The Application of Zishen Yutai Pill in Aged Women Undergoing in Vitro Fertilization-embryo Transfer: a Multi-center Double-blind Randomized Controlled Trial
Phase: NA
Conditions: Infertility, Female
Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

I
Protocol
The Application of Zishen Yutai Pill in Advanced Maternal Aged Women Undergoing IVF-ET
ClinicalTrials.gov ID-NCT03703700 (https://clinicaltrials.gov/study/NCT03703700)
Version 3
Date written
May 24, 2019
Date approved
May 30, 2019

II
Note: The Steering Committee and the Data and Safety Monitoring Board have discussed and
revised this protocol thoroughly, including two major revisions. The final version was written
on May 24, 2019, and was approved by the IRB of Sun Yat-Sen Memorial Hospital of
Sun-Yat Sen University on May 30, 2019. After its IRB approval, this protocol has been
implemented and adhered to without amendment. The Statistical Analysis Plan is contained
within the protocol.

III
CONTENTS
1. Committee composition....................................................................................................... 1
1.1 Protocol committee...........................................................................................................1
1.2 Steering committee...........................................................................................................1
1.3 Data coordination committee........................................................................................... 3
1.4 Third-party data statistical unit.........................................................................................3
1.5 Sponsor and contact information......................................................................................3
1.6 Publication committee......................................................................................................3
2. Background...........................................................................................................................4
3. Objectives..............................................................................................................................5
4. Participants........................................................................................................................... 5
4.1 Inclusion criteria...............................................................................................................5
4.2. Exclusion criteria.............................................................................................................5
4.3 Drop-out........................................................................................................................... 6
5. Study design.......................................................................................................................... 6
5.1 General design..................................................................................................................6
5.2 Randomization and blinding............................................................................................ 7
5.3 Intervention of IVF/ICSI and study drug......................................................................... 7
5.4 Intervention of study drug................................................................................................ 8
6. Study procedures and visits...............................................................................................11
6.1 General visit setting........................................................................................................11
6.2 Screening visit................................................................................................................ 13
6.3 Gn initiation visit............................................................................................................13
6.4 ET visit........................................................................................................................... 13
6.5 Biochemical pregnancy test visit....................................................................................14
6.6 Clinical pregnancy test visit........................................................................................... 14
6.7 Delivery visit.................................................................................................................. 14
7. Physical examination..........................................................................................................15
8. Transvaginal ultrasound scan........................................................................................... 15
9. Laboratory tests..................................................................................................................15
10. Outcome measures........................................................................................................... 15

IV
11. Timeline and recruitment plan....................................................................................... 20
12. Statistical analysis plan....................................................................................................20
12.1 General statistical consideration...................................................................................20
12.2 Sample size estimation................................................................................................. 20
12.3 Type of analysis............................................................................................................21
12.4 Interim analysis............................................................................................................ 21
13. Adverse event reporting...................................................................................................21
13.1 Risks and discomforts.................................................................................................. 21
13.2 Adverse event definitions.............................................................................................23
13.2.1 Definition of adverse event................................................................................... 23
13.2.2 Definition of serious adverse event.......................................................................24
13.3 Recording of adverse events.........................................................................................25
13.4 Causality and severity assessment................................................................................25
13.4.1 Causality assessment............................................................................................. 25
13.4.2 Severity assessment...............................................................................................26
13.5 Reporting of serious adverse events and unanticipated problems................................27
14. Concomitant medication..................................................................................................27
15. Monitoring........................................................................................................................ 28
15.1 Data and Safety Monitoring Board...............................................................................28
15.2 Ethics............................................................................................................................29
16. Data handling and record-keeping................................................................................. 29
16.1 Data entry and electronic case report form (eCRF)......................................................29
16.2 Data quality control and query management................................................................29
16.3 Data security.................................................................................................................30
16.4 Audit.............................................................................................................................30
16.5 Medical Coding............................................................................................................ 30
17. Publication policy............................................................................................................. 31
18. Acknowledgment section................................................................................................. 31
19. Protocol revision history..................................................................................................31
20. References......................................................................................................................... 32

1
1. Committee composition
1.1 Protocol committee
Table 1. Protocol Committee
Name
Affiliation
Email
Dongzi Yang
Sun
Yat-Sen
Memorial
Hospital
of
Sun
Yat-Sen
University
yangdz@mail.sysu.edu.cn
Yu Li
Sun
Yat-Sen
Memorial
Hospital
of
Sun
Yat-Sen
University
liyuliyu0922@163.com
Heping Zhang
Yale University
heping.zhang@yale.edu
Jie Zhou
Guangzhou
Evidence-Based
Medicine Tech Co., Ltd
zhouj@gz-ebm.com
1.2 Steering committee
Table 2. Steering Committee
Name
Affiliation
Email
Chair
Dongzi Yang
Sun
Yat-Sen
Memorial
Hospital
of
Sun
Yat-Sen
University
yangdz@mail.sysu.edu.cn
Co-investigators
Heping Zhang
Yale University
heping.zhang@yale.edu
Yu Li
Sun
Yat-Sen
Memorial
Hospital
of
Sun
Yat-Sen
University
liyuliyu0922@163.com

2
Site-investigators
Hong Ye
Women
and
Children's
Hospital
of
Chongqing
Medical University
yehong1210@163.com
Xiaohong Wang
Tangdu Hospital, the Fourth
Military Medical University
wangxh919@fmmu.edu.cn
Linli Hu
The First Affiliated Hospital
of Zhengzhou University
hulinli1999@163.com
Xiaolin Ma
The
First
Hospital
of
Lanzhou University
maxl2005@123.com
Li Fan
Liuzhou Maternity and Child
Healthcare Hospital
3641917@qq.com
Wei Huang
West
China
Second
University Hospital, Sichuan
University
hdyynfm@163.com
Hong Li
The
Affiliated
Suzhou
Hospital of Nanjing Medical
University
hongliszivf@163.com
Haiyan Bai
Northwest
Women’s
and
Children's Hospital
bhy1212@126.com
Fei Gong
Reproductive and Genetic
Hospital
of
CITIC-Xiangya
lj_0305@126.com
Yichun
Guan
The Third Affiliated Hospital
of Zhengzhou University
lisamayguan@163.com
Ze Wang
Hospital
for
Reproduction
Medicine
Affiliated
to
Shandong University
wangze0806@163.com

