Cardioprotective effects of Platycodon grandiflorum Granules in HER2-positive early breast cancer patients receiving Trastuzumab plus Pertuzumab: study protocol for a double blind randomized controlled trial

Cardioprotective effects of Platycodon grandiflorum Granules in HER2-positive early breast cancer patients receiving Trastuzumab plus Pertuzumab: study protocol for a double blind randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Cardioprotective effects of Platycodon grandiflorum Granules in HER2-positive early breast cancer patients receiving Trastuzumab plus Pertuzumab: study protocol for a double blind randomized controlled trial Wei Hao, Chenping Sun, Chunyu Wu, Youyang Shi, Yuenong Qin, Sheng Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4423878/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Breast cancer, particularly the Human epidermal growth factor receptor 2 (HER2) positive subtype, poses a significant health challenge for women worldwide. Trastuzumab plus Pertuzumab therapy has shown efficacy in treating HER2-positive breast cancer, but its use is limited by associated cardiotoxicity. Traditional Chinese Medicine (TCM) suggests that Platycodon grandiflorus A. DC. (PG) may have cardioprotective effects due to its ability to nourish qi and blood. This study aims to investigate the effective and safety of PG in preventing cardiotoxicity associated with anti-HER2 therapy. Method In this double-blinded, randomized, placebo-controlled trial, approximately 120 patients will be randomly assigned to either the PG or placebo groups, alongside undergoing 12 months of dual anti-HER2 therapies in a 1:1 ratio. Cardiotoxicity will be assessed at a median follow-up of 1 year. The primary outcome measure is left ventricular global longitudinal strain, with secondary outcomes including: (1) changes in left ventricular ejection fraction, (2) the occurrence of cardiotoxicity, (3) the occurrence of trastuzumab plus pertuzumab interruption, and (4) event free survival and overall survival rates among patients. Discussion This will be the first clinical study to determine whether PG can reduce the cardiotoxicity induced by trastuzumab plus pertuzumab treatment in HER2-positive early breast cancer patients. Trial registration Chinese Clinical Trial Registry (Registration Number ChiCTR2200061011) Figures Figure 1 Introduction Breast cancer has become the most common malignant tumor in the world [ 1 ]. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–30% of breast cancer patients which has the characteristics of strong invasiveness and short remission period of chemotherapy and this causes poor clinical outcomes [ 2 ]. The widespread clinical application of HER2 blockers such as trastuzumab and pertuzumab has significantly improved the prognosis of patients with HER2-positive early breast cancer (EBC) [ 3 ]. Although anti-HER2 therapy is well tolerated, cardiotoxicity is still one of its major adverse effects. Cardiotoxicity associated with HER2-targeted therapy is characterized by left ventricular systolic dysfunction [ 4 ]. Some studies reported 27% of participants occurred left ventricular dysfunction receiving trastuzumab with anthracycline chemotherapy [ 5 ]. Base on the consideration of cancer therapy–related cardiac dysfunction (CTRCD), current guideline suggested primary prevention with cardioprotective medication and more sensitive cardiac function assessment and monitoring methods to detect subclinical cardiac dysfunction [ 6 ]. For primary prevention, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blocker (ARB) and beta-blockers (BB) were reported have cardioprotective effect. However, these studies only showed prevention of anthracycline induced cardiotoxicity, and their primary prevention of anti-HER2 caused cardiotoxicity were still remain controversy [ 7 – 9 ]. Furthermore, these drugs reduce heart rate or blood pressure could cause fatigue, which are poor tolerated for cancer patients who are receiving anti-cancer treatments. Therefore, a safe and effective cardioprotective medications is crucial for cancer patients. The main symptoms of CTRCD are palpitations and chest pain could be included in the categories of "xinji" and "xiongmen" in traditional Chinese medicine (TCM). “Qi deficiency” and “blood stasis” is the major syndrome. Platycodon grandiflorus A. DC. (PG) is one of the most wildly used Chinese herbal medicine (CHM), which could nourish Qi, removes stasis and promotes circulation. In clinical practice, we found that PG could release the symptoms caused by target therapy such as short of breath, palpitations and chest pain. Therefore, we believe PG has the potential to prevent CTRCD. However, there have been no highly quality clinical trials to evaluate the effective and safety of PG in preventing CTRCD. Objective We conducted this study to evaluate the efficacy and safety of Platycodon grandiflorus A. DC. granules (PGG) on preventing cardiotoxicity induced by trastuzumab and pertuzumab in breast cancer patients. And we believe that the result of this study could be the clinical evidence for a large scale randomize control trial (RCT) and shed light on integrated treatment on preventing CTRCD in future. Method Study design This is a prospective single-center, double-blinded, randomize placebo-controlled, parallel group trial and was conducted from Dec 1 2022 to Dec 1 2024. About 120 participants will be recruited from Longhua hospital. The first participant was enrolled in Dec 1 2022. This trial is reported according to the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) guideline Recruitment (details see additional file 1). This trial performs following the principles of the Declaration of Helsinki (Version Edinburgh 2000) and registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2200061011) on June 2021. This trial also approved by the Ethical Committee of Long Hua Hospital (2018LCSY205). The flow chart of the study is described in Fig. 1. Eligibility criteria Inclusion criteria Patients will be eligible for inclusion if they meet all the following criteria; Pathologically confirmed breast cancer Compliant with immunohistochemistry (IHC) method: HER-2 (+++) and/or Fluorescence in situ hybridization (FISH): HER-2 gene amplification; Karnofsky Performance Status (KPS) ≥ 60 Age between 20–70 years old Patients voluntarily participated in the trial and signed the informed consent. Exclusion criteria Patients will be excluded if they meet any of the following criteria: History of myocardial ischemia injury, congenital heart disease, cardiomyopathy and cardiac insufficiency before treatment Previous anti-HER2 target therapy Pregnant or breastfeeding women Patients with mental disorders Allergic to the study drug Participation in other clinical trial(s) within 3 months prior to this trial Criteria for Termination of the Trial: (1) Participants experiencing severe adverse reactions during the trial; (2) Identification of significant errors in the designated clinical trial protocol during the trial process, making it difficult to assess the trial's effects; or significant deviations occurring during implementation, making it difficult to evaluate the trial's effects. Randomization, allocation concealment, and