This is a randomized, double-blind, multi-center controlled trial which aims at exploring
the efficacy of YH0618 granule on chemotherapy-induced hair loss in patients with
breast cancer and elucidating the potential mechanism from the aspect of kidney deficiency
or renal dysfunction. To achieve this goal, a total of 214 breast cancer patients
who will receive first chemotherapy will be recruited for the study. The patients
will be randomly divided into group A (YH0618 granule) and group B (placebo) using
a 1:1 allocation ratio, adhering to the “CONSORT statement” [
17] and “SPIRIT statement” [
18]. The primary outcome of this study is the time point of occurrence of hair loss
reaching grade II assessed by WHO Toxicity Grading Scale, and objective indexes of
hair quality and hair follicle recorded by a hair and scalp conditioners (CBS-603, CBS-Medical Skin Analysis, Taiwan). Secondary outcomes include changes
of facial color and thumbnails color, grading of thumbnails ridging, assessment of
quality life, fatigue, routine blood test, hepatic and renal function, and some medical
indicators which can reflect kidney deficiency in Chinese Medicine. The flow chart
of the study is shown in Figure 1 and Table 1. The recruitment, evaluation and data
collection will be conducted at Galactophore Department of Guangdong Provincial Hospital
of Chinese Medicine, Galactophore Department of The First Affiliated Hospital of Guangzhou
University of Chinese Medicine, and Galactophore Department of The Third Hospital
Ethical approvals have been confirmed from the institutional review board at Guangdong
Provincial Hospital of Chinese Medicine (BF2018-100-01), The First Affiliated Hospital
of Guangzhou University of Chinese Medicine (ZYYECK【2019】006) and The Third Hospital
of Nanchang (2018-011). The trial was registered in the Chinese Clinical Trials Registry:
ChiCTR1800020107. Patients will receive a detailed information sheet and complete
written consent forms.
The trial is managed by the School of Chinese Medicine, HKU and data will be supervised
by Data and Safety Monitoring Board (DSMB), which is an independent group of experts
that advises funding agency and study investigators. DSMB members includes three experts
from different fields (Western medical sciences, Chinese medicine and statistics).
The DSMB is for quality control of this research data and make sure the integrity
of the study. The protocol compliance, safety, and on-schedule study progress are
also monitored by the DSMB. Auditing trial will be conducted every 3 months and the
process will be independent from investigators. Study documents (soft- and hard-copies)
will be retained in a secure location for 5 years after trial completion.
A total of 214 eligible patients will be recruited at different clinical centers.
Inclusion criteria include: (1) females with stage I or II breast cancer aged between
18-75 years; (2) will receive first chemotherapy; (3) planning to receive chemotherapeutic
agents containing taxanes or/and anthracyclines; (4) chemotherapy regimen will last
at least 6 cycles with every three weeks a cycle; (5) adverse events assessed using
WHO toxicity classification criteria< II grade; (6) a life expectancy is at least
6 months. Exclusion criteria are: (1) subjects with a medical history of hair transplantation;
(2) suffer from psoriasis or severe scalp infection; (3) hair loss induced by alopecia
areata, alopecia totalis or scalp injury, etc.; (4) pregnancy, lactation or potential
pregnancy; (5) allergic to some specific food, like black soybean, etc.; (6) severe
cardiac, hepatic, renal, pulmonary and hematic lesions or other diseases which will
affect their survival; (7) who have any severe mental or behavioral disorders that
cannot be fully informed; (8) be suspected or do have a history of alcohol and drug
abuse; (9) cannot understand or fill in questionnaires because of cognitive disorders
or low level of literacy; (10) a variety of factors affecting drug taking and absorption,
such as inability to swallow, chronic diarrhea, intestinal obstruction, etc. Eligible
patients will be invited to participate in this study after obtaining their written
consent form. All participants will be closely monitored in the study.
Estimation of sample size
The primary outcome in this study is the time point of occurrence of chemotherapy-induced
hair loss reaching grade II measured by WHO Toxicity Grading Scale for Determining
the Severity of Adverse Events. Our previous results showed that YH0618 could cause
the incidence of hair loss grade <II to reach 50% for patients who have completed
chemotherapy, and the difference between the incidence of hair loss grade <II in YH0618
group and control group was 15%. Thus, the difference in proportion between the two
groups will be measured by Z-test. To achieve a two-sided type I error alpha = 0.05
and power: (1-beta) = 80%, the minimal number of subject need in each group is 85.
We estimated a 20% attrition rate at the end of follow-up; hence, a sample size of
at least 107 in each group (214 in total) is planned for this study.
Randomization and blinding
Each subject will obtain an unique number after completing written consent. A computer
blocked random number sequence with a block size of four will be generated centrally
by a statistician not involving in this study. As YH0618 granule and placebo show
the same appearance, a double-blind model will be adopted. Therefore, the randomization
sequence and different groups will be kept hidden from subjects, practitioners, data
collectors and statisticians.
Intervention and control condition
Prior to intervention, baseline data will be collected including demographics, medical
characteristics, assessment of chemotherapy-induced hair loss, facial color, thumbnails
color, grading of thumbnails ridging, quality of life, blood routine test, and hepatic
and renal function. After that, subjects assigned to group A will receive YH0618 granules
three times a day (6 g each time), 6 days a week, mixing with 300 ml warm water from
the first to the fourth chemotherapy cycle. Subjects in group B will receive the placebo
granule in the same manner. Then, all the subjects will be followed up until one month
after chemotherapy. All specific methods, such as scalp cooling, used for reducing
hair loss will be prohibited during the clinical trial. Both YH0618 granules and placebo
are produced by Guangzhou Kanghe Pharmaceutical Co., Ltd., which meets national standards.