3
1.3 Data coordination committee
Prof. Heping Zhang at Yale University will lead the Data Coordination Committee
consisting of the personnel from Sun Yat-Sen Memorial Hospital of Sun Yat-Sen
University, including registering the trial at the Chinese Clinical Trial Registry
(http://www.chictr.org/cn/) and ClinicalTrials.gov (http://www.ClinicalTrials.gov).
The daily operation of the Data Coordination Center is fully executed by the
personnel at Sun Yat-Sen Memorial Hospital.
1.4 Third-party data statistical unit
Table 3. Third-party data statistical unit
Name
Affiliation
Email
Jie Zhou
Guangzhou Evidence-Based
Medicine Tech Co., Ltd
zhouj@gz-ebm.com
1.5 Sponsor and contact information
Table 4. Sponsor and contact information
Name
Affiliation
Email
Na Ning
Guangzhou Baiyunshan
Zhongyi Pharmaceutical Co.
Ltd.
ningna0821@163.com
1.6 Publication committee
Members of the publication committee include Dongzi Yang, Yu Li.

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2. Background
The deferment of childbirth has emerged as a significant concern in recent years. Over
the past forty years, the prevalence of primiparity at age of 35 years or older increased
by 9 times (1). Advanced maternal age (AMA), defined as pregnancy at 35 years or
older, is commonly linked with reduced fecundity (2,3). AMA patients are more
inclined to the use of assisted reproductive technology (ART), including in vitro
fertilization (IVF) and intracytoplasmic sperm injection (ICSI) (4). Nonetheless, their
pregnancy outcomes are typically less favorable compared to their younger
counterparts, as aging adversely affects both oocyte quality and ovarian reserve (5).
Traditional Chinese Medicine (TCM) has been employed for over two millennia in
the treatment of a myriad of conditions, including infertility (6). A representative
formula for the treatment of infertility is the Zishen Yutai Pill (ZYP). ZYP is a patent
Chinese medicine invented by Professor Yuankai Luo (7). Since its market debut in
1983, ZYP was renowned for its therapeutic effects on threatened miscarriage and
recurrent miscarriage. ZYP is consisted of fifteen Chinese medicine, including
Cuscutae Semen, Ginseng Radix et Rhizoma, Dipsaci Radix, Taxilli Herba,
Eucommiae Cortex, Morindae Officinalis Radix, Cervi Cornu Degelatinatum,
Codonopsis Radix, Atractylodis Macrocephalae Rhizoma, Asini Corii Colla, Lycii
Fructus, Rehmanniae Radix Praeparata, Polygoni Multiflori Radix Praeparata,
Artemisiae Argyi Folium, and Amomi Fructus (8).
In previous clinical practice, the administration of ZYP was observed to enhance the
ovulation and pregnancy rate, while decrease the miscarriage rate among patients with
polycystic ovary syndrome (PCOS) (9). Another clinical report had suggested that
oral intake of ZYP around the luteal phase could significantly increase the embryo
implantation rate (10). Our previous multicenter, placebo-controlled, randomized
clinical trial had suggested that the intervention of ZYP among advanced maternal
aged women could significantly increase the clinical pregnancy rate during ART.
However, this analysis constituted a post hoc subgroup analysis, lacking the statistical
power to detect the between-group difference. Therefore, the design of the current

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study aims to provide data regarding the efficacy and safety of ZYP in IVF/ICSI for
the AMA patients.
3. Objectives
The present study aims to investigate the efficacy and safety of ZYP on liver birth
rates among AMA infertile women during IVF/ICSI-ET. The primary objective is to
determine the difference of live birth rate between the ZYP and placebo group. The
secondary outcomes will include counts and rates of oocytes/embryos (oocytes
retrieved, 2 pro-nuclei zygotes, cleavage zygotes, available embryos, high-quality
embryos), pregnancy outcomes (rates of biochemical pregnancy, implantation,
clinical pregnancy and miscarriage), incidences of maternal, fetal and neonatal
complications, and neonate information (newborn birthweight and length, congenital
malformation).
4. Participants
4.1 Inclusion criteria
Participants who meet all of the following criteria will be included in this study.
(1) Infertile women aged between 35 and 42 years old.
(2) Intend to undergo IVF-ET (GnRH-a long protocol or GnRH-ant protocol).
(3) BMI<28 kg/m2.
(4) Bilateral ovaries exist.
(5) Patients who voluntarily sign the informed consent and agreed to be followed up
as required by the study protocol.
4.2. Exclusion criteria
Participants who meet one of the following criteria will be excluded in this study.
(1) Recurrent implantation failure (previous three times or more IVF/ICSI-ET
failure).

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(2) Adenomyosis, the uterine cavity line constricted by uterine fibroids.
(3) Untreated bilateral hydrosalpinx.
(4) Endometrial diseases that have not been cured.
(5) Known diseases that are not suitable for undergoing ART or at the present not
suitable for pregnancy;
(6) Recent therapy (within one month) for infertility with TCM.
4.3 Drop-out
Participants will dropout when:
(1) subjects who have adverse events that cannot be tolerated.
(2) Severe breach of the protocol.
(3) Subjects who exit due to personal or unpredictable reasons (detailed information
need to be recorded).
(4) Subjects considered inappropriate to continue to participate in the study for other
medical reasons.
5. Study design
5.1 General design
It will be a multicenter, prospective, randomized (1:1 treatment ratio) clinical trial
comparing the live birth rates in AMA women assigned to these treatment arms after a
fresh ET in 1466 infertile patients undergoing IVF or ICSI. Patients will be
randomized into either of two groups, receiving ZYP or the placebo during IVF/ICSI.
All of the participants will receive standardized controlled ovarian hyperstimulation
(COH) protocols, i.e., GnRH agonist (GnRH-a) long protocol or GnRH antagonist
(GnRH-ant) protocol), as appropriate, and then undergo embryo transfer (ET).