blinding All eligible patients will be randomly assigned to receive PGG treatment or placebo at a ratio of 1:1. A randomization list will be generated in advance by using IBM SPSS software version 20.0 (IBM, Armonk, NY, USA) for group allocation and concealed in coded, individual, opaque envelopes. The envelops will not be opened until the statistical analysis or emergency unblinding. The randomization method will be performed by a professional statistician who is not involved in the patient recruitment process. The study investigators and study participants, other research team members will remain blinded in the whole period of study and group allocation will not be revealed until the end of the study. Intervention All the participants will be allocated to either the PGG group or the placebo control group. Patients in PGG group will receive trastuzumab plus pertuzumab therapy together with PGG 3g (equivalent to 6g raw herb). Patients in placebo control group will receive trastuzumab plus pertuzumab therapy together with placebo granules 3g. Both the PGG and placebo granules were prepared by Jiangyin Tianjiang Pharmaceutical, Co. Ltd (Jiangyin, China), a manufacturer own the Good Manufacturing Practice (GMP) certificates for TCM Formula Granules. Quality control was conducted by the company according to the China Food and Drug Administration (CFDA) (Approval number YBZ-PFKL-2021177). The placebo granules were composed of 5% of PGG, lactose, dextrin, a bittering agent, among other compounds, giving the placebo an identical color, smell, taste and packaging as the PG granules. Patients will be instructed to dissolve one package of granules in 150 mL hot water twice daily after meals for 6 cycles (3 weeks for 1 cycle). Outcomes measurement Primary outcomes The primary outcome is the final Left ventricular ejection fraction (LVEF), defined as the LVEF within 3 days of completion of last targeted therapy in this trial. Ejection fraction is measured by echocardiography (EPIQ 5, Philips Ultrasound, Amsterdam, The Netherlands) using 3D measurement via Simpson’s biplane method following American Society of Echocardiography guidelines [ 10 ]. LVEF will be performed by the same professional Ultrasound doctor. Secondary outcomes The second outcomes include subclinical heart failure which defined LVEF less than 55% or a drop of more than 10% from baseline in this trial [ 11 ]; LV global longitudinal strain (GLS), Circulating biomarkers such as B-type natriuretic peptide (BNP), troponin I (TnI) [ 12 ]; Event free survival (EFS) and Overall survival (OS) of patients; incidence of trastuzumab plus pertuzumab interruption. Table 1 summarizes the study schedule for enrollment, interventions, and assessments in accordance with the SPIRIT 2013 statement. Table 1 Schedule of enrollment, interventions and assessments (using the SPIRIT 2013 statement [ 26 ]) Baseline Allocation Visit 1 Visit 2 Visit 3 Visit 4 Follow-up Timepoint (weeks) 0 Within 3 days of admission 3 6 9 12 18 24 Enrollment : Eligibility screen X Medical history X Physical exam X Allocation X Informed consent X Intervention : PGG Placebo Assessment : LVEF X X X X X X X LV GLS X X X X X X X TNI X X X X X X BNP X X X X X X EFS X X X X X X X OS X X X X X X X Adverse events X X X X X X X Distributions of treatment or placebo drugs X X X X Other medication X X X X X X X Compliance X X X X X X X Abbreviations: PGG: Platycodon grandiflorus A. DC. Granules; LVEF: Left ventricular ejection fraction; GLS: global longitudinal strain; TnI: troponin I; BNP: brain natriuretic peptide; EFS: Event free survival; OS: Overall survival; X represents the indicators tested in the specific time period Safety assessment and monitoring The routine physiological examination such as blood pressure, heart rate, heart rhythm, respiratory rate, blood routine, liver and kidney function will be evaluated according to the National Cancer Institute “Common terminology criteria for adverse events (NCI-CTCAE v 4.03) [ 13 ]. The type, grade, medical treatment, time of occurrence and duration of adverse effects (AEs) will be recorded at every visit in all patients. All AEs should be tracked to be normal or substantially normal. Serious adverse effects (SAEs) defined death, immediately life-threatening, requires hospitalization or prolonged hospitalization, disability, a congenital anomaly or birth defect and other sever medical conditions. All SAEs will be reported to ethics committees immediate. The ethics committees will determine to unblind the case in the event of a medical emergency. Data collecting and management This trial will utilize electronic Case Report Forms (eCRFs) for data collection and management. Data collection will be conducted by specialized clinical trial coordinators using EpiData 3.1 software (The EpiData Association, Denmark, Europe), There will be corresponding documentation for data entry. Dual-entry by two individuals will be performed to ensure data accuracy. Any necessary data modifications must be discussed and approved by both the representative from the research center and the data center, with records of the discussion and approval being signed by both parties. The researchers, data managers, and statistical analysts will collectively conduct the final review of unresolved issues in the data under blinded conditions. They will also categorize the study population and verify records of serious adverse events reporting and handling in accordance with the clinical trial protocol. Data analysis Data analysis will be performed by an independent professional statistician. Statistical analysis will be performed using IBM SPSS software version 19 (IBM, Armonk, NY, USA). All statistical tests will be two-tailed, and a p-value less than 0.05 will be considered statistically significant. For Continuous data that follows a normal distribution and has homogeneity of variance, statistical descriptions will be conducted using counts (n), means ± standard deviations. Between-group comparisons will utilize one-way analysis of variance (ANOVA) and SNK multiple comparisons. Data measured at multiple time points before and after treatment will undergo repeated measures analysis of variance (ANOVA) and multivariate analysis of variance. If the data do not follow a normal distribution, statistical descriptions will involve counts (n), median (M), minimum (min), and maximum (max) values. Between-group comparisons will utilize the Kruskal-Wallis H test and Nemenyi test for multiple comparisons. For numerical variables measured at multiple time points before and after treatment, as well as binary and multinomial ordinal variables, generalized estimating equations or mixed-effects models will be conducted. For count data, statistical descriptions will include frequencies, relative frequencies, and rates. When the analysis indicator is unordered, Chi-Squared tests will be used; when the analysis indicator is ordered, the Wilcoxon rank-sum test will be applied. Data with different bidirectional ordered attributes will undergo linear tests, rank-sum tests. Survival rates will be calculated using the Kaplan-Meier method and survival curves will be plotted. Sample size There have been no previous clinical trials to evaluate the efficacy and safety