Cardioprotective effect of Platycodon grandiflorum in patients with early breast cancer receiving anthracycline-based chemotherapy: study protocol for a randomized controlled trial

The primary objective of this study is to ascertain the potential cardioprotective effects and safety of P. grandiflorum compared to placebo in patients with early breast cancer receiving anthracycline-based chemotherapy. The secondary objective is to determine whether there are other possible effects of P. grandiflorum on protecting against other, non-cardiac anthracycline toxicities.

We hypothesize that: (1) after 12 weeks, fewer patients taking P. grandiflorum will develop cardiac damage compared with patients receiving placebo, (2) P. grandiflorum will be safe at the dosage used in this trial, and (3) P. grandiflorum will have similar effects to placebo on non-cardiac anthracycline toxicities.

This is a single-center, double-blinded, randomized, placebo-controlled, parallel-group trial. Figure 1 depicts a flow chart of the study. A Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist for this protocol is also provided (see Additional file 1).

The study will be performed in the Breast Surgery Unit (Integrated Traditional Chinese and Western Medicine) of Longhua Hospital affiliated with Shanghai University of Traditional Chinese Medicine. The study will identify patients diagnosed with early breast cancer at our center who are receiving anthracycline-based chemotherapy. Patients receiving either adjuvant or neoadjuvant chemotherapy will be recruited. Participants who initially present to our hospital through both inpatient and outpatient units will be screened. Eligible patients who agree to participate will be asked to sign an informed consent form. To achieve adequate participant enrollment, study drug will be provided to participants at no cost. No other financial incentives will be provided to either treating physicians or patients.

To minimize selection bias, all eligible patients will be randomized in a 1:1 ratio to the treatment group or control group. We will use IBM SPSS software version 19 (IBM, Armonk, NY, USA) for group allocation according to a randomization list. Randomization will be performed by a professional, independent statistician who is not involved in the recruitment process of the study. The randomization codes will be concealed in sequentially prepared, coded, individual, opaque envelopes prepared by research assistants who are not involved in the recruitment process. The envelopes will be kept secure in the Good Clinical Practice (GCP) Centre of Longhua Hospital and will not be opened until after statistical analysis or in the case of a medical emergency. The study participants, study investigators, other research team members, pharmacists, nurses, and technicians will remain blinded to the allocation of study medication versus placebo.

CHM extract granules have been used in China for many years. In this study, the P. grandiflorum and placebo granules used were both manufactured by Jiangyin Tianjiang Pharmaceutical Co., Ltd (Jiangyin, China), a manufacturer of CHM extract granules that has been certified for Good Manufacturing Practice. P. grandiflorum granules have been approved by the China Food and Drug Administration (CFDA). Quality control was conducted by the company. P. grandiflorum granules contain a single herb, P. grandiflorum. A raw P. grandiflorum herb weighing 3 g was cooked in boiling water. The residual was then filtered, concentrated, spray-dried, and mixed with starch and sucralose. Finally, the P. grandiflorum granules were packaged in small pouches weighing 2 g each. The placebo granules are composed of 10% P. grandiflorum (a sub-therapeutic dose) and 90% starch, giving the placebo an identical appearance, smell, taste, and packaging as the P. grandiflorum granules.

CRFs will be used to collect data. To promote data quality and accuracy, one trained investigator will complete the CRFs and a second investigator will independently review all CRFs. Once data collection is complete, all data will be entered in duplicate into a computer database using EpiData 3.1 software (The EpiData Association, Denmark, Europe), by two individual data managers working independently through separate authorized identification codes and passwords. Figure 2 summarizes the study schedule of enrollment, interventions, and assessments according to the SPIRIT 2013 statement. Regular backups and off-site storage will be performed. The original CRFs and any other paper records will be kept on file at the clinical study center for 5 years after completion of the study.

Both adverse events (AEs) and serious adverse events (SAEs) will be assessed in this study. AEs are defined as unintended or unfavorable clinical symptoms, signs, laboratory results, or diseases that do not necessarily have a causal relationship with the study intervention. AEs in all participants in this clinical trial will be recorded at every visit. Details of all AEs will be recorded, including starting and ending date, grade (using the National Cancer Institute “Common terminology criteria for adverse events (NCI-CTCAE v 4.03)” [24]), and relation to the study medication. SAEs are defined as death, illness requiring hospitalization, events deemed life-threatening, events that result in persistent or significant disability or incapacity, a congenital anomaly or birth defect, or other important medical conditions. The Data and Safety Monitoring Board (DSMB) for this study will comprise one independent statistician, one senior pharmacist, one physician, and one individual with experience supervising a clinical trial. All members of the DSMB are independent from the trial sponsor and have no competing interests. The DSMB will organize a conference before allocation of the study and will review the trial documentation at least once to ensure that the trial is being conducted according to the trial protocol and GCP principles and that the data and SAEs are accurately and appropriately recorded on the CRF. All SAEs will be reported to the DSMB, ethics committees, sponsors, and the CFDA immediately. If a patient experiences a SAE, the DSMB has permission to unblind the case in the event of a medical emergency.

The study aims to detect the cardioprotective effects of P. grandiflorum in patients with early breast cancer receiving anthracycline-based chemotherapy. Sample size was calculated on the basis of the primary outcome. Since no randomized controlled trials (RCTs) have been previously performed on the cardioprotective effects of P. grandiflorum in patients receiving anthracycline-based chemotherapy, we proposed this study to evaluate the feasibility of a large-scale clinical trial. Anticipating a 20% dropout rate, a total of 120 patients, with 60 patients in each group, will be recruited for the pilot study.

An independent, professional statistician will perform the data analysis for the results and the AEs. Intention-to-treat (ITT) analysis will be carried out in all participants who complete the clinical trial. Missing data will be adjusted for using the last observation carried forward (LOCF) principle to obtain a complete database. Continuous data will be presented as means and standard deviations \( \left(\overline{X}\pm SD\right) \), or medians and quartiles. The comparability of the two groups will be assessed using the independent samples t test for continuous variables and the chi-square (χ²) test or Wilcoxon test, when appropriate, for categorical variables. The cumulative dose of anthracycline to cause cardiotoxicity will be estimated in each group using Kaplan-Meier curves; differences between the curves will be assessed using the log-rank method. The crude and adjusted hazard ratios and 95% confidence intervals will be estimated using a Cox proportional hazards regression model. All analyses will be performed using IBM SPSS software version 19 (IBM, Armonk, NY, USA). A two-tailed P value <0.05 was set for statistical significance.

Participant recruitment and randomization began in November 2016. Recruitment is ongoing.