ is a disease-specific functional status measure that was developed to quantify the physical and emotional effects of CAD [6].Each SAQ dimension (anginal frequency, physical limitation, anginal stability, disease perception, and treatment satisfaction) was scored on a scale of 0 to 100 and the clinical significance was defined as a difference of 8 points or more on the physical-limitation scale, 25 or more on the angina-stability scale, 20 or more on the angina-frequency scale, 12 or more on the treatment-satisfaction scale, and 16 or more on the quality-of-life scale [7].Patients will complete the SAQ at 0,8, and 20 weeks.
 Change from baseline in the blood stasis syndrome and the proportion of patients who had significant syndrome improvement.
Blood stasis syndrome which a common syndrome of chronic stable angina in TCM including the following symptoms: angina, choking sensation in the chest, palpitation, dark purple lips, ecchymosis on the tongue, and fine-choppy pulse.The syndrome score was assessed by using the Quantification score of TCM syndrome(with higher scores indicating higher severity, see page20 for details)and administered by the physician in charge of the study at 2, 4, 6, 8 and 20 weeks in each center.
The significant syndrome improvements defined as clinical signs and symptoms have been greatly improved, and decrease in syndrome score ≥70% [3].
 Change from baseline in ECG exercise test (the first 1/3 of patients included at each site)performed at 0 and 8 weeks.
Investigators should be aware of the contraindications to exercise test, and patients should be closely monitored during the test to ensure his/her safety, including ECG, BP, and angina.
 Change from baseline in serum lipid: total cholesterol, triglyceride, HDL cholesterol, and LDL cholesterol, measured at 0 and 8 weeks during treatment.
 Related signs: heart rate, rhythm, murmur, and BP, recorded before and after Treatment.
 Accompanying symptoms after treatment: fatigue, shortness of breath, aversion to cold, cold extremities and etc. (recorded as "yes" or "no"). If the changes in main symptoms are inconsistent with those in ECG features, that of lower efficacy shall prevail.

Evaluation of angina changes
The evaluation of angina changes should be based on the quantification score of angina pectoris:  Markedly effective: angina symptoms disappear or almost disappear, and decrease in angina score ≥70%;  Effective: attack frequency, severity and duration of angina have been greatly improved, and decrease in angina score ≥30% but <70%;  Ineffective: angina symptoms remain unchanged, and decrease in angina score <30%;  Worsening: angina symptoms become worse, and decrease in angina score <0.

Evaluation of syndrome changes
The evaluation of syndrome changes should be based on the quantification score of the TCM syndrome:  Markedly effective: clinical signs and symptoms have been greatly improved, and decrease in syndrome score ≥70%;  Effective: clinical signs and symptoms have been somewhat improved, and decrease in syndrome score ≥30% but <70%。  Ineffective: clinical signs and symptoms remain unchanged, and decrease in syndrome score <30%;  Worsening: clinical signs and symptoms become worse, and decrease in syndrome score <0.
The dynamic changes in the phenotypic group should also be assessed.  Worsening: clinical signs and symptoms become worse.

Use of nitroglycerin
 Withdrawal: complete withdrawal after treatment;  Dose reduction: the number of doses decreased at least 50% after treatment;  Unchanged: the number of doses decreased less than 50% after treatment.

Background information about drug-related safety issues
Based on the data from preclinical pharmacological and toxicological studies provided by the sponsor, evidence of XXK-related adverse reactions is not identified.

Definition
Adverse event (AE): An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Pre-existing conditions which worsen during a study are also to be reported as AEs.

Serious Adverse Event (SAE):
A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution. It is any AE that at any dose fulfils at least one of the following criteria: is fatal; is life-threatening; required in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above.

Adverse drug reaction (ADR):
An ADR is any unintended harm or injury associated with the use of given medications at a normal dosage during normal use. In clinical trials of any new drug or any new usage of a certain drug, any unintended harm or injury that has a causal relationship to the use of the drug should also be considered as an ADR.

Recording
For all AEs encountered during the clinical study, the following must be assessed and recorded on the adverse events form of the case report form (CRF): intensity, relationship to study drug, action taken regarding study drug, and outcome to date. All AEs, especially those for which the relationship to test drug is not "unrelated", should be followed up until they have returned to baseline status or stabilized. The follow-up procedures could be performed in clinic visits or during hospitalization, or via home visit, telephone or mail, depending on the severity of AEs.

Severity of An AE
Mild: events require minimal or no treatment and do not interfere with the subject's daily activities.
Moderate: events result in a low level of inconvenience or concern with the therapeutic measures. Moderate events may cause some interference with functioning.
Severe: events interrupt a subject's usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually incapacitating.

Relationship to study drugs
Attribution of an AE can be categorized as not related, unlikely related, possibly related, probably related, or definitely related to the study drugs.

Not related:
The AE is clearly not related to the investigational agent/procedure. -i.e.
Another cause of the event is most plausible; and/or a clinically plausible temporal sequence is inconsistent with the onset of the event and the study medication administration; and/or a causal relationship is considered biologically implausible.