7
5.2 Randomization and blinding
The participants will be randomized 1:1 to receive double-blind single-dummy
monotherapy with placebo or ZYP using the permuted block randomization method.
The randomization will be stratified by the age (35-37, 38-39 and 40-42) by following
the Human Fertilisation and Embryology Authority (11). The web-based Interactive
Response Technology system is managed by independent statisticians, guiding drug
dispensing.
Patients, investigators and clinical staff performing this trial will be blinded to
treatment allocation. The package, appearance and odor are the same in the placebo
and ZYP. The allocation and detailed information of randomization will be kept by
the independent statisticians managing the Interactive Response Technology system.
Blinding will be maintained until the completion of the analysis. Unblinding will be
allowed in case of a medical emergency. The cause and time of unblinding will be
recorded in detail and signed by the treating physicians.
When all live birth information is retrieved, the computer system will disclose the
allocation.
5.3 Intervention of IVF/ICSI and study drug
5.3.1 Controlled Ovarian Hyperstimulation (COH)
Two COH protocols will be applied.
1) GnRH-a long protocol: All subjects in two groups will undergo COH after
down-regulation with long-acting or short-acting GnRH-a in midluteal phase.
Hormone levels, including follicle-stimulating hormone (FSH), luteinizing hormone
(LH) level and estradiol (E2) will be measured on the gonadotropin (Gn) initiation day.
Follicular development (diameter and counts) and endometrial thickness will also be
evaluated by means of transvaginal ultrasonography. COH will be initiated when the
serum LH < 5 IU/L and E2 < 50 ng/ml or endometrial thickness < 5 mm. The
initiation dose and total Gn dose will be adjusted according to a combined
consideration of age, weight, basal hormone levels, antral follicular count (AFC) and

8
previous cycle response.
2) GnRH-ant protocol: Initiation will be conducted on day 2 to day 4 of menstrual
cycle. Hormone levels, including FSH, LH and E2 levels will be measured on the Gn
initiation day. Follicular development (diameter and counts) and endometrial
thickness will also be evaluated by means of transvaginal ultrasonography. The
initiation dose and total Gn dose will be adjusted according to a combined
consideration of age, weight, basal hormone levels, AFC and previous cycle response.
5.3.2 Ovulation monitoring
The mean diameter of all follicles and endometrial thickness will be monitored by
means of ultrasonography, along with testing of serum hormonal levels, including
FSH, LH, E2 and progesterone (P4) on the day 5 to day 6 after Gn initiation.
5.3.3 Oocyte retrieval and embryo transfer
When the diameter and counts of follicles meet the criteria (two leading follicles≥18
mm; or ≥3 follicles ≥17 mm; or ≥4 follicles ≥16 mm), ovulation will be triggered by
injecting human chorionic gonadotropin (HCG). Testing of serum FSH, LH, E2 and P4
levels will be conducted on HCG injection day. Oocyte collection will be performed
36 hours later. Luteal support will be started on oocyte retrieval day. Fertilization will
be achieved by conventional IVF or ICSI with the husband’s semen. On day 3 to day
5 after oocyte retrieval, one to three embryos will be transferred.
High-quality embryos is defined according to Istanbul consensus and Gardner criteria
(12, 13).
Day 2
4 cells, cell fragments <10%, no multi-nucleus
Day 3
8 cells, cell fragments <10%, no multi-nucleus
Day 5
stage 4 blastocyst, grade A inner cell mass, trophectoderm at grade A
5.4 Intervention of study drug
Eligible subjects will be allocated to receive ZYP or the placebo 3 times daily, 5 g

9
each time on down-regulation day (GnRH-a long protocol) or day 19 to day 23 of
previous menstrual cycle (GnRH-ant protocol). Study drug will be suspended during
the 1st day to the 4th day of menstrual cycle. Continuation of the study intervention
will be determined by the serum β-HCG pregnancy test carried out two weeks after
embryo transfer. Intervention of study drug will be stopped if the pregnancy test is
negative. For patients with positive results on the pregnancy test, the study medicine
will be given until a confirmed clinical pregnancy (five weeks after ET).
5.4.1 Zishen Yutai Pill
The manufacture of ZYP complies with the relevant requirements of law of China’s
Drug Administration and Good Manufacturing Practice (GMP), with approval from
the China National Medical Products Administration (Permit No.Z44020008).
Table 5. Herbal drugs used in Zishen Yutai Pill (ZYP) and the origins and medicinal
parts
Herbal drugs
Origin of natural medicine
Cuscutae Semen
Ripe dried seed of Cuscuta Chinensis Lam.
Ginseng Radix et Rhizoma
Dried root and rhizome of Panax ginseng C. A. Mey.
Dipsaci Radix
Dried root of Dipsacus asper Wall. ex DC.
Taxilli Herba
Dried leafy stem and branch of Taxillus chinensis
(DC.) Danser
Eucommiae Cortex
Dried bark of Eucommia ulmoides Oilv.
Morindae Officinalis Radix
Dried root of Marinda officinalis How
Cervi Cornu Degelatinatum
Residue after water extraction of ossified antler of
Cervus nippon Temminck
Codonopsis Radix
Dried root of Codonopsis pilosula (Franch.) Nannf.
Atractylodis Macrocephalae
Rhizoma
Dried rhizome of Atractylodes macrocephala Koidz.
Asini Corii Colla
Solid glue prepared by stewing and concentrating
from the hide of Equus asinus L.
Lycii Fructus
Dried ripe fruit of Lycium barbarum L.
Rehmanniae Radix
Praeparata
Steamed and dried root of Rehmannia glutinosa
(Gaertn.) DC.
Polygoni Multiflori Radix
Praeparata
Steamed and dried root of Polygonum multiflorum
Thunb.
Artemisiae Argyi Folium
Dried leaf of Artemisia argyi Lévl. et Vant.
Amomi Fructus
Dried fruit of Amomum villosum Lour.

