The Impact of Laser-Assisted Hatching on Pregnancy Outcomes After Vitrified-Warmed Embryo Transfer in Advanced-age Patients: A Randomized Controlled Trial
Phase: NA
Conditions: Assisted Hatching, Advanced Age
Sponsor: Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University

The Impact of Assisted Hatching on Pregnancy 
Outcomes After Vitrified-Warmed Embryo 
Transfer in Advanced-age Patients 
1. Protocol Summary 
Study Title 
The Impact of Assisted Hatching on Pregnancy Outcomes After 
Vitrified-Warmed Embryo Transfer in Advanced-age Patients 
Version No. 
V2.1 
Sponsoring and 
Participating 
Institutions 
Reproductive Medicine Center, Shanghai Jiao Tong University School of 
Medicine Affiliated Ninth People's Hospital 
Study Nature 
Randomized Controlled Clinical Trial 
Study Objective 
To investigate whether laser assisted hatching (LAH) of thawed embryos 
prior to frozen-thawed embryo transfer can improve the live birth rate in 
advanced age patients. 
Study 
Population 
Advanced age women undergoing non-donor IVF/ICSI cycles and 
planning vitrified-warmed embryo transfer. 
Study Method 
Single-center, parallel-group, open-label RCT with 1:1 stratified block 
randomization. 
Inclusion 
Criteria 
1. Female age ≥35 years.2. First or second frozen-thawed embryo 
transfer cycle.3. Transferred embryos meet the quality criteria: Grade I, 
Grade II, or CP and above (cleavage-stage embryos); 4BC/CB and 
above (blastocysts).4. Provided written informed consent. 
Exclusion 
Criteria 
1. Use of donor oocytes or donor sperm; or scheduled for 
preimplantation genetic testing (PGT).2. Severe immune or 
chromosomal abnormalities.3. Uterine cavity abnormalities (i.e., 
adenomyosis, submucous fibroids, hydrosalpinx, uterine septum, and 
endometrial polyps).4. Embryos with abnormal zona pellucida.5. 
Complicated with severe underlying diseases (such as uncontrolled 
hypertension/diabetes, active malignant tumor).6. History of recurrent 
implantation failure (≥2 cycles) or recurrent spontaneous abortion (≥2 

episodes). 
Study Progress 
Plan 
Subject enrollment will last for 18 months, with monitoring every 
quarter, and the entire study is expected to be completed within 36 
months. 
Statistical 
Analysis 
Methods 
Analysis Population: ITT analysis includes all randomized patients 
(primary analysis), missing data is handled by multiple imputation 
(MICE); PP analysis includes patients who comply with the protocol 
(sensitivity analysis).Continuous Variables: Normally distributed data 
are expressed as mean ± standard deviation, and t-test is used for inter-
group comparison; non-normally distributed data are expressed as 
median (interquartile range), and Mann-Whitney U test is used for inter-
group comparison.Categorical Variables: Expressed as frequency 
(percentage), and χ² test or Fisher's exact test (when expected frequency 
< 5) is used for inter-group comparison.Subgroup Analysis: Preset 
subgroup analysis by age (<40 years and ≥40 years) and embryo stage 
(cleavage-stage embryos, blastocysts).Statistical Software: SAS 9.4 and 
R 4.3.0 software are used, with a two-sided P<0.05 considered 
statistically significant. 
Forms of Study 
Outcome 
Publication 
The study results will be published in peer-reviewed journals and 
presented at international conferences. A plain language summary of the 
study results will be provided to participants (sent during offline follow-
up or via email). 
 
Principal 
Investigator 
Jiang 
Shutian 
Title 
Attending 
Physician 
Date of 
Birth 
October 1991 
Key 
Members of 
the Research 
Team 
Name 
Date of 
Birth 
Title 
GCP 
Certificate 
Research Duties 
Jiang 
Shutian 
October 
1991 
Attending 
Physician 
Yes 
Principal Investigator 
Li 
Wenzhi 
May 1989 
Senior 
Technician 
Yes 
Clinical Execution 
(Embryologist) 
Guo 
Haiyan 
October 
1981 
Associate 
Chief 
Physician 
Yes 
Clinical Execution 
(Clinician) 

Lü 
Qifeng 
September 
1970 
Researcher 
Yes 
Quality Control 
Jiang 
Xueyi 
January 
1999 
Physician 
No 
Statistical Analysis 
Li 
Danjun 
February 
1995 
Physician 
No 
Data Management 
 