of PGG in preventing cardiotoxicity induced by trastuzumab and pertuzumab in EBC patients. This is a pilot clinical study, which serves as a preliminary basis for large-scale clinical trials in the future. Based on the estimated number of HER-2 positive EBC in Longhua Hospital being approximately 150 patients per year, assuming a dropout rate of 10%, we have decided to enrol 120 participants, with 60 in each group. Discussion Although the mechanism by which trastuzumab and pertuzumab induces cardiotoxicity remains unclear, the HER-2 signaling pathway plays a significant role in the embryonic development and maintenance of normal cardiac function [ 14 , 15 ]. Trastuzumab and pertuzumab exerts an antagonistic effect on the HER-2 receptor, which may affect the stress response, damage repair, and survival status of myocardial cells, thereby exacerbating cardiac toxicity [ 16 – 18 ]. Pharmacological studies have found that PG could reduce oxidative stress responses in cardiac cells, decrease lipid peroxidation, thereby protecting myocardial cell endothelium, and inhibiting cell apoptosis [ 19 , 20 ]. LVEF decline was usually used as the gold standard for diagnosing CTRCD, with an overall incidence rate ranging from 4.2–13.1%. The variation in occurrence rates is mainly associated with the racial background, age, past cardiac history of enrolled patients, and diagnostic criteria for LVEF decline. There is controversy regarding the diagnostic criteria for LVEF decline across various clinical trials. In PACS-04, the criterion was an LVEF of less than 45% [ 21 ], while in BCIRG 006, it was defined as a decrease in LVEF of more than 10% compared to baseline [ 22 ]. The NCCTG N9831 trial considered absolute LVEF value below 50% or a decrease more than 15% as indicative of LVEF decline [ 23 ]. In NSP-B31, patients with an LVEF value below 55% or a decrease of more than 10% were classified as LVEF decline [ 24 ]. The HERA trial had the most stringent diagnostic criteria: a pre-treatment LVEF greater than 55%, a decline in LVEF of more than 10% post-treatment, and an absolute value dropping below 50% [ 25 ]. In our study, we used final LVEF instead the LVEF decline due to the controversial diagnostic criteria. Global longitudinal strain (GLS) GLS is measured through strain imaging technology in echocardiography, assessing the ability of the myocardium to contract and relax. It provided a more sensitive evaluation of cardiac function compared to LVEF [ 26 ]. However, the current lack of authoritative guidelines on the threshold (absolute or relative) for GLS to diagnose CTRCD is the primary barrier in diagnosing subclinical cardiac with GLS and initiating therapeutic [ 27 ]. Thus, in this study, we measured GLS before and after treatment to determine responsiveness to PGG therapy by observing changes in its numerical values. For patients with HER2-positive breast cancer, targeted therapy is paramount. However, cardiotoxicity ranks among its most significant adverse effects, and currently, there is a dearth of safe and effective therapeutic drugs. This study to assess the clinical efficacy safety of PGG in managing CTRCD through a double-blind randomized controlled trial. The results of this study can guide large-scale clinical studies in the future. This protocol follows high-quality methodology and adheres to the Consolidated Standards of Reporting Trials (CONSORT) statement for randomized controlled trials (RCTs) of herbal medicines [ 28 ] and the SPIRIT 2013 statement [ 29 ]. Trial status Participant recruitment and randomization began in Dec 1 2022. Recruitment is ongoing. Abbreviations HER2: Human epidermal growth factor receptor 2 EBC: Early breast cancer CTRCD: Cancer treatment-related cardiac dysfunction ACEi: Angiotensin-converting enzyme inhibitor ARB: Angiotensin receptor blocker BB: Beta-blocker TCM: Traditional Chinese medicine PG: Platycodon randiflorus A. DC. CHM: Chinese herbal medicine RCT: Randomize control trial SPIRIT: Standard Protocol Items Recommendations for Interventional Trials IHC: Immunohistochemistry FISH, Fluorescence in situ hybridization KPS: Karnofsky Performance Status GMP: Good Manufacturing Practice CFDA: China Food and Drug Administration LVEF: Left ventricular ejection fraction GLS: Global longitudinal strain BNP: B-type natriuretic peptide TnI: Troponin I EFS: Event free survival OS: Overall survival AEs: Adverse event SAEs: Serious adverse effects NCI-CTCAE, National cancer institute’s “Common terminology criteria for adverse events” eCRFs: electronic Case Report Forms CONSORT: Consolidated Standards of Reporting Trials Declarations Ethics approval and consent to participate This study protocol performed following the principles of the Declaration of Helsinki (Version Edinburgh 2000) and registered in the Chinese Clinical Trial Registry (Registration number：ChiCTR2200061011) on June 2021. This study protocol also approved by the Ethical Committee of Long Hua Hospital (2018LCSY205). An informed consent file will be obtained and kept for each study participant. Any modifications to the protocol or informed consent document must be approved by the relevant ethics committee before being implemented. Consent for publication No identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. Model informed consent forms are available upon request to the corresponding author. Availability of data and materials The authors declare that they have no competing interests. Funding This study has been authorized and funded by technology commission of Shanghai Municipality (20Z21900300). The funding body played no role in the design of the study, collection, analysis, and interpretation of data; or in writing the manuscript. Authors' contributions WH participated in the design and coordination of the study. SL contributed to funding management. YNQ and YYS participated in data collection and assembly. CPS participated in data analysis and interpretation. YYS participated in the provision of study materials and patients. WH and CYW participated in writing the manuscript. All authors have read and approved the final version of the manuscript. Acknowledgements We wish to thank all patients and their family members who participants in the study. Availability of data and materials Not applicable. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. Hanna WM, Slodkowska E, Lu FI, Nafisi H, Nofech-Mozes S. 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Strain Imaging in Cardio-Oncology. JACC: Cardio Oncol. 2020;2(5):677–89. Gagnier JJ, Boon H, Rochon P, Group CONSORT, et al. Recommendations for reporting randomized controlled trials of herbal interventions: explanation and elaboration. J Clin Epidemiol. 2006;59:1134–49. Chan AW, Tetzlaff JM, Gøtzsche PC. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. Additional Declarations No competing interests reported. Supplementary Files SPIRITchecklist.doc Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 19 Sep, 2024 Editor assigned by journal 31 May, 2024 Editor invited by journal 21 May, 2024 Submission checks completed at journal 21 May, 2024 First submitted to journal 15 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4423878","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":306192519,"identity":"ab60adef-48b0-4267-8cf2-fe9c046f6941","order_by":0,"name":"Wei Hao","email":"","orcid":"","institution":"Longhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Hao","suffix":""},{"id":306192520,"identity":"7a8fab3a-f9a7-48bc-96e0-6341c3127cc7","order_by":1,"name":"Chenping Sun","email":"","orcid":"","institution":"Longhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chenping","middleName":"","lastName":"Sun","suffix":""},{"id":306192521,"identity":"08d903f3-f37a-4638-9e8e-a6c4b22d2837","order_by":2,"name":"Chunyu Wu","email":"","orcid":"","institution":"Longhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chunyu","middleName":"","lastName":"Wu","suffix":""},{"id":306192524,"identity":"0371ed93-2707-4893-a8b6-7156c3287ea6","order_by":3,"name":"Youyang Shi","email":"","orcid":"","institution":"Longhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Youyang","middleName":"","lastName":"Shi","suffix":""},{"id":306192526,"identity":"e06e00b9-8dd8-4f39-a009-708c220b736d","order_by":4,"name":"Yuenong Qin","email":"","orcid":"","institution":"Longhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuenong","middleName":"","lastName":"Qin","suffix":""},{"id":306192527,"identity":"bc1b82d4-d201-4954-ad2b-aba0d6218f06","order_by":5,"name":"Sheng Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqklEQVRIiWNgGAWjYBACAwYGNhAtx8befoAELUC1xnw8ZxJI05I4T8LBgDgt5hLpzx5/qNmW3ibBkMDwo2IbYS2WM3LMDQ4cu53bJt14gLHnzG0iHHY7h03iYANQi8yBBGbGNqK0pD8DaUlnk0gwIFZLghlISwIJWu6/MZM4c+y2YRswkA8S55czx59JVNTclpdvbz/44EcFEVpQwAES1Y+CUTAKRsEowAUAVHQ//UnzB5kAAAAASUVORK5CYII=","orcid":"","institution":"Shanghai University of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Sheng","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-05-15 08:51:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4423878/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4423878/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57937461,"identity":"91fe0850-c47d-47b7-ae21-e78b92cb3d1b","added_by":"auto","created_at":"2024-06-07 17:38:48","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":53598,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4423878/v1/b96d1bb0a155a1db43363978.jpg"},{"id":57937504,"identity":"f5618ef0-52fd-4b0a-8c30-b6e75c79fcf0","added_by":"auto","created_at":"2024-06-07 17:38:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":610928,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4423878/v1/51e6be0c-25a4-474d-99d5-51a714f452a9.pdf"},{"id":57937462,"identity":"8c193886-c2c3-460b-ae21-4fe5f029a8da","added_by":"auto","created_at":"2024-06-07 17:38:49","extension":"doc","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":117248,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-4423878/v1/f6109c3ae6725dbfa88c25c4.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cardioprotective effects of Platycodon grandiflorum Granules in HER2-positive early breast cancer patients receiving Trastuzumab plus Pertuzumab: study protocol for a double blind randomized controlled trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer has become the most common malignant tumor in the world [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20\u0026ndash;30% of breast cancer patients which has the characteristics of strong invasiveness and short remission period of chemotherapy and this causes poor clinical outcomes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The widespread clinical application of HER2 blockers such as trastuzumab and pertuzumab has significantly improved the prognosis of patients with HER2-positive early breast cancer (EBC) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although anti-HER2 therapy is well tolerated, cardiotoxicity is still one of its major adverse effects. Cardiotoxicity associated with HER2-targeted therapy is characterized by left ventricular systolic dysfunction [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Some studies reported 27% of participants occurred left ventricular dysfunction receiving trastuzumab with anthracycline chemotherapy [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Base on the consideration of cancer therapy\u0026ndash;related cardiac dysfunction (CTRCD), current guideline suggested primary prevention with cardioprotective medication and more sensitive cardiac function assessment and monitoring methods to detect subclinical cardiac dysfunction [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. For primary prevention, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blocker (ARB) and beta-blockers (BB) were reported have cardioprotective effect. However, these studies only showed prevention of anthracycline induced cardiotoxicity, and their primary prevention of anti-HER2 caused cardiotoxicity were still remain controversy [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, these drugs reduce heart rate or blood pressure could cause fatigue, which are poor tolerated for cancer patients who are receiving anti-cancer treatments. Therefore, a safe and effective cardioprotective medications is crucial for cancer patients.\u003c/p\u003e \u003cp\u003eThe main symptoms of CTRCD are palpitations and chest pain could be included in the categories of \"xinji\" and \"xiongmen\" in traditional Chinese medicine (TCM). \u0026ldquo;Qi deficiency\u0026rdquo; and \u0026ldquo;blood stasis\u0026rdquo; is the major syndrome. Platycodon grandiflorus A. DC. (PG) is one of the most wildly used Chinese herbal medicine (CHM), which could nourish Qi, removes stasis and promotes circulation. In clinical practice, we found that PG could release the symptoms caused by target therapy such as short of breath, palpitations and chest pain. Therefore, we believe PG has the potential to prevent CTRCD. However, there have been no highly quality clinical trials to evaluate the effective and safety of PG in preventing CTRCD.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eWe conducted this study to evaluate the efficacy and safety of Platycodon grandiflorus A. DC. granules (PGG) on preventing cardiotoxicity induced by trastuzumab and pertuzumab in breast cancer patients. And we believe that the result of this study could be the clinical evidence for a large scale randomize control trial (RCT) and shed light on integrated treatment on preventing CTRCD in future.\u003c/p\u003e \u003c/div\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis is a prospective single-center, double-blinded, randomize placebo-controlled, parallel group trial and was conducted from Dec 1 2022 to Dec 1 2024. About 120 participants will be recruited from Longhua hospital. The first participant was enrolled in Dec 1 2022. This trial is reported according to the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) guideline Recruitment (details see additional file 1). This trial performs following the principles of the Declaration of Helsinki (Version Edinburgh 2000) and registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2200061011) on June 2021. This trial also approved by the Ethical Committee of Long Hua Hospital (2018LCSY205). The flow chart of the study is described in Fig.