Trial design
This is a single-center,randomized,double-blind,parallel group, placebo-controlled clinical trial. The trial aimed to study the effectiveness of Huangqin Decoction in Treating Diarrhea Associated with Abemaciclib. The study protocol followed the SPIRIT guidelines.
Participants
Recruitment strategies
Participants will be recruited from the Breast Surgery Department of Longhua Hospital of Shanghai University of Traditional Chinese Medicine. Recruitment posters will be distributed in the outpatient departments.
Diagnostic Criteria
According to the recommendations of the "National Comprehensive Cancer Network (NCCN) Breast Cancer Guidelines" (2023 Version 1) and the "Chinese Anti-Cancer Association Breast Cancer Diagnosis and Treatment Guidelines and Standards" (2023 Edition), Abemaciclib combined with ET regimen is used to treat HR+ early high-risk or locally advanced or metastatic breast cancer.
Inclusion criteria
Patients eligible for the study must comply with the following criteria:
(1) Female patients aged between 18 and 75 years;
(2) Pathological diagnosis and histological grading of stage I-III invasive breast cancer, with pathological results of HR(+), Her-2(-);
(3) Patients undergoing treatment with Abemaciclib;
(4) Diarrhea grade G of 0≤G≤3;
(5) ECOG<3 level;
(6) Willingness to participate in this trial and sign a written informed consent form, and able to comply with long-term follow-up.
Exclusion criteria
Participants meeting any of the following criteria will be excluded:
(1) Patients with diarrhea caused by organic diseases (such as inflammatory bowel disease, microscopic colitis, celiac disease, and Crohn's disease);
(2) Individuals with severe gastrointestinal symptoms such as significant gastrointestinal bleeding;
(3) Pregnant or breastfeeding women;
(4) Patients with severe cardiovascular or hematopoietic system diseases, or those with severe liver or kidney dysfunction;
(5) Individuals with severe mental illness or those unable to provide informed consent;
(6) Patients who have received diarrhea-related treatment within the past month;
(7) Participants who have previously taken part in similar clinical studies;
(8) Other conditions deemed unsuitable for inclusion by the researchers.
Discontinuation criteria
- Participants who experience a severe adverse event, whereby the physician deems it necessary to discontinue the clinical trial for that case.
- Participants whose condition worsens during the course of the disease, or other conditions affecting the observations of the trial emerge, and based on the physician's judgment, should discontinue the clinical trial. These cases will be treated as ineffective.
- Significant deviations occur in the implementation of the clinical trial protocol, such as extremely poor compliance, making it difficult to evaluate the drug effect.
- Participants who are unwilling to continue with the clinical trial process and request to withdraw from the clinical trial to the supervising physician.
Dropout criteria
- Participants who experience an allergic reaction or severe adverse event, or develop other complications and special physiological changes, whereby the physician deems it necessary to discontinue the study;
- Participants who are unwilling or unable to continue with the clinical research for any reason, and request to withdraw from the study to the supervising physician, resulting in study discontinuation;
- Participants who do not explicitly request to withdraw from the study but cease to accept medication and testing, resulting in loss to follow-up.
For cases that drop out, researchers should try to contact the participants by making house calls, scheduling follow-up visits, via phone, or through letters, in order to inquire about the reasons, record the time of the last medication intake, and complete any possible evaluation items; for cases that withdraw from the study due to allergies or other adverse reactions, or due to treatment ineffectiveness, researchers should take corresponding therapeutic measures based on the actual situation of the participants.
Sample size
This study adopts a randomized controlled trial. The primary indicators include the incidence of reduced diarrhea grade. Regarding the incidence of reduced diarrhea grade, literature and preliminary experiments show that the incidence of reduced diarrhea grade associated with Abemaciclib treated by Loperamide is estimated to be 55%, and the incidence of reduced diarrhea grade by Baicalin Decoction is 30%. Assuming a 1:1 ratio for the experimental group and the control group, one-sided α=0.025, power of 80%, and considering an effective value of 1% (a 1% increase is considered clinically significant). Using the "Superiority by a Margin Tests for Difference Between Two Means" module in PASS 2021 software (NCSS, LLC. Kaysville, Utah, USA) to calculate the sample size, we obtain a sample size of 63 subjects per group. Considering a 10% dropout and refusal rate, at least 70 subjects per group are required, totaling at least 140 subjects for the study.