Mi Yan 
August 
1999 
Graduate 
Student 
No 
Data 
Management/Research 
Coordinator 
2. Research Background 
Hatching is a key step in a series of physiological events leading to final implantation. Failure 
of hatching caused by intrinsic abnormalities of the zona pellucida (ZP) may be one of the 
many factors limiting human reproductive efficiency. Assisted hatching (AH) refers to the 
artificial thinning or disruption of the zona pellucida to promote embryo hatching and 
implantation into the endometrium, and is considered an auxiliary technology to improve 
embryo implantation and pregnancy outcomes after in vitro fertilization (IVF) or 
intracytoplasmic sperm injection (ICSI). Assisted hatching was first described by Cohen et al. 
in the 1980s [3], and the current implementation methods mainly include mechanical method 
[4], acidification method, laser method [8], and piezoelectric micromanipulator method [9], 
among which the laser method is the most commonly used clinical assisted hatching method 
[10]. At present, the safety of assisted hatching has been verified to a certain extent. 
To date, there is no consensus on whether assisted hatching can improve pregnancy outcomes 
after IVF/ICSI [1]. Some studies have reported a significant increase in the clinical pregnancy 
rate of patients, and pointed out that assisted hatching is beneficial to patients with repeated 
failures or advanced age. However, other studies have shown that the clinical pregnancy rate 
may not increase after assisted hatching, and assisted hatching may not affect the live birth 
rate. There is also some uncertainty about whether assisted hatching can improve the embryo 
implantation rate, and the research conclusions have not reached a consistent conclusion. 
However, since cryopreserved embryos must undergo in vitro culture and freeze-thaw 
processes, which cause changes in the glycoprotein matrix and lead to zona pellucida 
hardening [27], assisted hatching is recommended for use in FET cycles to improve 
pregnancy outcomes. A recent randomized controlled trial (RCT) study confirmed that the use 
of AH on previously cryopreserved embryos has higher clinical pregnancy rate and 
implantation rate, but failed to prove a significant effect on live birth rate. Unfortunately, the 
sample size of the included study was small, and it focused on cleavage-stage embryos. In 
fact, the effect of AH on frozen embryos is inconclusive based on existing data. Current 
studies are focused on retrospective studies, lacking RCT studies. Moreover, these studies 
have high heterogeneity, making it impossible to draw any definite conclusions about the 
actual effect of AH. 

Considering the possible benefits of AH for advanced age patients, studying whether the use 
of AH on cryopreserved embryos of advanced age patients can improve the live birth rate may 
have more important clinical significance. To fill the gaps in current research, we have 
developed this protocol for a randomized trial to compare the effect of laser-mediated AH on 
the ZP of vitrified/warmed embryos with non-AH control on pregnancy outcomes after 
transfer in advanced age patients. 
3. Study Objectives 
3.1 Primary Objective 
To investigate whether laser assisted hatching (LAH) of thawed embryos prior to frozen-
thawed embryo transfer can improve the live birth rate in advanced age patients. 
3.2 Secondary Objectives 
Secondary outcomes include pre-transfer embryo morphological characteristics, implantation 
rate, biochemical pregnancy rate, clinical pregnancy rate (ultrasound-visible gestational sac), 
ectopic pregnancy rate, ongoing pregnancy rate, miscarriage rate, multiple pregnancy rate, 
preterm birth (gestation <37 weeks) rate, obstetric and neonatal complications, and congenital 
anomaly rate. 
4. Study Methods 
4.1 Overall Study Design 
This study is a single-center prospective study adopting a parallel randomized controlled 
design, aiming to investigate whether laser-mediated AH of thawed embryos prior to frozen-
thawed embryo transfer can improve the live birth rate in advanced age patients after transfer. 
Eligible advanced age patients (age ≥35 years) will be randomly assigned to the study group 
(AH group) and the control group (non-AH group) at a ratio of 1:1. Stratified block 
randomization (variable block size of 4 or 6) will be used according to age (<40 years, ≥40 
years) and embryo stage (cleavage-stage embryos and blastocysts). Subject enrollment will 
last for 18 months, with monitoring every quarter, and the entire study is expected to be 
completed within 36 months. 
4.2 Sample Size 
Sample size calculation is based on the assumption that the live birth rate in the non-AH 
group is 25% and the live birth rate in the AH group is increased by 10% (i.e., 35%), with a 
test power of 90%, α=0.05, and a dropout rate of 10%. A total of 916 patients need to be 
enrolled (458 patients in each group). 
4.3 Randomization 
All participants will be divided into two groups at a ratio of 1:1 through online software 

