Multi-national, Multi-center, Randomized Controlled Trial to Evaluate the Clinical Utility of Non-invasive Endometrial Receptivity Test (Ora) in Patients With Implantation Failure
Phase: NA
Conditions: IVF, Window of Implantation, microRNA, Implantation, Non-invasive Testing, Endometrial Receptivity
Sponsor: Inti Labs

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 1 of 21 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Multi-national, multi-center, randomized controlled trial to evaluate 
the clinical utility of non-invasive endometrial receptivity test 
(oraTM) in patients with implantation failure 
 
Name of Study Test Non-Invasive Endometrial 
Receptivity Test 
Study Acronym ORA RCT 
Sponsor Inti Taiwan, Inc. 
Clinical Protocol 
Doc. No. ORA-PTL-2024-01 
Version 1.0 
Date 2024/01/10 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 2 of 21 
Sponsor contact details 
 
Name  
Inti Taiwan, Inc. 
Address 
7f-6, No. 66, Shengyi 5th Road, Zhubei City, Hsinchu County, 30261 
Contact person 
Winter Hong 
E-mail 
winterhong@intilabs.com 
Telephone 
+8863 658 1031 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 3 of 21 
Principal Investigator Signature Page 
 
● I agree to conduct this study in accordance with the Regulations on Good Clinical Practice for Medical 
Devices and ISO 14155:2020, all applicable legal and regulatory requirements, and in compliance with 
the provisions of this Protocol. 
 
● I am responsible for ensuring that the investigation is conducted according to this protocol and for 
protecting the rights, safety, and welfare of research subjects.  
 
● I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments. 
 
 
Principal Investigator Name/ Title/ Site 
Principal Investigator Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 4 of 21 
List of abbreviation  
 
AE 
Adverse Event 
BMI 
Body Mass Index 
CIOMS 
Council for International Organization of Medical Sciences  
CRF 
Case Report Form 
FBT 
Frozen-thawed blastocyst transfer 
FET 
Frozen Embryo Transfer 
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act  
HRT 
Hormone Replacement Therapy 
ICF 
Informed Consent Form 
ICSI 
Intracytoplasmic Sperm Injection 
IEC 
Institutional Ethics Commitee 
IRB 
Institutional Review Board 
IVF 
In Vitro Fertilization 
LDT 
Laboratory Developed Test 
MRN 
Medical Record Number 
NGS 
Next Generation Sequencing 
SAE 
Serious Adverse Event 
SET 
Single Embryo Transfer 
WOI 
Window of Implantation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 5 of 21 
Table of Contents 
Sponsor contact details ............................................................................................................................................................. 2 
Principal Investigator Signature Page ....................................................................................................................................... 3 
List of abbreviation..................................................................................................................................................................... 4 
Table of Contents ....................................................................................................................................................................... 5 
1. Protocol Synopsis .................................................................................................................................................................. 6 
2. Introduction ............................................................................................................................................................................ 8 
2.1. 
Background and Study Rational ........................................................................................................................... 8 
2.2. 
Test Description .................................................................................................................................................... 8 
3. Objectives and Endpoints ...................................................................................................................................................... 9 
3.1. 
Description of the Study ........................................................................................................................................ 9 
3.2. 
Study Objectives .................................................................................................................................................... 9 
3.3. 
Study Endpoints ..................................................................................................................................................... 9 
4. Study Population .................................................................................................................................................................. 10 
4.1. 
Number of Subjects ............................................................................................................................................ 10 
4.2. 
Inclusion criteria .................................................................................................................................................. 10 
4.3. 
Exclusion Criteria ................................................................................................................................................. 10 
4.4. 
Withdrawal criteria .............................................................................................................................................. 10 
5. Study Procedures ................................................................................................................................................................. 11 
5.1. 
Overall Design ...................................................................................................................................................... 11 
5.2. 
Subject Recruitment ............................................................................................................................................ 11 
5.3. 
Informed Consent Process and Informed Consent Text .................................................................................. 11 
5.4. 
Payment for the Participation ............................................................................................................................. 11 
5.5. 
Data collection and protection ........................................................................................................................... 12 
5.6. 
Research Process................................................................................................................................................ 12 
5.7. 
Schedule of Activities .......................................................................................................................................... 15 
6. Risk and benefit analysis ..................................................................................................................................................... 16 
7. Statistical considerations .................................................................................................................................................... 16 
7.1. 
Sample size calculation ...................................................................................................................................... 16 
7.2. 
Data Evaluation and Statistical Considerations ................................................................................................ 16 
7.3. 
Data Management ............................................................................................................................................... 16 
8. Adverse events (AE), Adverse reactions and medical device deficiency ......................................................................... 17 
8.1. 
Adverse Events .................................................................................................................................................... 17 
8.2. 
Serious Adverse Events ...................................................................................................................................... 17 
9. Regulatory, Ethical and Study Oversight Considerations .................................................................................................. 18 
9.1. 
Regulatory and Ethical Considerations .............................................................................................................. 18 
9.2. 
Financial Disclosure ............................................................................................................................................ 18 
9.3. 
Informed Consent Process ................................................................................................................................. 19 
9.4. 
Data Protection .................................................................................................................................................... 19 
9.5. 
Data Quality Assurance ....................................................................................................................................... 20 
9.6. 
Source Documents .............................................................................................................................................. 20 
9.7. 
Study and Site Closure ........................................................................................................................................ 21 
9.8. 
Insurance ............................................................................................................................................................. 21 
10. 
References ................................................................................................................................................................. 21 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 6 of 21 
1. 
Protocol Synopsis 
Protocol Title: Multi-national, multi-center randomized controlled trial to evaluate the clinical utility of 
non-invasive endometrial receptivity test oraTM in patients with implantation failure 
Sponsor: Inti Inc., Taiwan 
Intended use: The oraTM test is a laboratory-developed test (LDT) designed to analyze the expression 
profile of miRNA isolated from plasma. It is intended to identify the optimal window of implantation 
(WOI) in patients undergoing in vitro fertilization (IVF). 
Investigational product/ Model name： Non-invasive endometrial receptivity test / oraTM 
Objective: To evaluate the clinical utility of non-invasive endometrial receptivity test (oraTM) in patients 
with implantation failure. 
Population: Patients who have experienced at least one implantation failure with a euploid or low-level 
mosaic (< 30%) embryo transfer in the past two years. 
 