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5.4.2 Composition and manufacturing process of the placebo
1) Composition: Pregelatinized starch, microcrystalline cellulose, black iron oxide,
refined honey, dextrin.
2) Manufacturing process: Pregelatinized starch, microcrystalline cellulose, and black
iron oxide are mixed, crushed, and sieved. The refined honey is added to the mixed
powder to make the wet pill with the required size. After drying, it is coated with a
mixture of black iron oxide and talc powder, 3% dextrin solution, 75% ethanol
solution, and refined honey. Finally, eligible pills are polished using Chinese insect
wax, selected, and packaged.
5.4.3 Adherence of study drug
Patients’ adherence of study drug will be assessed. An actual dosage above 80% of
required drug dosage will be considered consistent with protocol requirements.
In order to record and improve the adherence of study drug, a diary card will be used.
The diary card includes information of participants, study drug dosage, date of drug
administered. In addition, each participant will be assigned a clinical research
coordinator to assure the adherence of study drug and carry out follow-up.
5.4.4 Package and label of study drug
Both the ZYP and the placebo will be provided in the same label and appearance
(written in Chinese).

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Drug No.：
The Application of Zishen Yutai Pill in Aged Women Undergoing IVF-ET
（Clinical Use Only）
Dosage of one week
【Action and Use】Tonify Kidney and Spleen, invigorates Qi that nourishes Blood, placate the fetus and
strengthens the body. Used in pregnancy loss due to deficiency of Kidney and Spleen, debility of Chong
and Ren (treatment and prevention of threatened miscarriage and spontaneous miscarriage)。
【Package】5 g/package.
【Dosage and Administration 】Administered orally with honey water or dilute salt water. 5 g (1
package) each time, tid.
【Intervention period】11 weeks.
【Storage Condition】Please keep in seal and away from moister.
【Caution】Please keep the remaining drug and the package until the end of clinical trial. Stored away
from children.
Manufactured by Guangzhou Baiyunshan Zhongyi Pharmaceutical Co. Ltd.
Expired Date: ** Batch No.: **
6. Study procedures and visits
6.1 General visit setting
Briefly, five visit points are scheduled for this study. Visit 1 will be the screening visit.
Visit 2 will be performed on the day of Gn initiation. Visit 3 will be carried out on the
day of ET. Visit 4 will be carried out two weeks after ET to confirm biochemical
pregnancy. Visit 5 will carried out five weeks after ET to confirm clinical pregnancy.
Follow-up after delivery will be conducted through web or telephone contact to
ascertain the live birth outcomes of participants (Figure 1).

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Figure 1. Study flowchart. Gn, gonadotropin; hCG, human chorionic gonadotropin;
ZYP, Zishen Yutai Pill.

13
6.2 Screening visit
If the patient express interest toward the clinical trial, a screening visit will be
performed. Patients will be informed about the study thoroughly. During the screening
visit, the following procedures will be completed.
(1) Going through all the inclusion and exclusion criteria. Obtaining the signed
informed consent form.
(2) Collecting baseline information, including age, medical record number, and birth
date.
(3) Reviewing the medical history, including infertility history, childbearing history,
gynecological surgery history, disease history and menstrual information.
(4) Carrying out a physical examination and gynecologic examination.
(5) Measuring the baseline sex hormones, including E2, FSH, LH, prolactin (PRL),
and testosterone (T).
(6) Reviewing the previous ET/FET cycle record.
(7) Dispensing information.
6.3 Gn initiation visit
During the Gn initiation visit, the following procedures will be completed.
(1) Adverse events and treatment (if necessary).
(2) Medication on Gn initiation, including type, name, initiation dose.
(3) Serum hormone levels, including E2, FSH, LH, and P4.
(4) Dispensing and return information.
6.4 ET visit
During the ET visit, the following procedures will be completed.
(1) Adverse events and treatment (if necessary).
(2) Summary of COH including type, name and total amount.
(3) B-mode ultrasound and basal serum hormonal level.

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(4) Information about semen collection, embryo development, embryo transfer
information.
(5) Information about the medicines used in luteal phase support, including name,
dose, duration, and total amount.
(6) Dispensing and return information.
6.5 Biochemical pregnancy test visit
At 14 days after transplantation, a biochemical pregnancy test will be performed.
(1) Adverse events and treatment (if necessary).
(2) Serum level of β-HCG pregnancy test (β-HCG >50 IU/L is defined as biochemical
pregnancy).
(3) Drug dispensing and return information will be recorded.
6.6 Clinical pregnancy test visit
If the pregnancy test is positive, transvaginal ultrasonography will be performed 3
weeks later to confirm clinical pregnancy.
(1) Adverse events and treatment (if necessary).
(2) Clinical pregnancy will be confirmed using B-mode ultrasound. Clinical
pregnancy is defined as the presence of intrauterine gestation sac with fetal
motion under transvaginal ultrasonography.
(3) Drug return information will be recorded.
(4) If a clinical pregnancy is confirmed, contact information and intention of delivery
hospital will be checked.
6.7 Delivery visit
When the participant is preparing to deliver, the investigator will collect the delivery
information and infant information according to the form designed for this visit. The
delivery information mainly includes the delivery mode and pregnancy complications.
The neonate information mainly includes gender, birth weight and length, birth