Ethics and trial registration
The ethics and informed consent materials for this study were approved by the Ethics Committee of Longhua Hospital affiliated with Shanghai University of Traditional Chinese Medicine on May 16, 2024, with the committee approval number: 2024LCSY052. Besides, the study has been registered at the China Clinical Trial Registration Center, with the registration number: ChiCTR2400084945.
Procedure
Participants will be assessed for eligibility by breast surgeons for clinical trial enrollment. Those who meet the criteria will obtain informed consent. Then, participants will undergo randomization and allocation before being included in the treatment. Scale assessments and laboratory tests will be conducted according to the timeline (Figure 1). After the intervention period, participants will continue to receive one month of follow-up. Patients in the experimental group will receive two months of free traditional Chinese medicine treatment, while the control group will be provided with professional treatment guidance after the follow-up period ends. The total follow-up duration is three months, with visits every two weeks.
Randomization
The experiment employs a randomization method for group allocation, using the SAS 9.4 system to generate random numbers. When eligible subjects agree to participate in the trial, their information is entered into the clinical trial electronic data capture system, which produces a random number. Subsequently, subjects are enrolled in the treatment according to the assigned group.
Blinding
Investigators and subjects are both blinded. After the trial ends, all observational data will be entered into the database. The data in the database will be locked by professional statisticians of the project before the blinding is revealed uniformly. In case of an emergency (such as pregnancy of the subject, occurrence of unexpected serious adverse events, etc.) that seriously threatens the safety of the subject and it is necessary to know the treatment group of the subject, authorized personnel for unblinding will follow the operation procedures for maintaining blindness to open the emergency letter or log in to the electronic randomization system to unblind the individual subject, and record the specific time, reason and name of the person who performed the unblinding (sign and date) in a timely manner. At the same time, the monitor should be notified as soon as possible, and a safety event report should be submitted to the ethics committee. When unblinding, researchers should take necessary measures to rescue promptly to ensure the safety of the subjects.
Treatment Protocol
(I) Name and Specifications of Trial Medication
Traditional Chinese Medicine (TCM): Huangqin Decoction
Control Medication: Placebo Both the treatment group and the control group's TCM medications are manufactured by Shanghai Wanshicheng Pharmaceutical Co., Ltd. into decocted granules for consistent packaging. Standard chemotherapy drugs in Western medicine are used according to clinical standards.
(II) Allocation of Trial Medication
The trial medication is allocated based on the sequence of random codes assigned to the trial drugs and the number of cases allocated. A designated trial medication administrator is appointed by the research unit. Researchers screen eligible subjects and, after obtaining informed consent and documenting the study medical records, the trial medication administrator dispenses the medication on a case-by-case basis according to the sequence of patient visits and the ascending order of drug codes, recording each dispensation in the "Clinical Trial Medication Use Record Form."
(III) Inventory of Trial Medication
During each visit, researchers must record the amount of trial medication dispensed, the amount taken by the subject, and the amount returned.
(IV) Intervention Measures
Treatment Group: On top of the standard Western medical treatment protocol, the treatment group receives TCM treatment with Huangqin Decoction granules.
Control Group: On top of the standard Western medical treatment protocol, the control group receives a placebo that mimics the treatment group's medication. Traditional Chinese Medicine Treatment: ① Treatment Group: Huangqin Decoction Granules (Baical Skullcap 6g, Peony 6g, Licorice 6g, Jujube 9g). Medication begins after case enrollment, with one dose per day, continuing for 2 months or until disease progression, the patient cannot tolerate the side effects of the medication, the patient withdraws consent, is lost to follow-up, or dies. ② Control Group: Placebo (Placebo contains 10% extract of Huangqin Decoction with 90% color-matched excipients added). Western Medical Treatment: Standard treatment protocols recommended by the NCCN Guidelines (2023 Edition) and CSCO Guidelines (2023 Edition).