Unlikely related:
The AE is doubtfully related to the investigational agent/procedure.

Possibly related:
The AE follows a reasonable temporal sequence from administration of the study drug/procedure, follows a known or expected response pattern to the suspected drug, but that could readily have been produced by a number of other factors.
Probably related: The AE is likely related to the investigational agent/procedure.

Definitely Related:
The AE is clearly related to the investigational agent/procedurei.e. An event that follows a reasonable temporal sequence from administration of the study drug, follows a known or expected response pattern to the suspected drug, that is confirmed by improvement on stopping and reappearance of the event on repeated exposure and that could not be reasonably explained by the known characteristics of the patient's clinical state.

Handling of SAEs
All SAEs should be managed properly and timely, and recorded on the appropriate SAE CRF. Any AE considered serious by the investigator or which meets the aforementioned criteria must be submitted on a signed and dated SAE form to the sponsor, ethics review committee and relevant authorities within 24 hours of site awareness. And the sponsor should also inform all study sites of such SAEs in a timely manner to ensure subjects' safety in accordance with applicable laws and regulations.
Fatal or life-threatening events considered to be caused by the study drugs must be reported immediately to the sponsor and relevant authorities via telephone, fax, EMS or E-mail.

Opening and handling of emergency envelops
The emergency envelope provided along with each test drug in its package should only be opened in case of a serious complication or a serious adverse event, which is called emergency unblinding. Once unblinded, the patient should be withdrawn from the study and regarded as a dropout case. Information about when, where and why the emergency unblinding occurs as well as each personnel's signature should also be documented.

Follow-up of unresolved AEs
All AEs should be followed up until they have been resolved, stabilized or returned to baseline status.

SAFETY EVALUATION
Level 1: safe, no ADRs; Level 2: relatively safe, treatment continues without any intervention; Level 3: safety issues observed, but treatment can be continued after proper intervention; Level 4: study termination due to ADRs.

Collection and fulfillment of CRF
The investigators fill in the 3-copy CRF of every patient enrolled in a complete, accurate, and timely manner. After the monitors review the completed CRF, the first copy of the CRF will be sent to the statisticians for data collection and management. Once the first copy of the CRF is submitted, the CRF will not be done any modification.

Data collection and management
The statisticians are responsible for data collection and management. Data management will be performed via EpiData 3.0. To assure the accuracy of the data, two statisticians should record the data from the CRF independently. Once there are any queries about the CRF, the statisticians should fill in a data queries form (DQF), and send it to the monitors. Then the monitors require the investigators to resolve the queries as soon as possible. The statisticians will do the data modification according to the correspondence from the investigators. The statisticians could send another DQF if necessary.

Data Lock
After confirming the accuracy of the database established from the CRF, the investigators, sponsor, statisticians will agree to lock the data. The locked database should not be done any modification. Any problems found after the data lock will be resolved in the procedure of statistical analysis. For primary outcome measures, statistical analyses will be performed separately in both FAS and PPS populations.

Safety analysis set
The safety analysis set (SS) is defined as a subset of subjects who took at least 1 dose of study drug after randomization.

Dynamic statistical plan
One interim analyses will be conducted under blinding conditions after 1/2 of the total number of cases have completed the trial.
Statisticians and principal investigators are responsible for drafting a written plan for statistical analysis according to the study protocol. It includes the number of included, excluded or withdrawal patients, the demographic and baseline characteristics of included patients, treatment compliance, efficacy analysis and safety analysis. Qualitative data will be described with absolute and relative (proportion or percentage) values; and quantitative data will be summarized with mean, standard deviation, maximum, minimum, and median. Paired t-test will be used for comparison before and after treatment within a treatment group. In analysis of variance (ANOVA) for multiple comparisons within a group, if the variances are assumed to be equal, then Student-Newman-Keuls (SNK) significance test will be used for pairwise comparison; if the variances are not assumed to be equal, then non-parametric test will be applied. Two-samples t-test will be used for comparison between treatment groups. Fourfold table will be displayed for comparison of categorical parameters: Chi-squared test for nominal categorical data and rank sum test for ordinal categorical data. Also, the analysis of covariance (ANCOVA) can be used to control for potential confounding variables.
All P values are two-side. Statistical significant level is set to be 0.05.
For between-group comparisons, chi-square test, Fisher's exact test, Wilcoxon rank test or Cochran-Mantel-Haenszel (CMH)  2 test may be used for qualitative data; while t-test, ANOVA, Wilcoxon rank test or ANCOVA may be applied for quantitative data.
Baseline analysis: Demographic and baseline characteristics will be reported for each subject. Comparisons between the treatment groups will be conducted using ANOVA or Chi-square test to assess the degree to which comparability of randomization can be achieved.

Dropout analysis:
The overall dropout rate and the dropout rate due to AEs will be compared between the treatment groups by using Chi-square test.