15
defects, admission to newborn intense care unit within 1 month and stillbirth.
7. Physical examination
A physical examination will be conducted on all participants by the corresponding
investigator. The parameters include height, weight and they will be recorded to the
nearest 0.1 cm, 0.1 kg. Height and weight will be measured without shoes, and
patients will be dressed in light clothing.
8. Transvaginal ultrasound scan
An ultrasound scan with a transvaginal probe will be carried out. Uterine dimension,
endometrial thickness and type, bilateral ovarian dimension, and follicle number will
be measured through the ultrasound scan. The uterine size will be determined at the
widest diameter. The investigator will determine endometrial types. Endometrial
thickness is the largest anterior-posterior measurement of the endometrium in the
sagittal plane. Ovarian dimension is measured by analysis of the largest plane of the
ovary in two dimensions. In addition, antral follicle count (AFC) will be recorded.
9. Laboratory tests
Hormone and pregnancy tests will be performed at the local laboratories. In addition,
blood work will be performed on screening visit, Gn initiation visit, hCG trigger day,
and 2 weeks after ET. The blood sample (5 ml) will be collected with an anticoagulant
tube and stored at -80℃for further analysis.
10. Outcome measures
The live birth rate is the primary outcome. The secondary outcomes will include
counts and rates of oocytes/embryos (oocytes retrieved, 2 pro-nuclei zygotes,
cleavage zygotes, available embryos, high-quality embryos), pregnancy outcomes
(rates of biochemical pregnancy, implantation, clinical pregnancy and miscarriage),

16
incidences of maternal, fetal and neonatal complications, neonate information
(newborn birthweight and length, congenital malformation) (14).
Live birth is defined as delivery of any viable infants after 28 weeks of gestation.
The number of oocytes retrieved will be defined as the total number of oocytes
retrieved through ultrasound-guided transvaginal aspiration. The rate of oocytes
retrieved will be defined as the number of retrieved oocytes divided by the number of
follicles with a diameter ≥10mm on the HCG injection day. Matured oocytes will be
defined as those with pronuclei or polar bodies observed on Day 1 after oocyte
retrieval in IVF patients, or as the number of MII oocytes on the day of oocyte
retrieval in ICSI patients. Cleavage oocytes will be defined as the number of fertilized
oocytes that undergo cleavage on Day 2 after oocyte retrieval. The rate of cleavage
will be defined as the number of cleaved embryos divided by the number of fertilized
oocytes (2PN + 1PN + multiple PN). Available embryos will be defined as the sum of
the number of embryos transferred and the number of embryos frozen. The rate of
available embryos will be defined as the number of available embryos divided by the
number of cleaved oocytes. High-quality embryo will be defined according to the day
of embryo transfer, following the Istanbul consensus and Gardner criteria, Day 2: 4
cells, cell fragments <10% and no multi-nucleus; Day 3: 8 cells, cell fragments <10%,
no multi-nucleus; Day 5: stage 4 blastocyst, grade A inner cell mass, grade A
trophectoderm (12,13). The rate of high-quality embryos will be defined as the
number of high-quality embryos divided by the number of available embryos.
Biochemical pregnancy will be defined as positive when β-HCG >50 IU/L.
Implantation rate will be defined as the number of gestational sacs per the number of
embryos transferred. Clinical pregnancy will be defined as the presence of intrauterine
gestation sac with fetal motion under transvaginal ultrasonography. Miscarriage rate
will be calculated among patients with biochemical pregnancies and patients with
clinical pregnancies.
Incidences of maternal, fetal and neonatal adverse events were assessed, including
moderate or severe OHSS, gestational diabetes mellitus (GDM), gestational

17
hypertension, postpartum hemorrhage, preterm delivery, congenital anomalies,
puerperal infection, stillbirth, neonatal jaundice, neonatal infection, neonatal death,
ectopic pregnancy, and low birth weight infant. The definitions of these safety indexes
were shown in Table 6.

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Table 6. Definitions of safety outcomes
Safety outcome
Definitions
Ovarian hyperstimulation syndrome (OHSS)
OHSS is defined according to the Golan criteria. Mild OHSS is diagnosed by the presence
of abdominal distension and discomfort with or without nausea, vomiting, and/or diarrhea.
Moderate OHSS is diagnosed when ultrasonographic ascites were present in addition to the
above features. Severe OHSS is diagnosed when there is clinical evidence of ascites and/or
hydrothorax or breathing difficulties with or without hemoconcentration, coagulation
abnormalities, and diminished renal function.
Pregnancy loss
Pregnancy loss is defined as pregnancies that eventuate in spontaneous abortion or
therapeutic abortion that occurred throughout pregnancy.
Gestational diabetes mellitus
GDM is defined as carbohydrate intolerance of variable severity with onset or first
recognition during pregnancy as determined from the diagnosis in the obstetrical medical
record.
Gestational hypertension
Gestational hypertension is defined as blood pressure ≥140/90 mmHg with negative
proteinuria, which appeared during pregnancy and returned to normal 12 weeks after
delivery. It may have upper abdominal discomfort or thrombocytopenia.
Postpartum hemorrhage
Postpartum hemorrhage is defined as the loss of 500 ml of blood or more after completion
of the third stage of labor.
Preterm delivery
Delivery of a fetus at less than 37 and more than 28 weeks gestational age.
Congenital anomalies
Congenital anomalies are defined as structural or functional anomalies that occur during
intrauterine life, including minor and major anomalies.
Puerperal infection
Any bacterial infection of the genital tract after delivery and during puerperium.

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Stillbirth
The absence of signs of life at or after birth.
Neonatal jaundice
Neonatal jaundice is yellowing of the skin and other tissues of a newborn infant.
Neonatal infection
Neonatal infection is defined as a variety of infections in neonates caused by bacteria, fungi,
viruses, etc., as determined from the diagnosis in the neonatal medical record.
Neonatal death
The death of a live-born neonate within 28 days after delivery.
Low birth weight infant
Neonatal birth weight ≤2500 g.
Ectopic pregnancy
Ectopic pregnancy is one in which the blastocyst implants at any site other than the
endometrial lining of the uterus cavity.

