Comparison of Buyang Huanwu Granules and Naoxintong Capsules 1 in Treatment of Stable Angina Pectoris: Rationale and Design of a 2 Randomized, Double-blind, Multicenter Clinical Trial

22 Background: Stable angina pectoris (SAP) is seriously threatened the health of 23 human life currently, and the mortality is in a continuous rising stage. The current 24 treatment strategies mainly include pharmaceutical therapy and revascularization. In 25 China, Buyang Huanwu granules (BYHW) and Naoxintong capsule (NXT) have been 26 used in the treatment of SAP, but it is not clear which one is better in terms of 27 relieving symptoms and improving quality of life. Therefore, we design a clinical trial 28 to compare the efficacy and safety between NXT and BYHW in the treatment of SAP. 29 Methods: This is a randomized, double-blinded, parallel controlled, multicenter 30 clinical trial protocol. On the basis of western medicine standardized treatment, a total 31 of 128 SAP patients will be randomly divided into intervention group 1 (NXT group), 32 intervention group 2 (BYHW group) and control group (placebo group) at a 2:1:1 33 ratio. A 2-week run-in period is required prior to randomization, and 1-week baseline 34 period and 4-week treatment period are included in this study. The primary outcome 35 is the efficacy rate of stable angina symptom score improvement; the secondary 36 outcomes include the effect of electrocardiogram, Seattle Angina Questionnaire 37 scores, and the nitroglycerin consumption. 38 Discussion: This study will evaluate the efficacy and safety between NXT and 39 BYHW in the treatment of SAP. The results will provide critical evidence of the 40 Chinese herbal medicine for SAP.


Title {1}
Protocol for a randomized, double-blind, multicenter clinical trial to compare efficacy rate of stable angina symptom score improvement between Buyang Huanwu granules and Naoxintong gapsules for adults with stable angina pectoris Introduction 49 Background and rationale {6a} 50 In recent years, cardiovascular disease is one of the major causes of death globally, 51 seriously threatening human life and health [1,2]. The mortality rate due to 52 cardiovascular diseases accounted for more than 40% of all-causes deaths in China [3]. 53 Coronary artery disease (CAD), a common cardiovascular disease, is the leading 54 cause of morbidity and mortality worldwide [4,5]. Angina pectoris is the most 55 common symptom of CAD, and a major cause of disability. Stable angina pectoris 56 (SAP), as one of the common types of angina pectoris, is a chronic medical condition 57 with an appreciable incidence of acute coronary events and increased mortality [6]. In 58 2017, the prevalence rate of SAP is 3.6% in China [7] and the numbers are rapidly 59 increasing due to the aging, dramatic lifestyle changes, and expanding population of 60 multiple risk factors for angina pectoris, such as hypertension, diabetes mellitus, etc.

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SAP significantly influences patients' quality of life and places a heavy burden on 62 society and healthcare systems [8]. As a consequence, it is now urgent that the society 63 mounts a comprehensive attack on SAP, harnessing all available resources to slow, 64 arrest, and possibly even reverse the epidemic of cardiovascular diseases [9]. 65 The aim of SAP management is to stop or minimize symptoms, and to improve  This study is a randomized, double-blinded, multicenter parallel-group, 100 placebo-controlled clinical trial. The study consists of a 2-week placebo run-in period, 101 1-week baseline period and 4-week treatment period. The specific study procedures are shown in Figure 1. The eligible patients will be randomly allocated to intervention 103 group 1, intervention group 2, and control group at the ratio of 2:1:1. Helsinki Declaration. All participants will be informed about every detail of the trial 119 and provide written informed consent according to the Helsinki Declaration before 120 participating. To protect participants' privacy, data forms and eCRFs involved in this 121 study will be maintained in secure storage at the coordinating center.

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Patients will be included after written informed consent and enrolled in the study 124 when the inclusion and exclusion criteria are met.

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Patients will be eligible for this study if they strictly meet the following criteria.

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(2) Diagnosis with SAP by the 'Guidelines for diagnosis and treatment of chronic  Patients who have any of the following criteria may not participate in this test.

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(1) History of MI or coronary revascularization or cardiac pacemaker installation 139 within 3 months;

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(4) Chest pain caused by severe cardiovascular neurosis, climacteric syndrome, 146 cervical spondylosis, bone and joint diseases, the digestive system diseases and 147 the respiratory system diseases;

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(5) Patients with severe liver and kidney dysfunction (including dialysis patients) 149 and active liver disease (including primary biliary cirrhosis and unexplained 150 persistent liver dysfunction), and/or alanine aminotransferase (ALT), aspartate 151 aminotransferase (AST)>1.5 times the normal upper limit, creatinine (Cr)> the 152 normal upper limit and total bilirubin (TBIL) ≥2 times the normal upper limit; 153 (6) Other severe cardio-cerebro-vascular, liver, kidney, and hematopoietic system 154 diseases, and those who have undergone major surgery recently;  On the consent form, participants will be informed that their data will be anonymized.

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This trial does not involve collecting biological specimens for storage.  The two interventions NXT group and BYHW group will be compared to placebo 178 group to evaluate the efficacy of NXT and BYHW in the treatment of SAP, and 179 further, the NXT group need to be compared to BYHW group to evaluate whether 180 Eligible participants will experience a 2-week run-in period, 1-week baseline period 183 and 4-week treatment period. The interventions during the treatment period are as 184 follows:

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In the study, NXT, BYHW, capsule placebo, and granule placebo are provided by  or >120%); (7) the blinding is uncovered or emergency unblinding is required.

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If a subject withdraws from the trial, no additional data will be collected, but the 205 existing data will be used for statistical analysis. The time of treatment or trial 206 discontinuation and the reason for withdrawal will be documented on the CRF.