Efficacy analysis:
The effect of different study sites on efficacy parameters will be considered and analyzed. Safety analysis: Safety will be evaluated by tabulations of adverse events and will be presented with descriptive statistics at baseline and follow-up visits for each treatment group. Adverse event incidence rates will be summarized by system organ class, preferred term, and severity of the adverse event All information pertaining to adverse events noted during the study will be listed by subject, preferred term, system organ class, date of onset, date of resolution, severity, and relationship to study drug.

Laboratory quality control
The laboratories at each study site should have standard operating procedures (SOPs) and quality control procedures.

Investigator training
All investigators at each study site should attend a training session before participation to have a deep understanding of all the requirements in the conduct of the clinical trial.

Compliance enhancement
The informed consent procedure is essential to ensure patients' compliance to treatment.
The study drug, laboratory examinations, transportation and healthcare consultation will be provided by the sponsor free of charge.
Compliance rate is calculated by taking the amount of drug ingested divided by the amount the patient should have ingested and multiply by 100%. A compliance rate at 80%-120% defines good compliance; while that < 80% or > 120% defines poor compliance.
Patients should be asked to report all the concomitant medications while on study. Patients who have poor efficacy or poor compliance should be closely followed up.

Study monitoring
Clinical Study Coordinators (CSCs) will be designated to conduct on-site monitoring during the trial. The main responsibilities of CSC include: -Assure the protection of the rights, safety and well being of study subjects.
-Analyze and evaluate clinical data, to ensure investigator and site compliance with the study drug protocol, overall clinical objectives, and applicable regulations.
-Identify, help in the study site selection process, initiate, and eventually close out clinical study sites.
-Monitor the progress of clinical study sites and assure the protocol is followed and data is reported accurately.
-Make certain that the scientific integrity of the data collected is protected and verified.
-Assure that adverse events are correctly documented and reported.
-Review all case report forms and compare them to source documents.

Multi-center study coordination committee
A multi-center study coordination committee is set up to further ensure the quality of the clinical trial, which includes a Data Monitoring Committee (DMC) and a Implementation & Decision-making Committee. The multi-center study coordination committee is made up of the principal investigators, leaders of each study site and representatives of the sponsor.

ETHICAL ASPECTS
The investigator will ensure that this study is conducted in full conformance with the principles of the "Declaration of Helsinki" and applicable laws and regulations on the conduct of clinical trials.
This protocol and any accompanying material provided to the subject will be submitted by the investigator to the Ethics Committee of the Institute of Basic Clinical Research, China Academy of Chinese Medical Sciences. Approval from the board must be obtained before starting the study.
Informed consent is a process that is initiated prior to the individual's agreeing to participate in the study and continues throughout the individual's study participation. Extensive discussion of risks and possible benefits of this treatment will be provided to the subjects and their families. Consent forms describing in detail the study interventions/products, study procedures, and risks are given to the subject and written documentation of informed consent is required prior to starting intervention/administering study product. It must also be explained to the patients that they are completely free to refuse to enter the study or to withdraw from it at any time for any reason. A copy of the informed consent document will be given to the subjects for their records.

Investigator's files/retention of documents
The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. These documents should be classified into two different separate categories: investigator's study file, and patient clinical source documents.
The investigator's study file will contain the protocol/amendments, a paper representation of the CRF, Ethics Committee and governmental approval with correspondence, sample informed consent, drug records, staff curriculum vitae and authorization forms and other appropriate documents/correspondence etc. Patient clinical source documents would include patient hospital/clinic records, physician's and nurse's notes, appointment book, original laboratory reports, ECG, and special assessment reports, signed informed consent forms, consultant letters, and subject screening and enrollment logs.
In all sites the investigator must keep these two categories of documents (including the archival compact disk) on file for at least 10 years after completion or discontinuation of the study. After that period of time the documents may be destroyed once the site has provided written notification 60 days prior to destruction of the documents, subject to local regulations. No records should be disposed of without the written approval of the sponsor.

Source documents and background data
CSCs will perform ongoing source data verification to confirm that critical protocol data (i.e., source data) entered on the CRFs by authorized site personnel are accurate, complete, and verifiable from source documents. In no case is the CRF to be considered as source data for this trial.
The investigator shall supply the sponsor on request with any required background data from the study documentation or clinic records. This is particularly important when errors in data transcription are suspected. In case of special problems and/or governmental queries or requests for audit inspections, it is also necessary to have access to the complete study records, provided that patient confidentiality is protected.
Source documents that are required to verify the validity and completeness of data transcribed on the CRFs must never be obliterated or destroyed.

Audits and inspections
The investigator should understand that source documents for this trial should be made available to appropriately qualified personnel from the sponsor's quality assurance group or its designers or to health authority inspectors after appropriate notification. The verification of the CRF data must be by direct inspection of source documents.

Case Report Forms
Data for this study will be managed on computer via Epidata 3.0 from Case Report Forms. The data is entered on to the computer using the off-line mode. An audit trail will maintain a record of initial entries and changes made; reasons for change; time and date of entry; and user name of person authorizing entry or change. The investigator will connect on a regular basis, using an analog phone line, and the data will be transferred directly to the Sponsor's database.