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11. Timeline and recruitment plan
The planned duration of recruitment will be 24 months with 12 centers. The
enrollment target of our clinical trials is 1466 randomized participants. The number of
participants taken in each center will be allocated according to the actual situation.
The treatment period may need about 3 months and another 9 months to trace the
pregnancy outcome. In short, a total of 36 months will be required to complete this
trial, from initial recruitment to pregnancy outcome period.
12. Statistical analysis plan
12.1 General statistical consideration
For continuous variables, the Kolmogorov-Smirnov test will be applied to evaluate
the distribution. Variables with normal distribution will be presented as means and
standard deviation (SD), and intergroup comparisons will be performed using the
2-tailed, student’s t test. Variables with non-normal distribution will be presented as
medians and interquartile ranges (IQR), and intergroup comparisons will be
performed using the Mann-Whitney U test. Categorical variables will be summarized
with frequencies and percentages and compared using chi-square test or Fisher exact
test, as appropriate. All statistical analysis will be conducted with the use of the
statistical package SPSS, version 19.0 (SPSS Inc). A two-sided P value of <0.05 will
be considered as significantly different.
12.2 Sample size estimation
In our previous clinical research, the live birth rate was 0.42 per embryo transfer in
ZYP treated group and 0.33 per embryo transfer in placebo control group among
AMA women. By assuming the same live birth rates, a sample size of 454 women in
each group can provide a power of 80% at a significance level of 0.05. According to
previous study, the dropout rate before ET was 15% and the cycle cancellation rate
was 23% in AMA women. For this trial, a total rate of 38% (dropout and cancellation)
is considered in the sample size calculation. Therefore, a total of 1466 participants

21
will be recruited in this study, 733 participants in each group.
12.3 Type of analysis
We will utilize an intent-to-treat approach to examine differences in the live birth rates
for the first embryo transfer cycle in the two treatment arms in the primary analysis by
the Pearson χ2 test. Safety parameters and secondary efficacy parameters, such as
pregnancy rate, miscarriage rate and other rates, will be analyzed using the Pearson χ2
test or Fisher exact test as appropriate. Secondary efficacy parameters, including the
counts and rates of oocytes/embryos, will be analyzed using the Mann-Whitney U
test.
For the primary and secondary outcomes, we will also perform analysis in the
per-protocol set (PPS), excluding those who have major protocol deviation(s), cancel
cycle or do not complete the pre-set minimum exposure dosage of the assigned study
drug (at least 80% compliance), from the ITT population. Subgroup analysis will be
conducted as stratified by age (35-37, 38-39, 40-42).
Prior to unblinding, missing value in the primary outcome (live birth) and secondary
outcomes (biochemical pregnancy, clinical pregnancy) in the ITT analysis will be
imputed as not having an event.
12.4 Interim analysis
No interim analysis is planned.
13. Adverse event reporting
13.1 Risks and discomforts
Compared with the usual IVF patients, participating in this study will not increase
additional risks. The possible risks and discomforts in common IVF technology are
detailed in the informed consent, including in vitro fertilization ET, embryo freezing,
and so on. The table below lists all procedures, including related risks and
discomforts.

22
Table 7. Potential risks and discomfort of intervention during study process
Procedures and events
Risks and discomfort
Controlled
ovarian
hyperstimulation (COH)
Frequent subcutaneous injection, frequent venipuncture,
frequent transvaginal ultrasound scan. Supra-physiologic E2
may increase the risk of cancer ovary torsion or ovary
rupture.
Ovarian
hyperstimulation
syndrome (OHSS)
Massive enlargement of the ovaries, ascites, bloating,
nausea, and vomiting. Severe cases may have thoracic
edema, breathing difficulties, oliguria, even anuria, and may
require hospitalization, medication, or puncture drainage. A
very severe case may suffer from thrombosis, damage to the
liver or renal function, and even death.
Oocyte retrieval
Anesthesia accident, pelvic organ injury, intra-abdominal
hemorrhage, puncture site hemorrhage, in serious case
surgery or transfusion may be needed, infection.
ICSI
Microinjection may injure an oocyte, pass an unknown
disease gene to the next generation.
Embryo transfer
Infection.
Embryo frozen and thaw
Embryotic development arrest. The survival rate of thawed
embryos is 95%.
Standard venipuncture for
blood work
Slight pain, ecchymosis at the site of puncture, infection, or
bleeding at the site.
Transvaginal ultrasound
Abdominal or pelvic discomfort.
Ectopic pregnancy
May require medical or surgical treatment. In severe cases,
pregnancy
site
rupture
can
result
in
intra-abdominal
hemorrhage, even shock, or death if treatment is delayed.
Multiple pregnancies
May require embryo reduction, increase risk of pregnancy

23
complication, fetus abnormalities, and preterm delivery.
Infertility treatment
Anxiety or emotional distress to various degrees.
Zishen Yutai Pills
It has been reported that some patients who took the Zishen
Yutai pill suffered from nausea, dry mouth, and constipation
that disappeared after drug withdrawal.
The participants are not expected to have all of these complications, and they will be
allocated to a treatment group at random. The treatment may be less effective or have
more complications than the other research treatment.
In this study, the GnRH-a long protocol and GnRH-ant protocol will be performed
according to each patient’s actual situation. The GnRH-ant protocol will be used to
minimize the risk of OHSS. The initial dose will be determined according to the age,
basal FSH level, basal AFC, weight, and previous situation promoting ovulation. The
initiation dose and total Gn dose will be adjusted according to a combined
consideration of age, weight, basal hormone levels, AFC and previous cycle response.
In addition, in case of high ovarian response, the cycle will be canceled to avoid
OHSS. If there are three or more fetuses, then a reduction will be performed to
minimize the risks of multiple pregnancies. A responsible investigator or a resident
doctor on 24 h call can be contacted at each site if any adverse event occurs during
this study.
Every effort will be taken to avoid injury as a result of participation. If adverse events
occur, active treatment will be provided. Furthermore, if a medical dispute is involved,
it will be disposed of as a routine medical event.
13.2 Adverse event definitions
13.2.1 Definition of adverse event
Adverse event means any untoward or unfavorable medical occurrence associated
with the subject’s participation in the research, whether or not considered related to
the study intervention.
Adverse events can be any of the following:

24
• Physical signs or symptoms, including medication side effects.
• Abnormal laboratory values.
• Changes in vital signs, physical exam findings, or test results.
• An increase in the frequency or intensity (worsening) of a condition or illness
presents before study enrollment.
Note: In this trial, adverse events will not include:
• Pre-existing conditions or illnesses that do not worsen during the study period
(record these in the medical history).
• Normal conditions associated with pregnancy.
13.2.2 Definition of serious adverse event
Serious adverse event: Any event temporally associated with the subject’s
participation in research that meets any of the following criteria:
• Death.
• Life-threatening (at immediate risk of death).
• Severely or permanently disabling.
• Requires in-patient hospitalization or prolongation of existing hospitalization.
• Pregnancy loss after 20 weeks gestation.
• Results in a congenital anomaly/birth defect.
• Or any event so deemed as serious by the PI at the site.
Note: A “severe” adverse event is not the same as a “serious adverse event” or SAE.
Severity is based on the event’s intensity, whereas seriousness is based upon the event
outcome as it poses a threat to the patient’s life or functioning.
13.2.3 Definition of Serious Unexpected Suspected Adverse Reaction (SUSAR)
SUSAR is defined as an serious adverse reaction that is both unexpected and meets
the definition of an serious adverse reaction.
An adverse event is considered “unexpected” if its characteristic or severity exceed

25
current available product information, including the instruction of product or
Investigator's Brochure.
13.3 Recording of adverse events
All adverse events will be observed during the clinical trial. The investigators will
require the participants to reflect the change in patients’ condition truthfully after
using the drug and avoid suggestive questions. Adverse events and unexpected side
effects (including symptoms, signs, and laboratory tests) will be observed while
observing the curative effect. In order to determine whether adverse events are
associated with the experimental drug, they will be recorded in the eCRF in detail,
including the occurrence time, symptoms, signs, degrees, duration, laboratory
examination indicators, treatment methods, procedures, results, follow-up time, and so
on. Concomitant medication will be recorded in detail to analyze the correlation
between adverse events and experimental drugs. In addition, the record will be signed
and dated.
When adverse reactions occur, the investigator will take necessary measures, such as
adjusting the dose, temporarily discontinuing the medication, and decide whether to
terminate the trial or not. If a serious adverse event occurs, the unit undertaking the
study must immediately take necessary treatment measures to ensure the subject’s
safety.
13.4 Causality and severity assessment
13.4.1 Causality assessment
According to the documented adverse events and abnormal test findings, the
investigator will need to determine that if the abnormal test finding should be
classified as an adverse event and if the adverse events are related to the study
intervention or meet the criteria for a serious adverse event. The relationship between
the experimental drug and adverse events are divided as “related”, “probably related”,
“possibly related”, “possibly unrelated”, and “unrelated”. AEs with the former three

26
kinds of relations are defined as adverse drug reactions (ADRs). The considerations of
causality analysis include five aspects:
(1) There is a reasonable chronological relation between drug administration and the
occurrence of suspected ADRs (occurrence after drug administration).
(2) Suspected ADRs are in accordance with known ADRs of the drug (literature
compliance).
(3) Suspected ADRs cannot be explained by concomitant medication, previous
medication, existing clinical conditions of patients, or the effects of other therapies
(other explanation).
(4) After drug discontinuation or dose reduction, suspected ADRs disappear or relieve
(disappearance after drug discontinuation).
(5) Suspected ADRs recur after re-exposure to the same drug (Recurrence after
re-administration).
The investigators should assess the possible relation between AEs and the research
drug or the concomitant medication.
Consideration
Occurrence after
drug
administration
Literature
compliance
Other
explanation
Disappearance
after drug
discontinuation
Recurrence after
re-administration
Related
+
+
-
+
+
Probably related
+
+
-
+
?
Possibly related
+
+
±
±
?
Possibly unrelated
+
-
±
±
?
Unrelated
-
-
+
-
-
13.4.2 Severity assessment
The level of adverse event response will be evaluated and reported as follows:
Mild: The participant can tolerate the event, and it does not affect the treatment. It
need not take special actions and is not harmful to the participant.
Moderate: The participant is intolerant and requires withdrawal or special treatment,
which has a direct impact on their health.

27
Severe: It is a life-threatening, fatal, or disabling event and requires withdrawal or
emergency treatment immediately.
13.5 Reporting of serious adverse events and unanticipated problems
Whether or not related to the study drugs, serious adverse events during the trial
should be treated and reported to the primary investigator in the trial center promptly.
Moreover, it should be reported to the Ethics Committee of Sun Yat-Sen Memorial
Hospital of Sun Yat-Sen University within 24 h. The investigator will have to
document this serious adverse event and take necessary measures to ensure the
participants’ safety and interests. It should also be timely reported to the drug
administration according to the legislation. At the same time, it should be notified to
the investigator involved in the same clinical trials. If it is confirmed as a serious
adverse event related to the experimental drug, the investigator will bear the rescue
and treatment cost and the corresponding economic compensation.
The investigator must fill in the “serious adverse events report form”. The time, the
treatment and to whom the SAEs are reported should be recorded in the original data.
14. Concomitant medication
To avoid possible interference from other traditional Chinese medicine, recent therapy
(one month prior to and during the IVF/ICSI process) for infertility with TCM will be
considered as protocol violation.
The following medications will be allowed during this study, and concomitant
medication should be recorded.
(1) Anti-diabetic agents and anti-hypertension agents.
(2) Folic acid supplement aimed at preventing neural tubal defect.
(3) For patients with abnormal bleeding/prolonged amenorrhea, progestin, micronized
progesterone, or dydrogesterone.
(4) During controlled ovarian stimulation, human menopausal gonadotropin will be
allowed to use in patients with slow E2 increase or follicles development.