Outcome assessments
Primary outcome
Patient-graded incidence of diarrhea, grading evaluation of patient diarrhea
Secondary outcomes
Diarrhea Clinical Symptom Score: The score is determined based on the inquiry into the patient's diarrhea-related symptoms.
Frequency and Duration of Diarrhea: Record and analyze the daily frequency and duration of the patient's diarrhea.
Fecal Microbiota Analysis: Patient fecal samples were collected at baseline and 8 weeks after drug treatment. The changes in gut microbiota in the feces of the patients were analyzed using techniques such as 16s rRNA sequencing analysis and metabolomics analysis.
Karnofsky Performance Score (KPS): The KPS is a scoring criterion for functional status. It is used to assess changes in the patient's quality of life. The higher the score, the better the health condition, the more tolerant the patient is to the side effects of treatment, and therefore the more likely they are to receive thorough treatment.
Safety Evaluation Index: ECG, routine blood tests, and serum liver and kidney function tests will be performed before and after treatment to evaluate drug safety.
Observational Results
Objective Response Rate (ORR): ORR is the proportion of patients whose tumor volume reduction reaches a predefined value (30%) and can be maintained for a minimum duration. It is the sum of the rates of Complete Response (CR, i.e., the tumor completely disappears) and Partial Response (PR, i.e., the tumor shrinks by 30% or more).
Progression-free survival (PFS) at 1 year/2 years:PFS refers to the period from the start of treatment for tumor diseases until disease progression is observed or death occurs due to any cause. By comparing the changes in PFS at 1 year and 2 years after treatment, the efficacy of Huangqin Decoction in treating tumors can be evaluated.
Participant timeline
Data collection
The rating scales for the clinical symptom scores of diarrhea, diarrhea grades, KPS scores, as well as the assessment of drug safety, will be conducted in the Case Report Form (CRF). According to the participant timeline (Table 1), three sets of questionnaires should be filled out by the patients themselves or with the assistance of designated data collectors. Participants will complete the first questionnaire before the initial treatment, and the scale information will be collected again at 2, 4, 6, and 8 weeks after treatment. Follow-up visits will be conducted at 10th week and 12th week after the conclusion of the 8-week treatment period. Data collection will be carried out by a data collection team to ensure the neutrality of the results.
Table 1 Time schedule of enrolment, interventions, and assessments
|
Experimental Cycle
|
Baseline
|
Medication Period
|
Observation Period
|
|
Visit Time
|
First Follow-up
(0 weeks)
|
Second Follow-up
(2 weeks)
|
Third Follow-up
(4 weeks)
|
Fourth Follow-up
(6 weeks)
|
Fifth Follow-up
(8 weeks)
|
Sixth Follow-up (10 weeks)
|
Seventh Follow-up (12 weeks)
|
|
Obtaining Informed Consent
|
●
|
|
|
|
|
|
|
|
Review of Inclusion and Exclusion Criteria
|
●
|
|
|
|
|
|
|
|
Completion of General Information and Past Medical History
|
●
|
|
|
|
|
|
|
|
Recording of Breast Cancer Pathology Results
|
●
|
|
|
|
|
|
|
|
Previous Treatment Regimens for Breast Cancer
|
●
|
|
|
|
|
|
|
|
Vital Signs
|
●
|
●
|
●
|
●
|
●
|
●
|
●
|
|
Physical Examination
|
●
|
●
|
●
|
●
|
●
|
●
|
●
|
|
TNM Staging
|
●
|
●
|
●
|
●
|
●
|
●
|
●
|
|
ECOG Scoring
|
●
|
●
|
●
|
●
|
●
|
●
|
●
|
|
Complete Blood Count
|
●
|
|
|
|
●
|
|
|
|
Routine Stool Examination
|
●
|
|
|
|
●
|
|
|
|
Liver Function Tests
|
●
|
|
|
|
●
|
|
|
|
Renal Function Tests
|
●
|
|
|
|
●
|
|
|
|
Electrocardiogram (ECG)
|
●
|
|
|
|
●
|
|
|
|
Diarrhea Clinical Symptoms Scoring Scale
|
●
|
●
|
●
|
●
|
●
|
●
|
●
|
|
Diarrhea Grading
|
●
|
●
|
●
|
●
|
●
|
●
|
●
|
|
Karnofsky Performance Scale
|
●
|
●
|
●
|
●
|
●
|
●
|
●
|
|
Dispensing of Investigational Drugs
|
●
|
|
|
|
|
|
|
|
Recovery of Remaining Drugs
|
|
|
|
|
●
|
|
|
|
Recording of Concomitant Medications
|
|
●
|
●
|
●
|
●
|
●
|
●
|
|
Documentation of Adverse Events
|
|
●
|
●
|
●
|
●
|
●
|
●
|
|
Review by Principal Investigator
|
●
|
●
|
●
|
●
|
●
|
●
|
●
|
Data management
(I) Research Medical Records
Given the common practice in our country's hospitals where outpatient medical records are often brought by patients themselves, a dedicated "Research Medical Record" is designed for this trial to ensure the complete preservation of primary data from clinical trials. The Research Medical Record is the source document for clinical trial participants and should be kept at the hospital. It serves as the medical record for outpatient participants and, together with the inpatient medical record, constitutes the complete medical record for inpatient participants.