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Drop-out patients will not be replaced.
In order to improve adherence to intervention protocols, during the treatment phase, 210 we will distribute medicines once a week to grasp the patient's drug consumption and 211 monitor patient compliance in time. Face-to-face adherence reminder sessions will 212 take place at the medicines dispensing process. After treatment, the package will be 213 returned to the researchers.  If SAEs occur during the study period, the participants are also required followed up 234 after the study period. Appropriate measures are taken to fully protect the interests of participants such as outpatient or inpatient care or referral to other specialists.

Outcomes {12}
237 Primary outcome 238 The primary outcome is the efficacy rate of stable angina symptom score 239 improvement [19]. The stable angina symptom score includes the number of angina 240 attacks, duration and degree of pain. The indicators of baseline period (0 weeks) and 241 treatment period (4 weeks) will be compared.  The sample size is calculated using PASS 15 software (NCSS, Kaysville, UT), and 258 driven by the efficacy rate of stable angina symptom score improvement. According to the referenced literature [22,23], the efficacy rate in relieving stable angina 260 symptoms of NXT is expected to be 85%, 70% for BYHW and 50% for placebo.

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Considering the drop rate of 20%, the estimated total sample size of 128 cases would 262 achieve 80% statistical power (two sided with type I error rate of α=0.05 and type II 263 error rate of β=0.2) to detect a significant difference. According to the ratio of 2:1:1, 264 there will be 64 cases in intervention group 1, 32 cases each in the intervention group 265 2 and control group.

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The potential participants will be recruited by advertisement, oral promotion by  If errors and omissions are made, the researcher shall be corrected promptly. All data 308 will be stored securely in line with local data management arrangements. Data 309 management will be implemented by Beijing Yilian Zhongkang Technology Co., Ltd.
To promote participant retention, at each medicine distribution visit, participants are 312 scheduled by phone, sent message, and called the day before. Missed visits are 313 rescheduled and followed up. The sponsor will provide compensation for 314 transportation costs.

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CRFs are paper-based. Source data will be collected in each site from the investigator 317 and will be transferred into the CRFs. Source data is stored in the respective center.

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The destruction of any paper files will be at least 5 years from the termination of the 319 study and will be authorized by the sponsor and the principle investigator.   This protocol, CRFs and other documents and materials related to the trial will be 332 kept strictly confidential and will not be disclosed to third parties unless expressly  The statistical analysis plan will be specified before data analysis. Statistical Analysis 344 System v9.4 (or higher version) will be used for statistical analysis. Professional 345 statisticians who are independent of all other processes of our study will carry out 346 analyses.

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For continuous variables, we will calculate the mean, standard deviation, median, 348 minimum, maximum, and interquartile range. For categorical variables, we will 349 describe various frequencies or percentages. The chi-square test or Fisher's exact test 350 will be used for categorical variables. For variables with a normal distribution, 351 inter-group comparisons will be analyzed with one-way ANOVA, whereas pairwise 352 comparisons before and after treatment will be performed with Student's t test. For 353 data that does not have a normal distribution, intra-group or inter-group differences 354 before and after treatment will be analyzed by the Wilcoxon rank-sum test. The 355 proportion of patients with AEs will be compared using the chi-square test or Fisher's 356 exact test.

Interim analyses {21b}
358 Since the number of recruited cases is not large, no interim analysis is planned.

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Methods for additional analyses (e.g., subgroup analyses) {20b} 360 We will include sex, center, complication, concomitant medication as covariates in an 361 analysis of covariance (ANCOVA) for statistical differences between groups by 362 reducing the error variance.

methods to handle missing data {20c}
365 This study will consistent with the CONSORT statement and intention-to-treat (ITT) 366 principle, and the last observation carried forward method will be used for missing 367 values. Cases in per protocol set (PPS) will be those who adhere to the protocol 368 closely without the absence of baseline characteristics. Analysis of primary outcome 369 and curative effect will be carried out using full-analysis-set and PPS approach. The 370 safety analysis set will include all randomized patients who have accomplished at 371 least one study visit. Participating centers will be required to sum-up participant 372 numbers in each center and list participants who have been removed from PPS.

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Plans to give access to the full protocol, participant level-data {31c} 374 After the publication of the results of this trial, the de-identified version of the 375 database will be available upon reasonable request for principal investigator.  Composition of the data monitoring committee, its role and reporting structure 387 {21a} 388 carry out clinical supervision and data monitoring, and set up safety officers to be 390 responsible for security review. All the medical records of the subjects will be 391 carefully assessed, and all harms and complications of the treatment will be reported.

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The harms will be categorized to AEs and SAEs as described in the AEs section. We  Any changes to the eligibility criteria, outcomes, or analyses will be reviewed by the 411 trial steering committee and updated in ClinicalTrials.gov.

Dissemination plans {31a}
presentations at local, national, and international academic conferences, and reports to 415 the funders. In addition, a summary of the primary outcome findings will be created in 416 English and Chinese and shared with the study participants.  However, this study has limitations. First, AEs will only be recorded and processed 460 during the 4-weekintervention period, which is relatively short, but the short-term 461 results could encourage further prospective studies with different treatment regimens 462 and longer follow-up. Second, due to the short intervention period, this study lacks 463 long-term observations of mortality and cardiovascular events. A large-scale and 464 long-term study in the future with mortality and cardiovascular events as the primary 465 endpoint is expected.

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In conclusion, under rigorous design and strict quality control, we expect that the 467 results will provide valuable evidence to determine whether the effect of NXT is 468 superior to BYHW for improving the symptoms of patients with SAP.