according to the following strata: 
1. 
Age <40 years and ≥40 years. 
2. 
Embryo stage: cleavage-stage embryos and blastocysts. 
Block randomization will be used to reduce bias and achieve allocation balance. Variable 
block sizes (4 or 6) will be used to avoid allocation prediction. Investigators involved in the 
randomization process will not know the block size. SAS 9.4 software will be used to 
generate the random allocation sequence. 
Randomization will be performed before embryo thawing. The coordinator will inform the 
patient, clinician and embryologist of the grouping result, all of whom will know the grouping 
information on the day of transfer (to facilitate the implementation of AH and arrangement of 
subsequent transfer work). 
4.4 Control and Blinding 
4.4.1 Control Selection 
Allocation concealment will be achieved through a third-party hosted central randomization 
system. On the day of transfer, the study center coordinator will log in to the system, enter the 
patient information (age, embryo stage), and obtain the grouping result (AH/non-AH). 
4.4.2 Blinding Implementation 
An open-label design will be adopted, and the patient, clinician and embryologist will all 
know the grouping information to manage and arrange AH and transfer surgery (unblinded). 
The outcome assessor (independent obstetrician and gynecologist) will be unaware of the 
grouping throughout the study to ensure the objectivity of outcome judgment. There will be 
no foreseeable circumstances allowing unblinding. 
4.4.3 Unblinding Method and Emergency Unblinding Procedure 
Unblinding Method: Data analysis will be unblinded uniformly by an independent statistician 
after data locking. 
Emergency Unblinding: Only in the case of a serious adverse event that requires clarification 
of the grouping information to implement rescue, the researcher can log in to the "Emergency 
Unblinding" module of the central randomization system for operation after approval by the 
PI. The system will automatically record and notify the PI and the Ethics Committee at any 
time, and a written report will be submitted within 24 hours. The unblinded subject will 
withdraw from the study treatment but continue follow-up, and the data will be included in 
the safety analysis. If the cumulative unblinding rate >5%, the DMC will evaluate whether to 
terminate the study. 
4.5 Follow-up Time Points 
Subject enrollment will last for 18 months, which is expected to be completed from March 
2026 to September 2027. Follow-up will be carried out in stages of "post-transfer follow-up, 

pregnancy follow-up, and post-delivery follow-up". 
Follow-up Phase 
Follow-up Time Point 
Follow-up Examinations 
Post-embryo Transfer 
Follow-up 1 
12-15 days after embryo 
transfer 
Serum β-hCG test to 
determine biochemical 
pregnancy 
Post-embryo Transfer 
Follow-up 2 
28 days after embryo 
transfer 
Transvaginal ultrasound 
examination to determine 
pregnancy type (clinical 
pregnancy [intrauterine 
gestational sac]/ectopic 
pregnancy, number of 
gestational sacs) 
Pregnancy Follow-up 1 
12 weeks ±7 days of 
gestation 
Ultrasound to confirm 
intrauterine viable fetus and 
its number (ongoing 
pregnancy/early 
miscarriage) 
Pregnancy Follow-up 2 
28 weeks ±7 days of 
gestation 
Ultrasound to confirm 
intrauterine viable fetus and 
its number (ongoing 
pregnancy/mid-trimester 
miscarriage) 
Post-delivery Follow-up 
1 month ±7 days after 
delivery 
Delivery mode, gestational 
age, neonatal vital signs and 
health status, birth weight, 
obstetric complications (live 
birth outcome, neonatal 
outcome) 
5. Selection, Withdrawal and Management of Subjects 
5.1 Diagnostic Criteria 
Undergoing non-donor IVF/ICSI cycles and planning vitrified-warmed embryo transfer. 
5.2 Inclusion Criteria 
1. 
Female age ≥35 years. 