(II) Data Recording
Requirements for recording in Research Medical Records: ① Researchers must write in the Research Medical Record simultaneously while diagnosing and treating participants, ensuring that data recording is timely, complete, accurate, and truthful. ② Any corrections made to the Research Medical Record that are supported by evidence must be done by drawing a line through the error, annotating the corrected data beside it, and then signing and dating the correction by the researcher. Erasing or covering the original record is not permitted. ③ Original laboratory reports for outpatient participants should be attached to the Research Medical Record, while those for inpatient participants should be attached to their inpatient medical record. Laboratory results for both outpatient and inpatient participants must be filled into the "Laboratory Results Report Form" in the Research Medical Record.
(Ⅲ) Data will be recorded on CRFs in both paper and electronic form, with the electronic CRFs entered into the EDC system, all operations to be completed by the assessors. All original data will be stored in the medical record room of Longhua Hospital for 3 years, under the supervision of the Ethics Committee of Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine.
(Ⅳ) Review of Research Medical Records: After each participant's observation period ends, the researcher must submit the "Research Medical Record," "Informed Consent Form," and "Patient Medication Record Card" to the principal investigator of their unit for review within 3 working days. (III) Data Safety Monitoring Plan A Data Safety Monitoring Board is established to conduct data monitoring every 3 months. If any data issues arise, a discussion meeting will be convened to decide whether to proceed with further research or optimize the protocol, and progress reports will be submitted to the Ethics Committee.
Statistical analyses
All data will be analyzed using SPSS 25.0 statistical software.
(I) Analysis Data Sets
(1) Full Analysis Set (FAS)
Efficacy analysis will be performed on all cases that have been randomized and have taken the medication at least once. Missing data related to efficacy will be imputed using the last observation carried forward method. FAS is the primary population for efficacy evaluation.
(2) Per Protocol Set (PPS)
PPS subjects meet the inclusion criteria specified in the trial protocol, complete all planned observation periods; no use of other medications or treatments during the trial that could affect the evaluation of efficacy. The efficacy evaluation of this study is conducted on both FAS and PPS. PPS is the secondary population for efficacy evaluation.
(3) Safety Analysis Set (SS)
After randomization, all cases that have used the study medication at least once and have post-medication safety evaluation data constitute the safety analysis population of this study. SS is the primary population for safety evaluation.
(II) Statistical Processing
General Principles All statistical tests use two-sided tests, p≤0.05 will be considered statistically significant. Descriptive statistics of quantitative indicators will calculate means and standard deviations, maximum, minimum, and median values; descriptive statistics of categorical indicators will describe the number and percentage of each category. Statistical analysis is completed using SPSS professional statistical software.
Statistical Analysis Methods For count data, the Chi-square test (including CMH-Chi-square test) or Fisher's exact probability method will be used for inter-group comparisons. Measurement data are expressed as mean ± standard deviation (x±s), group design multiple sample mean comparisons use one-way ANOVA, inter-group comparisons use the least significant difference method (LSD-t test).
Dropout Analysis
The total dropout rate and the dropout rate due to adverse events in each group will be compared using the Chi-square test or Fisher's exact probability method.