Sample Size: The study is expected to enroll up to 800 subjects. 
Study design: 
◼ 
Study type: Prospective 
◼ 
Blinding：No 
◼ 
Randomization: Yes  
◼ 
Study location: Multi-national and multi-center 
◼ 
Study Period: 6-15 months  
◼ 
This study aims to enroll subjects who have experienced at least one implantation failure with a 
euploid or low-level mosaic (< 30%) embryo transfer in the past two years. Subjects should have a 
euploid embryo, and will be randomly assigned into two groups: control and study group. The 
study group will undergo frozen embryo transfer based on oraTM timing, while the other group will 
adhere to the standard timing protocol. The subjects will provide blood samples for the oraTM test 
during the mock cycle for the study group or during the frozen embryo transfer cycle for the control 
group. The study will compare pregnancy outcomes to assess whether oraTM timing provides 
clinical benefits to the patients.  
Endpoints (Outcome measure)： 
Primary endpoint: 
Clinical pregnancy, defined as presence of one or more intrauterine gestational sacs after 6 weeks of 
gestation. 
Secondary endpoint 
1. Ongoing pregnancy, defined as presence of fetal heartbeat after 12 weeks of gestation.  
2. Live birth, defined as baby survival after 20 weeks of gestation.   
3. Abortion and miscarriage rates.  
4. Frequency and intensity of adverse events (AEs). 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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Inclusion/Exclusion Criteria： 
Inclusion Criteria: 
1. Patients who have at least one implantation failure with a euploid or low-level mosaic (< 30%) 
embryo transfer in the past two years. 
2. Females within 28-45 years old. 
3. Those who agree to undergo one mock cycle for oraTM test and execute single frozen embryo transfer 
in the later cycle. 
4. Those who has at least one remaining euploid or low-level mosaic (< 30%) embryo. 
Exclusion Criteria: 
1. Known uterine factor (such as endometriosis, uterine fibroids) impacting the endometrium. 
2. Presence of any clinically relevant systemic disease (such as immune disease) that contraindicates 
assisted reproductive technology. 
3. Body mass index (BMI) exceeds than 30 kg/m2.  
Statistical Methodology: 
1. The outcome of clinical pregnancy, ongoing pregnancy and live birth rate per transfer will be 
compared between the study and control groups by chi-square analysis.  
2. The quantitative outcomes such as gestational age and BMI, etc. will be compared between treatment 
groups by the Mann-Whitney U test. 
 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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2. 
Introduction 
2.1. Background and Study Rational 
The successful implantation of blastocysts is a crucial milestone in human reproduction, requiring a 
harmonious alignment between a viable embryo and a receptive endometrium. Next-generation 
Sequencing (NGS) technology allows us to explore the intricate transcriptomic details of the human 
endometrium throughout the menstrual cycle.1 By analyzing the gene expression patterns in the human 
endometrium, we can identify distinctive gene expression patterns, particularly during the receptive 
phase.2 
Endometrial receptivity testing has emerged as an evaluation tool that takes advantages of the unique 
gene expression signature of the endometrium during the implantation window.3 One innovative test 
is the oraTM, which uses blood samples to examine over 110 differentially expressed miRNAs.4 The 
oraTM test categorizes the receptivity stages into three phases: pre-receptive, receptive, and post-
receptive. Based on the results, patients receive recommendations for the timing of frozen embryo 
transfers in subsequent cycles, whether it be earlier, later, or at the same time. 
The primary objective of this clinical trial is to investigate whether vitrified/thawed euploid embryo 
transfers result in improved pregnancy outcomes when precisely timed using the oraTM test. To achieve 
this, we propose implementing a randomized clinical trial. The outcomes, including clinical pregnancy 
rate and live birth rate, will be calculated. 
2.2. Test Description 
The oraTM test is a Laboratory Developed Test (LDT) performed within a single laboratory. Using 
NGS, the oraTM test is a miRNA-based endometrial receptivity test designed to identify the optimal 