\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eInclusion criteria\u003c/h2\u003e \u003cp\u003ePatients will be eligible for inclusion if they meet all the following criteria;\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePathologically confirmed breast cancer\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCompliant with immunohistochemistry (IHC) method: HER-2 (+++) and/or Fluorescence in situ hybridization (FISH): HER-2 gene amplification;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eKarnofsky Performance Status (KPS)\u0026thinsp;\u0026ge;\u0026thinsp;60\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAge between 20\u0026ndash;70 years old\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients voluntarily participated in the trial and signed the informed consent.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eExclusion criteria\u003c/h2\u003e \u003cp\u003ePatients will be excluded if they meet any of the following criteria:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHistory of myocardial ischemia injury, congenital heart disease, cardiomyopathy and cardiac insufficiency before treatment\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePrevious anti-HER2 target therapy\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePregnant or breastfeeding women\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with mental disorders\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAllergic to the study drug\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eParticipation in other clinical trial(s) within 3 months prior to this trial\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eCriteria for Termination of the Trial:\u003c/h2\u003e \u003cp\u003e(1) Participants experiencing severe adverse reactions during the trial;\u003c/p\u003e \u003cp\u003e(2) Identification of significant errors in the designated clinical trial protocol during the trial process, making it difficult to assess the trial's effects; or significant deviations occurring during implementation, making it difficult to evaluate the trial's effects.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eRandomization, allocation concealment, and blinding\u003c/h2\u003e \u003cp\u003eAll eligible patients will be randomly assigned to receive PGG treatment or placebo at a ratio of 1:1. A randomization list will be generated in advance by using IBM SPSS software version 20.0 (IBM, Armonk, NY, USA) for group allocation and concealed in coded, individual, opaque envelopes. The envelops will not be opened until the statistical analysis or emergency unblinding. The randomization method will be performed by a professional statistician who is not involved in the patient recruitment process. The study investigators and study participants, other research team members will remain blinded in the whole period of study and group allocation will not be revealed until the end of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eIntervention\u003c/h2\u003e \u003cp\u003eAll the participants will be allocated to either the PGG group or the placebo control group. Patients in PGG group will receive trastuzumab plus pertuzumab therapy together with PGG 3g (equivalent to 6g raw herb). Patients in placebo control group will receive trastuzumab plus pertuzumab therapy together with placebo granules 3g. Both the PGG and placebo granules were prepared by Jiangyin Tianjiang Pharmaceutical, Co. Ltd (Jiangyin, China), a manufacturer own the Good Manufacturing Practice (GMP) certificates for TCM Formula Granules. Quality control was conducted by the company according to the China Food and Drug Administration (CFDA) (Approval number YBZ-PFKL-2021177). The placebo granules were composed of 5% of PGG, lactose, dextrin, a bittering agent, among other compounds, giving the placebo an identical color, smell, taste and packaging as the PG granules. Patients will be instructed to dissolve one package of granules in 150 mL hot water twice daily after meals for 6 cycles (3 weeks for 1 cycle).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes measurement\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003ePrimary outcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome is the final Left ventricular ejection fraction (LVEF), defined as the LVEF within 3 days of completion of last targeted therapy in this trial. Ejection fraction is measured by echocardiography (EPIQ 5, Philips Ultrasound, Amsterdam, The Netherlands) using 3D measurement via Simpson\u0026rsquo;s biplane method following American Society of Echocardiography guidelines [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. LVEF will be performed by the same professional Ultrasound doctor.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eThe second outcomes include subclinical heart failure which defined LVEF less than 55% or a drop of more than 10% from baseline in this trial [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; LV global longitudinal strain (GLS), Circulating biomarkers such as B-type natriuretic peptide (BNP), troponin I (TnI) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]; Event free survival (EFS) and Overall survival (OS) of patients; incidence of trastuzumab plus pertuzumab interruption. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the study schedule for enrollment, interventions, and assessments in accordance with the SPIRIT 2013 statement.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSchedule of enrollment, interventions and assessments (using the SPIRIT 2013 statement [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e])\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAllocation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVisit 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVisit 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eVisit 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eVisit 4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eFollow-up\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTimepoint\u003c/p\u003e \u003cp\u003e(weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWithin\u003c/p\u003e \u003cp\u003e3 days of admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEnrollment\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEligibility screen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical exam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAllocation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformed consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntervention\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAssessment\u003c/b\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLV GLS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistributions of treatment or placebo drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther medication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompliance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviations: PGG: Platycodon grandiflorus A. DC. Granules; LVEF: Left ventricular ejection fraction; GLS: global longitudinal strain; TnI: troponin I; BNP: brain natriuretic peptide; EFS: Event free survival; OS: Overall survival;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eX represents the indicators tested in the specific time period\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSafety assessment and monitoring\u003c/h2\u003e \u003cp\u003eThe routine physiological examination such as blood pressure, heart rate, heart rhythm, respiratory rate, blood routine, liver and kidney function will be evaluated according to the National Cancer Institute \u0026ldquo;Common terminology criteria for adverse events (NCI-CTCAE v 4.03) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The type, grade, medical treatment, time of occurrence and duration of adverse effects (AEs) will be recorded at every visit in all patients. All AEs should be tracked to be normal or substantially normal. Serious adverse effects (SAEs) defined death, immediately life-threatening, requires hospitalization or prolonged hospitalization, disability, a congenital anomaly or birth defect and other sever medical conditions. All SAEs will be reported to ethics committees immediate. The ethics committees will determine to unblind the case in the event of a medical emergency.