2. 
First or second frozen-thawed embryo transfer cycle. 
3. 
Transferred embryos meet the quality criteria: Grade I, Grade II, or CP and above 
(cleavage-stage embryos); 4BC/CB and above (blastocysts). 
4. 
Provided written informed consent. 
5.3 Exclusion Criteria 
1. 
Use of donor oocytes or donor sperm; or scheduled for preimplantation genetic testing 
(PGT). 
2. 
Severe immune or chromosomal abnormalities. 
3. 
Uterine cavity abnormalities (i.e., adenomyosis, submucous fibroids, hydrosalpinx, 
uterine septum, and endometrial polyps). 
4. 
Embryos with abnormal zona pellucida. 
5. 
Complicated with severe underlying diseases (such as uncontrolled hypertension/diabetes, 
active malignant tumor). 
6. 
History of recurrent implantation failure (≥2 cycles) or recurrent spontaneous abortion 
(≥2 episodes). 
5.4 Exclusion and Withdrawal Criteria 
5.4.1 Exclusion Criteria 
1. 
Violation of important inclusion criteria; 
2. 
Subject did not receive the study treatment; 
3. 
No observation data after randomization. 
5.4.2 Withdrawal Criteria 
1. 
During the trial, the subject developed certain comorbidities, complications or special 
physiological changes that made it inappropriate to continue receiving the trial; 
2. 
Voluntary withdrawal by the subject. 
5.4.3 Data Processing of Withdrawn Subjects 
Regardless of the reason, for subjects who withdraw from the trial, their complete clinical 
data should be retained. All withdrawn subjects should fill in the trial conclusion form and the 
reason for withdrawal in the case report form. Generally, there are 6 reasons, namely 
occurrence of adverse events (including adverse drug reactions and allergic reactions), lack of 
efficacy (disease deterioration or occurrence of complications), violation of the trial protocol 
(including poor compliance), loss to follow-up (including voluntary withdrawal of the patient 
from the trial), termination by the sponsor, or others. 
5.5 Conditions for Terminating the Trial 

1. 
The clinical trial has not ended according to the protocol and is stopped entirely in the 
middle. 
2. 
Serious safety issues occur during the trial, which should be terminated in a timely 
manner; 
3. 
Major mistakes in the trial protocol or major deviations in implementation are found 
during the trial, making it difficult to evaluate the drug effect; 
4. 
Other circumstances requiring termination. 
5.6 Subject Management 
5.6.1 Subject Recruitment Methods 
The identification of study candidates will be carried out in cooperation with laboratory 
personnel and clinical staff. All couples planning to undergo frozen-thawed embryo transfer 
will be considered for inclusion. Women who agree to participate will be required to sign a 
written informed consent form, and they will receive a copy signed by the researcher. Any 
waste or exclusion due to failure to meet the inclusion criteria will be recorded. On the day of 
thawing, laboratory staff will assess whether a signed consent form exists, and if so, 
randomization will be performed. Subjects participating in the study will receive the same 
procedures except for LAH treatment. 
5.6.2 Informed Consent Process 
Adequate information will be provided, and a written informed consent form will be signed. 
6. Study Process 
6.1 Introduction to Study Drugs/Devices 
1. 
Cryotop system (Kitazato Biopharma Co Ltd, Japan); 
2. 
15% (v/v) ethylene glycol, 15% (v/v) dimethyl sulfoxide, and 0.5M sucrose as 
cryoprotectants; 
3. 
Thawing: stepwise dilution of cryoprotectants using 1M, 0.5M, and 0M sucrose solutions; 
4. 
G2 medium (G-2™ PLUS, Vitrolife Group). 
6.2 Drug/Device Administration Methods 
(1) Fertilization, Embryo Culture, Vitrification and Thawing 
According to semen parameters, the collected oocytes will undergo in vitro fertilization or 
intracytoplasmic sperm injection according to routine laboratory procedures. Cleavage-stage 
embryo quality will be observed on the third day after in vitro fertilization or intracytoplasmic 
sperm injection, and the number and regularity of embryo blastomeres and the degree of 
embryo fragmentation will be checked and graded according to Cummins criteria. Grade I 