window of implantation (WOI) based on miRNAs isolated from plasma processed from peripheral the 
whole blood samples of the patients. 
The results of WOI identification for endometrial receptivity are reported in three statuses: “PRE-
RECEPTIVE”, “RECEPTIVE”, and “POST-RECEPTIVE”. The pre-receptivity result, reported as 
“PRE”, indicates that the endometrium is not yet at peak receptivity at the time of sampling and the 
WOI is delayed. In the pre-receptivity status, the endometrium is not yet ready for embryo implantation, 
and it is recommended to delay embryo transfer from the sampling time. The receptive result, which 
is reported as “WOI”, indicates that the endometrium is at peak receptivity at the time of sampling and 
is ideal for embryo implantation. Embryo transfer is recommended at the same time of sampling. The 
post-receptive result, which is reported as “POST”, indicates that the endometrium has past peak 
receptivity at the time of sampling and the optimal time for embryo implantation has passed. Therefore, 
embryo transfer is recommended to take place earlier than the sampling time. 
Indication For Use 
The oraTM test is a Laboratory Developed Test (LDT) designed to analyze the expression profile of 
miRNAs isolated from plasma. It is intended to identify the optimal window of implantation (WOI) in 
patients undergoing in vitro fertilization (IVF). 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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3. 
Objectives and Endpoints 
3.1. Description of the Study 
The study is a two-arm, randomized controlled trial that aims to compare clinical pregnancy-related 
outcomes in different groups. Patients who have experienced at least one failed implantation with a 
euploid or low-level mosaic (< 30%) embryo transfer in the past two years will be recruited. They will 
undergo a single frozen embryo transfer, with the timing determined by either oraTM testing or a 
standardized approach. 
3.2. Study Objectives 
To evaluate the clinical utility of non-invasive endometrial receptivity test (oraTM) in patients with 
implantation failure. 
3.3. Study Endpoints 
(a) Primary Endpoint 
Clinical pregnancy, defined as presence of one or more intrauterine gestational sacs after 6 
weeks estimated gestational age. 
(b) Secondary Endpoint 
1) Ongoing pregnancy, defined as presence of fetal heartbeat after 12 weeks of gestation. 
2) Live birth, defined as baby survival after 20 weeks of gestation.   
3) Abortion and miscarriage rates.  
4) Frequency and intensity of adverse events (AEs). 
 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 10 of 21 
4. 
Study Population 
4.1. Number of Subjects 
The study is expected to enroll up to 800 subjects. 
4.2. Inclusion criteria 
(a) Subjects who have at least one implantation failure with a euploid or low-level mosaic (< 30%) 
embryo transfer in the past two years. 
(b) Females within 28-45 years old. 
(c) Those who agree to undergo one mock cycle for oraTM test and execute single frozen embryo 
transfer in the later cycle. 
(d) Those who has at least one remaining euploid or low-level mosaic (< 30%)embryo.  
4.3. Exclusion Criteria 
(a) Known uterine factor (such as endometriosis, uterine fibroids) impacting the endometrium. 
(b) Presence of any clinically relevant systemic disease (such as immune disease) that 
contraindicates assisted reproductive technology. 
(c) Body mass index (BMI) exceeds than 30 kg/m2.  
4.4. Withdrawal criteria 
(a) During the research process of this research project, all subjects can unconditionally choose to 
withdraw. 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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5. 
Study Procedures 
5.1. Overall Design 
This study aims to enroll up to 800 subjects who have experienced at least one implantation failure 
with a euploid or low-level mosaic (< 30%) embryo transfer in the past two years. Subjects should 
have at least one euploid or low-level mosaic (< 30%) embryo for the study. Subjects will be randomly 
assigned to either the control or study group. In the control group, subjects will simultaneously provide 
blood samples for the oraTM test and undergo Hormone Replacement Therapy (HRT) frozen embryo 
transfer during the standard implantation window (day 5 of progesterone supplementation: P+5/120 
hours). In the study group, subjects will provide blood samples for the oraTM test during a mock HRT 