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eData collecting and management\u003c/h2\u003e \u003cp\u003eThis trial will utilize electronic Case Report Forms (eCRFs) for data collection and management. Data collection will be conducted by specialized clinical trial coordinators using\u003c/p\u003e \u003cp\u003eEpiData 3.1 software (The EpiData Association, Denmark, Europe), There will be corresponding documentation for data entry. Dual-entry by two individuals will be performed to ensure data accuracy. Any necessary data modifications must be discussed and approved by both the representative from the research center and the data center, with records of the discussion and approval being signed by both parties. The researchers, data managers, and statistical analysts will collectively conduct the final review of unresolved issues in the data under blinded conditions. They will also categorize the study population and verify records of serious adverse events reporting and handling in accordance with the clinical trial protocol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eData analysis will be performed by an independent professional statistician. Statistical analysis will be performed using IBM SPSS software version 19 (IBM, Armonk, NY, USA). All statistical tests will be two-tailed, and a p-value less than 0.05 will be considered statistically significant. For Continuous data that follows a normal distribution and has homogeneity of variance, statistical descriptions will be conducted using counts (n), means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. Between-group comparisons will utilize one-way analysis of variance (ANOVA) and SNK multiple comparisons. Data measured at multiple time points before and after treatment will undergo repeated measures analysis of variance (ANOVA) and multivariate analysis of variance. If the data do not follow a normal distribution, statistical descriptions will involve counts (n), median (M), minimum (min), and maximum (max) values. Between-group comparisons will utilize the Kruskal-Wallis H test and Nemenyi test for multiple comparisons. For numerical variables measured at multiple time points before and after treatment, as well as binary and multinomial ordinal variables, generalized estimating equations or mixed-effects models will be conducted. For count data, statistical descriptions will include frequencies, relative frequencies, and rates. When the analysis indicator is unordered, Chi-Squared tests will be used; when the analysis indicator is ordered, the Wilcoxon rank-sum test will be applied. Data with different bidirectional ordered attributes will undergo linear tests, rank-sum tests. Survival rates will be calculated using the Kaplan-Meier method and survival curves will be plotted.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThere have been no previous clinical trials to evaluate the efficacy and safety of PGG in preventing cardiotoxicity induced by trastuzumab and pertuzumab in EBC patients. This is a pilot clinical study, which serves as a preliminary basis for large-scale clinical trials in the future. Based on the estimated number of HER-2 positive EBC in Longhua Hospital being approximately 150 patients per year, assuming a dropout rate of 10%, we have decided to enrol 120 participants, with 60 in each group.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough the mechanism by which trastuzumab and pertuzumab induces cardiotoxicity remains unclear, the HER-2 signaling pathway plays a significant role in the embryonic development and maintenance of normal cardiac function [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Trastuzumab and pertuzumab exerts an antagonistic effect on the HER-2 receptor, which may affect the stress response, damage repair, and survival status of myocardial cells, thereby exacerbating cardiac toxicity [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Pharmacological studies have found that PG could reduce oxidative stress responses in cardiac cells, decrease lipid peroxidation, thereby protecting myocardial cell endothelium, and inhibiting cell apoptosis [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLVEF decline was usually used as the gold standard for diagnosing CTRCD, with an overall incidence rate ranging from 4.2\u0026ndash;13.1%. The variation in occurrence rates is mainly associated with the racial background, age, past cardiac history of enrolled patients, and diagnostic criteria for LVEF decline. There is controversy regarding the diagnostic criteria for LVEF decline across various clinical trials. In PACS-04, the criterion was an LVEF of less than 45% [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], while in BCIRG 006, it was defined as a decrease in LVEF of more than 10% compared to baseline [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The NCCTG N9831 trial considered absolute LVEF value below 50% or a decrease more than 15% as indicative of LVEF decline [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In NSP-B31, patients with an LVEF value below 55% or a decrease of more than 10% were classified as LVEF decline [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The HERA trial had the most stringent diagnostic criteria: a pre-treatment LVEF greater than 55%, a decline in LVEF of more than 10% post-treatment, and an absolute value dropping below 50% [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In our study, we used final LVEF instead the LVEF decline due to the controversial diagnostic criteria.\u003c/p\u003e \u003cp\u003eGlobal longitudinal strain (GLS) GLS is measured through strain imaging technology in echocardiography, assessing the ability of the myocardium to contract and relax. It provided a more sensitive evaluation of cardiac function compared to LVEF [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, the current lack of authoritative guidelines on the threshold (absolute or relative) for GLS to diagnose CTRCD is the primary barrier in diagnosing subclinical cardiac with GLS and initiating therapeutic [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Thus, in this study, we measured GLS before and after treatment to determine responsiveness to PGG therapy by observing changes in its numerical values.