The primary outcome is the time point of occurrence of hair loss reaching grade II
assessed by WHO Toxicity Grading Scale, and objective indexes of hair quality and
hair follicle recorded by a hair and scalp detector (CBS-603, CBS, Taiwan) before the fifth chemotherapy.
Grading of chemotherapy-induced hair loss
WHO Toxicity Grading Scale is commonly used to monitor and rate severity of anticancer
drugs-induced toxicity [
20]. The grading criteria for hair loss is shown in Table 2. Alopecia assessments will
be conducted by a clinician blinded to treatment assignment, and by the participant.
Objective measurement of hair loss
In order to objectively evaluate the hair quality and hair follicle, a hair and scalp
detector (CBS-603) will be used. The detector obtained patents in the United States,
German, Japan, China, and China Taiwan, and many international authentication from
Conformite Europeenne (CE), Federal Communications Commission (FCC), and Restriction
of Hazardous Substances (RHoS). The detector is composed of 10X-200X Hair and Scalp
Camera and software. The whole top of the head, a wide range of hair loss and the
condition of hair follicles could be clearly filmed with 10X, 50X and 200X, respectively.
The software has a function of testing through which hair test and analysis can be
conducted. In this study, identification and classification of the level of hair loss,
hair diameter and quality will be analyzed.
Secondary outcomes include changes of facial color and thumbnails color, grading of
thumbnails ridging, assessment of quality life, fatigue, routine blood test, hepatic
and renal function, and some medical indicators which can reflect kidney deficiency
in Chinese Medicine.
Facial color and thumbnails color
The assessment of facial and thumbnails color is used by L*a*b system, which is the
same as the clinical trial we conducted before [
13]. In the fixed surroundings, the skin color of the forehead, right and left cheeks,
jaw, and the thumbnail color will be recorded by the hair and scalp detector with
Grading of thumbnails ridging
The grading of left and right thumbnail ridging will be measured by National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). The definition
of nail ridging is a disorder characterized by vertical or horizontal ridges on the
nails. The grading criteria for nail ridging is shown in Table 3.
Quality of life measurement
Quality of life has been regarded as an important index to measure and monitorcancer patients’ treatment outcomes [
21]. Chinese version of the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B)
with good reliability and validity will be used to measure breast cancer-specific
quality of life [
22].The tool includes 37 items scored on a 5-point Likert scale, ranging from 0 to 4 with
higher scores indicating better quality of life [
24]. The items are classified into five subscales: Physical Well-Being, Social/Family
Well-Being, Emotional Well-Being and Functional Well-Being, which constitute the FACT-General,
and the additional concerns for breast cancer, which is called the Breast Cancer Subscale.
A total score is calculated by summing all subscale scores.
Fatigue will be measured by the Chineseversion of FACIT-Fatigue version 4, a 13-item FACIT Fatigue Scale,which could be used for patients of any tumor type [
</a>]. Each itemscored on a 5-point Likert self-report scale, ranging from 0 to 4. A totalscore is obtained by summing all item scores and a high scoreindicates less fatigue.</p>
Clinical objective examination
Routine blood test, and assessment of liver and kidney function are the same as our previous trial [
13]. Based on the evaluation standard of kidney deficiency in Chinese Medicine, kidney
deficiency will be divided into deficiency of kidney qi, deficiency of kidney yang
and deficiency of kidney yin. Modern studies also found that kidney deficiency syndrome
has a modern pathophysiological basis, clinically manifested as changes in the relevant
medical indicators such as the adrenal axis, thyroid axis, gonadal axis, renin-angiotensin,
immune energy, liver and kidney function and hematopoietic function [
26]. So in this study, Immune indices including immunoglobulinM (IgM), alexin C3, Helper
T cells CD4+, CD8+T cell and some metabolic index of microelement such as Mg, Cu, Zn, Fe.
All participants will be assessed within 3 days before every chemotherapy from the
first to the fifth chemotherapy. Then, all the subjects will be followed up and the
final assessment will be conducted at one month after the last chemotherapy. Professional
research assistant will assign YH0618 granules or placebo, and notify the subjects
of dosage and time. Quality and compliance to intervention will be achieved by checking
attendance records and the diary of self-record kept by each participant.
Adverse events will be recorded through self-reports spontaneously by participants
or asking the participants the open-ended question “How are you feeling?” via phone
or face-to-face. Any questions concerning adverse events will be reported regardless
of whether they were deemed to be related to the treatment be assessors and be sent
to the Institutional Review Board of every clinical centers.
All analyses will be performed based on intention-to-treat principles, any missing
data in the follow up visits will be imputed using multiple imputation. Descriptive
analyses as means and standard deviations (SDs) will be used to describe the demographics
and clinical characteristics of the participants. The primary efficacy analysis compared
the hair loss grading between YH0618 granule and control before the fifth chemotherapy
using Fisher exact test. The changes of hair diameter between the two groups after
4 cycles of chemotherapy will be compared by independent samples t-test. A multivariable
logistic regression model will be used to explore the treatment effect. Potential
confounding variables will be identified as those that differ among treatment groups
at baseline and are significantly associated with outcomes. Changes from baseline
to the final assessment in quality of life assessed by the FACT-B and objective indicators in blood will be compared using Wilcoxon rank sum tests.
Unless otherwise specified, 2-sided statistical tests will be used and the significance level will be set at p < 0.05.