and II embryos (≥6 cells) are defined as high-quality embryos and will be vitrified. Other 
high-quality cleavage-stage embryos and poorer-quality (Grade III and IV) cleavage-stage 
embryos will be cultured into blastocysts. Blastocysts will be graded according to Gardner 
criteria on the fifth day. If blastocysts on day 5 or 6 are at stage 4 or above, and at least one of 
the inner cell mass or trophoblast cell grades is grade B, they will be vitrified. Blastocysts on 
day 7 must be at least 4CC to be vitrified. These blastocysts are frozen for subsequent FET 
cycles. Vitrification and thawing are performed according to routine methods, as described in 
previous studies. The Cryotop system (Kitazato Biopharma Co Ltd, Japan) is used for 
vitrification, with 15% (v/v) ethylene glycol, 15% (v/v) dimethyl sulfoxide, and 0.5M sucrose 
as cryoprotectants. For warming, 1M, 0.5M, and 0M sucrose solutions are used to dilute the 
cryoprotectants stepwise. All vitrification and thawing steps are performed at room 
temperature except for the first thawing step at 37℃. 
(2) Laser Assisted Hatching 
After thawing, cleavage-stage embryos and blastocysts will be transferred to G2 medium (G-
2™ PLUS, Vitrolife Group) for culture for 10~20 minutes. For cleavage-stage embryos, the 
zona pellucida will be thinned using a microlaser continuous puncher; for blastocysts, 1/4 to 
1/3 of the zona pellucida circumference will be removed using the same method. The 
embryos will then be transferred to fresh G2 medium droplets for transfer. Each viable 
embryo will be transferred within 3 hours after assisted hatching. 
(3) Endometrial Preparation and Frozen-Thawed Embryo Transfer 
Endometrial preparation and frozen-thawed embryo transfer protocols are performed 
according to the center's protocol, as described in previous studies. Endometrial preparation is 
performed under natural cycle, ovulatory cycle, or hormone replacement cycle according to 
the patient's condition. For all three protocols, day 2, 3, or 5~6 embryos are thawed on the 
second, third, or fifth day of endometrial transformation for transfer. Transfer is performed 
under ultrasound guidance using a Cook catheter according to the department's standard 
procedures. According to Chinese law, one to two embryos will be transferred to the middle 
of the uterine cavity. All embryos are thawed on the day of transfer, and embryos with ≥50% 
blastomeres after thawing are considered viable. Non-viable embryos will not be transferred. 
In this case, there are two options: (1) if there are additional vitrified blastocysts, a second 
embryo will be thawed and transferred according to the initially assigned random group; (2) if 
there are no additional vitrified blastocysts, the patient will not undergo embryo transfer. 
6.3 Treatment Course and Follow-up Points 
Subject enrollment will last for 18 months, which is expected to be completed from March 
2026 to September 2027. Follow-up will be carried out in stages of "post-transfer follow-up, 
pregnancy follow-up, and post-delivery follow-up". On-site monitoring will be conducted 
every 6 months to verify data integrity. The entire study is expected to be completed within 36 
months. 
7. Evaluation Indicators 

7.1 Baseline Indicators 
1. 
Demographic data: Subject's unique identification number, gender, age, BMI, infertility 
duration, cause of infertility, ovarian reserve status, etc.; 
2. 
General clinical data: Endometrial preparation protocol, endometrial thickness, hormone 
level on the day of transfer, comorbid diseases and concurrent medications, etc.; 
3. 
Embryological data: Embryo stage (cleavage-stage/blastocyst), embryo grade, number of 
embryos, etc. 
7.2 Efficacy Evaluation 
7.2.1 Primary Evaluation Indicator 
The primary outcome examined in this study will be the live birth rate, defined as the delivery 
of at least one neonate with heartbeat and respiration at ≥28 weeks of gestation, which will be 
recorded at delivery. 
7.2.2 Secondary Evaluation Indicators 
Secondary outcomes include pre-transfer embryo morphological characteristics, implantation 
rate, biochemical pregnancy rate, clinical pregnancy rate (ultrasound-visible gestational sac), 
ectopic pregnancy rate, ongoing pregnancy rate, miscarriage rate, multiple pregnancy rate, 
preterm birth (gestation <37 weeks) rate, obstetric and neonatal complications, and congenital 
anomaly rate. 
7.3 Safety Evaluation 
7.3.1 Vital Signs 
Changes in blood pressure, pulse, body temperature, respiration, and heart rate before and 
after treatment. 
7.3.2 Laboratory Examinations 
Laboratory examination results, changes in normal/abnormal status before and after the trial, 
and the relationship between abnormal changes and the trial drug. For those with abnormal 
results of the above examinations after drug administration, close follow-up and observation 
should be conducted until they return to normal, stable levels or pre-treatment levels. 
7.3.3 Adverse Events 
Serious adverse events (such as ectopic pregnancy) must be reported to the DMC, Ethics 
Committee, and Sponsor within 24 hours; all adverse events shall be recorded in the EDC 
system. 
7.3.4 Specific Risks Related to Laser-Assisted Hatching (LAH) 