\u003c/p\u003e \u003cp\u003eFor patients with HER2-positive breast cancer, targeted therapy is paramount. However, cardiotoxicity ranks among its most significant adverse effects, and currently, there is a dearth of safe and effective therapeutic drugs. This study to assess the clinical efficacy safety of PGG in managing CTRCD through a double-blind randomized controlled trial. The results of this study can guide large-scale clinical studies in the future. This protocol follows high-quality methodology and adheres to the Consolidated Standards of Reporting Trials (CONSORT) statement for randomized controlled trials (RCTs) of herbal medicines [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] and the SPIRIT 2013 statement [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTrial status\u003c/p\u003e \u003cp\u003eParticipant recruitment and randomization began in Dec 1 2022. Recruitment is ongoing.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHER2: Human epidermal growth factor receptor 2\u003c/p\u003e\n\u003cp\u003eEBC: Early breast cancer\u003c/p\u003e\n\u003cp\u003eCTRCD: Cancer treatment-related cardiac dysfunction\u003c/p\u003e\n\u003cp\u003eACEi: Angiotensin-converting enzyme inhibitor \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eARB: Angiotensin receptor blocker\u003c/p\u003e\n\u003cp\u003eBB: Beta-blocker \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTCM: Traditional Chinese medicine\u003c/p\u003e\n\u003cp\u003ePG: Platycodon randiflorus A. DC.\u003c/p\u003e\n\u003cp\u003eCHM: Chinese herbal medicine\u003c/p\u003e\n\u003cp\u003eRCT: Randomize control trial\u003c/p\u003e\n\u003cp\u003eSPIRIT: Standard Protocol Items Recommendations for Interventional Trials\u003c/p\u003e\n\u003cp\u003eIHC: Immunohistochemistry\u003c/p\u003e\n\u003cp\u003eFISH, Fluorescence in situ hybridization\u003c/p\u003e\n\u003cp\u003eKPS: Karnofsky Performance Status\u003c/p\u003e\n\u003cp\u003eGMP: Good Manufacturing Practice\u003c/p\u003e\n\u003cp\u003eCFDA: China Food and Drug Administration\u003c/p\u003e\n\u003cp\u003eLVEF: Left ventricular ejection fraction\u003c/p\u003e\n\u003cp\u003eGLS: Global longitudinal strain\u003c/p\u003e\n\u003cp\u003eBNP: B-type natriuretic peptide\u003c/p\u003e\n\u003cp\u003eTnI: Troponin I\u003c/p\u003e\n\u003cp\u003eEFS: Event free survival\u003c/p\u003e\n\u003cp\u003eOS: Overall survival\u003c/p\u003e\n\u003cp\u003eAEs: Adverse event\u003c/p\u003e\n\u003cp\u003eSAEs: Serious adverse effects\u003c/p\u003e\n\u003cp\u003eNCI-CTCAE, National cancer institute\u0026rsquo;s \u0026ldquo;Common terminology criteria for adverse events\u0026rdquo;\u003c/p\u003e\n\u003cp\u003eeCRFs: electronic Case Report Forms\u003c/p\u003e\n\u003cp\u003eCONSORT: Consolidated Standards of Reporting Trials\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study protocol performed following the principles of the Declaration of Helsinki (Version Edinburgh 2000) and registered in the Chinese Clinical Trial Registry (Registration number：ChiCTR2200061011) on June 2021. This study protocol also approved by the Ethical Committee of Long Hua Hospital (2018LCSY205). An informed consent file will be obtained\u003c/p\u003e\n\u003cp\u003eand kept for each study participant. Any modifications to the protocol or informed consent document must be approved by the relevant ethics committee before being implemented.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. Model informed consent forms are available upon request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been authorized and funded by\u0026nbsp;technology commission of Shanghai Municipality (20Z21900300).\u0026nbsp;The funding body played no role in the design of the study, collection, analysis, and interpretation of data; or in writing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWH participated in the design and coordination of the study. SL contributed to funding management. YNQ and YYS participated in data collection and assembly. CPS participated in data analysis and interpretation. YYS participated in the provision of study materials and patients. WH and CYW participated in writing the manuscript. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe wish to thank all patients and their family members who participants in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHanna WM, Slodkowska E, Lu FI, Nafisi H, Nofech-Mozes S. Comparative Analysis of Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer According to 2007 and 2013 American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations. J Clin Oncol. 2017;35(26):3039\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLynce F, Barac A, Tan MT, Asch FM, Smith KL, Dang C, et al. SAFE-HEaRt: Rationale and Design of a Pilot Study Investigating Cardiac Safety of HER2 Targeted Therapy in Patients with HER2-Positive Breast Cancer and Reduced Left Ventricular Function. Oncologist. 2017;22(5):518\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, Verma S, et al. HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice plus trastuzumab in patients with previously treated, anthracycline-na\u0026iuml;ve, HER2-positive, locally advanced/metastatic breast cancer. BMC Cancer. 2016;16:352.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKundu M, Butti R, Panda VK, Malhotra D, Das S, Mitra T, et al. Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer. Mol Cancer. 2024;23(1):92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCurigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al. ESMO Guidelines Committee. Electronic address: [email protected]. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020;31(2):171\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLivi L, Barletta G, Martella F, Saieva C, Desideri I, Bacci C, et al. Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial. JAMA Oncol. 2021;7(10):1544\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGupta V, Kumar Singh S, Agrawal V, Bali Singh T. Role of ACE inhibitors in anthracycline-induced cardiotoxicity: A randomized, double-blind, placebo-controlled trial. Pediatr Blood Cancer. 2018;65(11):e27308.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGujral DM, Lloyd G, Bhattacharyya S. Effect of prophylactic betablocker or ACE inhibitor on cardiac dysfunction \u0026amp; heart failure during anthracycline chemotherapy\u0026thinsp;\u0026plusmn;\u0026thinsp;trastuzumab. Breast. 2018;37:64\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1\u0026ndash;e3914.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHao W, Shi Y, Qin Y, Sun C, Chen L, Wu C, et al. Platycodon grandiflorum Protects Against Anthracycline-Induced Cardiotoxicity in Early Breast Cancer Patients. Integr Cancer Ther. 2020;19:1534735420945017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHao W, Liu S, Qin Y, Sun C, Chen L, Wu C et al. Cardioprotective effect of Platycodon grandiflorum in patients with early breast cancer receiving anthracycline-based chemotherapy: study protocol for a randomized controlled trial. Trials. 2017; 22;18(1):386.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eU.S. Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE). (v4.03: June 14, 2010). 2010. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\u003c/span\u003e\u003cspan address=\"http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIndini A, Rijavec E, Grossi F. Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors. Int J Mol Sci. 2021;22(9):4774.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBao Y, Chen J, Duan L, Wang F, Lai H, Mo Z, et al. Comparing the difference of adverse events with HER2 inhibitors: a study of the FDA adverse event reporting system (FAERS). Front Pharmacol. 2024;15:1288362.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuan M, Tse G, Zhang Z, Han X, Wu WKK, Li G, et al. The incidence of atrial fibrillation with trastuzumab treatment: A systematic review and meta-analysis. Cardiovasc Ther. 2018;36(6):e12475.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEsc\u0026oacute;rcio-Dourado CS, Alves-Ribeiro FA, Lima-Dourado JC, Dos Santos AR, de Oliveira Pereira R, Tavares CB, et al. Human Epidermal Growth Factor Receptor-2 gene polymorphism and breast cancer risk in women from the Northeastern region of Brazil. Clin (Sao Paulo). 2020;75:e2360.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou S, Cirne F, Chow J, Zereshkian A, Bordeleau L, Dhesy-Thind S, Ellis PM, Mukherjee SD, Aghel N, Leong DP. Three-Year Outcomes Following Permissive Cardiotoxicity in Patients on Trastuzumab. Oncologist. 2023;28(9):e712\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang S, Chai X, Hou G, Zhao F, Meng Q. Platycodon grandiflorum (Jacq.) A. DC.: A review of phytochemistry, pharmacology, toxicology and traditional use. Phytomedicine. 2022;106:154422.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang L, Niu H, Chen Y, Li X, Zhao Y, Zhang C, et al. Quality control of Platycodon grandiflorum (Jacq.) A. DC. based on value chains and food chain analysis. Sci Rep. 2023;13(1):14048.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpielmann M, Roch\u0026eacute; H, Delozier T, Canon JL, Romieu G, Bourgeois H, et al. Trastuzumab for patients with axillary-no de-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009;27(36):6129\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdvani PP, Ballman KV, Dockter TJ, Colon-Otero G, Perez EA. Long-Term Cardiac Safety Analysis of NCCTG N9831 (Alliance) Adjuvant Trastuzumab Trial. J Clin Oncol. 2016;34(6):581\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuntheralingam S, Fan CS, Calvillo-Arg\u0026uuml;elles O, Abdel-Qadir H, Amir E, Thavendiranathan P. Evaluation of Risk Prediction Models to Identify Cancer Therapeutics Related Cardiac Dysfunction in Women with HER2\u0026thinsp;+\u0026thinsp;Breast Cancer. J Clin Med. 2022;11(3):847.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Azambuja E, Ponde N, Procter M, Rastogi P, Cecchini RS, Lambertini M, et al. A pooled analysis of the cardiac events in the trastuzumab adjuvant trials. Breast Cancer Res Treat. 2020;179(1):161\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKar J, Cohen MV, McQuiston SA, Malozzi CM. Can global longitudinal strain (GLS) with magnetic resonance prognosticate early cancer therapy-related cardiac dysfunction (CTRCD) in breast cancer patients, a prospective study? Magn Reson Imaging. 2023;97:68\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Jennifer E, Barac A, Thavendiranathan P, Scherrer-Crosbie M. Strain Imaging in Cardio-Oncology. JACC: Cardio Oncol. 2020;2(5):677\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGagnier JJ, Boon H, Rochon P, Group CONSORT, et al. Recommendations for reporting randomized controlled trials of herbal interventions: explanation and elaboration. J Clin Epidemiol. 2006;59:1134\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan AW, Tetzlaff JM, G\u0026oslash;tzsche PC. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-complementary-medicine-and-therapies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcam","sideBox":"Learn more about [BMC Complementary Medicine and Therapies](https://bmccomplementmedtherapies.biomedcentral.com/)","snPcode":"","submissionUrl":"","title":"BMC Complementary Medicine and Therapies","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4423878/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4423878/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBreast cancer, particularly the Human epidermal growth factor receptor 2 (HER2) positive subtype, poses a significant health challenge for women worldwide. Trastuzumab plus Pertuzumab therapy has shown efficacy in treating HER2-positive breast cancer, but its use is limited by associated cardiotoxicity. Traditional Chinese Medicine (TCM) suggests that Platycodon grandiflorus A. DC. (PG) may have cardioprotective effects due to its ability to nourish qi and blood. This study aims to investigate the effective and safety of PG in preventing cardiotoxicity associated with anti-HER2 therapy.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eIn this double-blinded, randomized, placebo-controlled trial, approximately 120 patients will be randomly assigned to either the PG or placebo groups, alongside undergoing 12 months of dual anti-HER2 therapies in a 1:1 ratio. Cardiotoxicity will be assessed at a median follow-up of 1 year. The primary outcome measure is left ventricular global longitudinal strain, with secondary outcomes including: (1) changes in left ventricular ejection fraction, (2) the occurrence of cardiotoxicity, (3) the occurrence of trastuzumab plus pertuzumab interruption, and (4) event free survival and overall survival rates among patients.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis will be the first clinical study to determine whether PG can reduce the cardiotoxicity induced by trastuzumab plus pertuzumab treatment in HER2-positive early breast cancer patients.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eChinese Clinical Trial Registry (Registration Number ChiCTR2200061011)\u003c/p\u003e","manuscriptTitle":"Cardioprotective effects of Platycodon grandiflorum Granules in HER2-positive early breast cancer patients receiving Trastuzumab plus Pertuzumab: study protocol for a double blind randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-07 17:38:44","doi":"10.21203/rs.3.rs-4423878/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-19T13:38:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-31T13:36:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-21T05:13:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-21T05:05:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Complementary Medicine and Therapies","date":"2024-05-15T08:50:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-complementary-medicine-and-therapies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcam","sideBox":"Learn more about [BMC Complementary Medicine and Therapies](https://bmccomplementmedtherapies.biomedcentral.com/)","snPcode":"","submissionUrl":"","title":"BMC Complementary Medicine and Therapies","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7d49526f-e02b-440c-9107-b479402f0d77","owner":[],"postedDate":"June 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-05T15:09:53+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-07 17:38:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4423878","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4423878","identity":"rs-4423878","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}