Baseline Values Equilibrium Analysis Group t-tests or Chi-square tests are used to compare demographic data, vital signs, disease history, and other baseline value indicators to measure the balance between groups.
Compliance Analysis
Compliance is classified as good or poor, calculating the compliance situation of each group, and comparing the compliance of each group. Good compliance refers to 80%≤actual medication intake/required medication intake≤120%, poor compliance refers to actual medication intake/required medication intake <80% or >120%.
Effectiveness Analysis
The main time points for efficacy evaluation are at the end of each chemotherapy cycle (for PPS), and at the time of discontinuation from the group (for FAS population). Non-inferiority tests are used for inter-group comparisons of the primary efficacy indicators. Other measurement efficacy indicators are compared between groups using t-tests, such as analyzing changes relative to baseline, using a covariance analysis model for inter-group comparisons, with baseline as a covariate in the model.
Safety Analysis
The Chi-square test is used to compare the incidence of adverse events between groups, and to list and describe the adverse events occurring in this trial; laboratory test results before and after the trial normal/abnormal changes and the relationship between abnormal changes and trial drugs.
Ethics and Dissemination
The study protocol and informed consent documents for this research have been approved by the Ethics Committee of Longhua Hospital affiliated with Shanghai University of Traditional Chinese Medicine; Ethics Approval Number: 2024LCSY052. Informed consent must be obtained from each participant before they participate in the study. Before the recruitment phase, researchers will make contact with participants in advance, at which time all information about the study, its objectives, risks, and benefits will be thoroughly explained. Participants are entitled to withdraw from the study at any time without the need to provide any justification.
Protocol Amendments
Should any modifications to this research protocol be necessary, they must be jointly agreed upon by the members of the research team. Subsequently, the research team at Longhua Hospital will notify the China Clinical Trials Registration and Filing Information System of these approved changes. All amendments to the protocol will be formally documented, and the protocol will be accordingly updated in the clinical trial registry.
Ethical Principles
(I) Ethical Review: The clinical trial protocol is developed by the principal investigator and implemented after approval from the ethics committee. If revisions are made to the protocol during the implementation of the clinical trial, it must be resubmitted to the ethics committee for approval before proceeding. Should significant new information regarding the experimental medication arise, it is imperative to make written amendments to the informed consent form and submit it for ethics committee approval before obtaining renewed consent from the participants.
(II) Benefits and Risks: The benefits that participants may derive from this clinical trial include receiving effective clinical treatment for the disease being studied.
The risks that participants may face in this clinical trial include potential diarrhea side effects from the control medication. Medical countermeasures have been established for known side effects or adverse reactions, including the investigator's right to discontinue the clinical trial for a particular case based on their judgment;
(III) Medical Care and Protection of Participants: Researchers at each trial center are responsible for the medical care of participants, making medical decisions related to the clinical trial, and ensuring that participants receive appropriate treatment in the event of adverse incidents during the trial.
Researchers must promptly investigate any serious adverse events, take necessary measures to ensure the safety and rights of participants, and inform other researchers involved in the clinical trial of the adverse events.
Participants will receive the experimental medication free of charge during the scientific clinical trial. If adverse events related to the experimental medication occur, they will also receive free medical treatment.
(IV) Protection of Participant Privacy: Only research personnel involved in the scientific clinical trial will have access to participants' personal medical records. They will sign a "Researcher Declaration" or "Confidentiality Pledge" that includes confidentiality provisions. Data processing will employ "data anonymization," omitting information that could identify individual participants.
(V) Informed Consent Process: To screen qualified volunteers, researchers must explain the details of the clinical trial, including its purpose, procedures, potential benefits and risks, and the rights and obligations of participants, allowing them to fully understand and consider the information. Questions must be satisfactorily answered before obtaining consent. Participants must sign the "Informed Consent Form" before the clinical trial can commence. When each patient signs the informed consent form, doctors must provide their contact number to the patient so that they can reach the doctor at any time should their condition change.
Confidentiality
Only researchers involved in the clinical trial may have access to the subjects' medical records and will keep them confidential. Subjects will be de-identified for processing.