The study intervention LAH may have the following specific risks, and corresponding 
prevention and control measures have been formulated in the study protocol: 
(1) Risk of embryo damage: LAH operation may cause damage to embryonic blastomeres. 
Countermeasures: The operation shall be performed by senior embryologists with more than 5 
years of experience and special training in this study; 
(2) Risk of multiple pregnancy: LAH may increase the risk of multiple pregnancy, thereby 
causing maternal and infant complications such as preterm birth and low birth weight. 
Countermeasures: Strictly follow the principle of single embryo transfer (SET) for the first 
transfer in this center, and the twin pregnancy rate will be used as a key safety indicator for 
inter-group comparison. 
The above risks will be highlighted in plain and easy-to-understand language in the informed 
consent form, and subjects will be clearly informed that participation in the study is voluntary 
and they can withdraw unconditionally at any time. 
8. Data Quality Assurance 
8.1 Quality Control and Assurance 
Dual data entry is adopted, and original data are verified through medical record review. 
8.2 Data Management 
(1) Data Collection: An Electronic Data Capture (EDC) system (such as MedPro) is adopted. 
All variables related to the study protocol will be recorded and stored in a digital database, 
mainly including baseline data (such as age), embryo data (embryo stage, embryo grade, 
number of embryos, etc.), transfer cycle data (endometrial thickness on the day of transfer, P 
on the day of transfer, endometrial preparation plan, etc.), and outcome data (live birth rate, 
clinical pregnancy rate, etc.). Original data are verified through medical record review. 
(2) Data Management: Dual data entry, range check, and query resolution mechanisms are 
adopted. Data are stored on an encrypted server, and only authorized personnel can access 
them. 
(3) Trial Monitoring: On-site monitoring is conducted every 6 months to check data integrity; 
the DMC reviews Adverse Event (AE) reports every quarter. 
(4) The processing of personal data shall comply with relevant national regulations. 
9. Statistical Analysis 
9.1 Analysis Datasets 
The ITT analysis includes all randomized patients (primary analysis), and missing data are 
handled by the Multiple Imputation by Chained Equations (MICE) method; the PP analysis 
includes patients who comply with the protocol (sensitivity analysis). 

9.2 Statistical Methods 
(1) Continuous Variables: Normally distributed data are expressed as mean ± standard 
deviation, and t-test is used for inter-group comparison; non-normally distributed data are 
expressed as median (interquartile range), and Mann-Whitney U test is used for inter-group 
comparison. 
(2) Categorical Variables: Expressed as frequency (percentage), and χ² test or Fisher's exact 
test (when the expected frequency < 5) is used for inter-group comparison. 
(3) Subgroup Analysis: Preset subgroup analysis will be conducted by age (<40 years and ≥40 
years) and embryo stage (cleavage-stage embryos, blastocysts). 
(4) Statistical Software: SAS 9.4 and R 4.3.0 software are used, with a two-sided P < 0.05 
considered statistically significant. 
10. Ethical Requirements and Informed Consent Form 
10.1 Ethics Committee Review 
This protocol, written informed consent form, and materials directly related to subjects must 
be submitted to the Ethics Committee, and the study can be officially carried out only after 
obtaining written approval from the Ethics Committee. Investigators must submit an annual 
study report to the Ethics Committee at least once a year (if applicable). When the study is 
suspended and/or completed, the investigator must notify the Ethics Committee in writing; the 
investigator must promptly report all changes occurring in the study work (such as revisions 
to the protocol and/or informed consent form) to the Ethics Committee, and shall not 
implement these changes unless they are made to eliminate obvious and direct risks to 
subjects. In such cases, the Ethics Committee will be notified. 
10.2 Informed Consent 
Investigators must provide subjects or their legal representatives with an easy-to-understand 
informed consent form approved by the Ethics Committee, and give subjects or their legal 
representatives sufficient time to consider this study. Subjects shall not be enrolled until a 
signed written informed consent form is obtained from them. During the subjects' 
participation, all updated versions of the informed consent form and written information will 
be provided to the subjects. The informed consent form shall be retained as an important 
document of the clinical trial for inspection. 
11. Insurance 
No insurance is required. 
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