28
(5) For patients with moderate or severe OHSS, routine clinical treatment, such as
fluid infusion, albumin infusion, aspirin, or preventive antibiotics, will be used.
(6) For patients with threatening abortion, an extra dose of progesterone will be
allowed to use. Concomitant medication will be recorded.
(7) For patients with pregnancy complications, clinical standard care will be
performed. Concomitant medication will be recorded.
15. Monitoring
15.1 Data and Safety Monitoring Board
The clinical trial management office will review and interpret data generated from the
study and review the protocol’s revisions before their implementation. Its primary
objectives are to ensure the safety of study subjects and the integrity of the research
data. The office will advise on research design issues, data quality and analysis, and
research participant protections for the study. The office will hold regular conference
calls to review the protocol for ethical and safety standards, monitor the trials’ safety,
monitor the data’s integrity for original study design, and provide advice on study
conduct. The office will review the trial’s progress, adjudicate adverse events, and
decide on any premature closure of the study. The board will coordinate the call and
provide study updates before the call via email.
Table 8. Data and Safety Monitoring Board
Name
Affiliation
Email
Zhaosi Xu
Guilin
University
of
Electronic Technology
zhaosi.xu@jeeyor.com
Xiaoli Chen
Sun
Yat-Sen
Memorial
Hospital
of
Sun
Yat-Sen
University
gzxiaolichen@163.com
Jiewen Zhou
Guangzhou
University
of
Chinese Medicine
zhoujiewen0808@163.com

29
15.2 Ethics
Ethics approval has been sought from the Ethics Committee at Sun Yat-Sen Memorial
Hospital, with an ethic approval file entitled: "2017 Reproduction Ethnic Approval
No.2" (in Chinese, 2017 生殖伦审字第(02)号). Ethics approval will be obtained from
each participating center.
16. Data handling and record-keeping
Prof. Heping Zhang at Yale University will oversee the data collection and
management (including quality assurance/compliance measures) team consisting of
investigators from Sun Yat-Sen Memorial Hospital.
16.1 Data entry and electronic case report form (eCRF)
The trial investigators must go through Good Clinical Practice (GCP) training and
understand the protocol and relevant information in advance adequately. The protocol
will be executed strictly, and clinical trial drugs will be provided to enrolled subjects
after screening.
Clinical research coordinator (CRC) is responsible for entering the data of CRF into
the database. All data required on the eCRF must be recorded. Each blank of the
eCRF must be completed, and all items should be filled in. If the item is “not done”,
then select “ND”. Double data entry is performed by two independent CRCs
separately to make two databases, which will be compared by the data manager to
generate a list of inconsistent data. Any inconsistencies between the two databases are
identified by the data manager, and queried via the eCRF system until final
settlement.
16.2 Data quality control and query management
Data will be verified by independent statisticians to generate the data query list
according to the data verification plan (DVP). Then clinical research associate (CRA)

30
asks the corresponding investigator to answer the queries in the form, after which the
form with answers will be given back to the data manager. The database will be
revised based on these forms.
16.3 Data security
The database managers, Dr. Yu Li, biostatistician Prof. Heping Zhang, and project
leader Prof. Dongzi Yang, will be in charge of the eCRF records, and are responsible
for the assignment of the jurisdiction to the users. The database managers have the
highest jurisdiction to manage and monitor the data and actions. The users of each
sub-center will be allowed to enter their patients’ information and study results in
their center. The database managers take the responsibility to decide which data could
be disclosed to the public. Patients’ information that will or may lead to identity
recognition, includes but not limited to name, address, medical card number,
telephone numbers, will be critically protected and will never be allowed to be
disclosed.
In addition to the internal safeguards built into the computerized system, external
safeguards will be implemented. Data will be stored at the servers housed at Sun
Yat-Sen Memorial Hospital with access overseen by Prof. Heping Zhang. Records
will be regularly backed up, and record logs are maintained to prevent a catastrophic
loss and ensure the data’s quality and integrity.
16.4 Audit
Audit will be performed during the whole trial process to ensure the data quality. The
investigator team will compare data in the database against medical record in the
hospital information system (HIS). Identified errors will be resolved between the
DCC and clinical sites. The visits will assure data quality and patient protection.
16.5 Medical Coding
Adverse events are coded using MedDRA 21.0 (or higher version).

31
17. Publication policy
It is anticipated, there will be up to 14 authors in the final manuscript. Yu Li will be
the first author. Dongzi Yang and Heping Zhang will be the last two author. The other
authors’ order for the participating sites will be based upon subject recruitment, data
accuracy, and promptness of data report and will start at the position 2 and go to
position n-2. Each site’s PI will be responsible for documenting the contributions to
the study of that site’s authors. We encourage the site investigators to establish the
second hypothesis and have publications by sharing these data under the publication
committee’s supervision.
18. Acknowledgment section
The acknowledgment section will include other investigators and study personnel who
contributed substantially to the study by site and members of the advisory board and
Data Safety Monitoring Board. The designation will list the initials of the individual,
followed by their highest degree. Significant contributions include but are not limited
to protocol review, initiation and participation at each site, subject recruitment and
enrollment, study conduct, data analysis, and manuscript preparation.
19. Protocol revision history
The Application of Zishen Yutai Pill in Aged Women Undergoing IVF-ET. After the
initial version was prepared by the protocol committee, this protocol underwent two
major revisions by the investigators.
Version
1
Date written
December 26, 2016
Date approved
January 12, 2017
Version
2
Date written
August 22, 2018

32
Date approved
September 20, 2018
Version
3
Date written
May 24, 2019
Date approved
May 30, 2019
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