cycle; in the subsequent cycle, the subject will undergo HRT frozen embryo transfer during the period 
which the implantation window is confirmed as “Receptive” by oraTM’s analysis.  The study aims to 
compare pregnancy outcomes to evaluate whether oraTM timing offers clinical advantages to the 
patients. 
Control Group: Euploid embryo transfer at standard implantation window (day 5 of progesterone 
supplementation: P+5/120 hours) 
Study Group: Mock cycle followed by euploid embryo transfer at implantation window confirmed as 
“Receptive: by ora TM’s analysis. 
5.2. Subject Recruitment 
Subjects with at least one implantation failure with a euploid or low-level mosaic (< 30%) embryo 
transfer in the past two years will be invited based on the inclusion/exclusion criteria during a private 
fertility consultation with their physician. Subjects will be recruited for the current study only after 
presenting their own volition. 
5.3. Informed Consent Process and Informed Consent Text 
Before each subject is selected into this study, the investigator/researcher is responsible for fully and 
comprehensively introducing the purpose and possible risks of this study to the subject in written form. 
Subjects must be informed that they have the right to withdraw from the study at any time and that 
their personal information will be kept confidential.  
A written informed consent form (ICF) must be given to each subject prior to enrollment. It is the 
investigator's responsibility to obtain informed consent from each subject prior to entry into the study 
and to keep it in the study file. 
5.4. Payment for the Participation 
Subjects meeting inclusion/exclusion criteria and do not drop out of the study will be compensated for 
their participation in the study. The details of compensation will be provided to the subjects in the ICF. 
The expense for oraTM test will be covered by the Inti, Inc. Taiwan, and the expense of ultrasound, 
medication and bloodwork to assess the endometrial cycle will be covered by the testing sites. Subjects 
will be billed in the usual manner for screening, diagnostic costs, IVF/ICSI including egg retrieval and 
anesthesia, embryo vitrification, and FBT through the hospital or reproductive clinics (the testing sites). 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 12 of 21 
Standard IVF and endometrial preparation medications will be prescribed as per standard clinical 
practice and covered by the subject or her medical insurance as per usual. Subjects who wish to 
maintain embryo in cryopreservation will have to pay a standard annual storage fee as per routine. 
5.5. Data collection and protection 
All data obtained in clinical trials are subject to data protection. The paper informed consent and case 
report form (CRF) will be stored in a locker on the test facility and/or electronically separately. 
Investigators/researcher shall not disclose the subject’s name and other identifiable personal data 
(excluding year of birth/age, weight, height and medical record number (MRN)).  
Any documents submitted to Inti Labs do not contain names, but only subject codes. Likewise, data 
for statistical evaluation can only be accessed under the subject code. Only the researcher can identify 
the subject's name and other personal information through the code. If the name of a subject needs to 
be identified for medical reasons during the research, all subjects involved are obliged to keep it 
confidential. 
5.6. Research Process 
(a) Randomization: 
After signing the ICF, the investigator will assign a subject code to each enrolled subject. This 
subject code will consist of two parts: the center identification number and the subject 
identification number. For instance, TW01-001. 
1) The center identification number is structured using the first two letters of the country name 
followed by a two-digit site number. Examples include TW01, TW02, SG01, JP01, etc. 
2) Within each age category at each center, subjects will receive a subject identification number 
assigned based on their order of inclusion in the study. The first subject enrolled will be 
labeled as 001, followed by 002, and so forth, maintaining chronological order. 
Once the subject receives the unique subject code, the subject will be randomized to one of the 
two study groups through a simple 1: 1 randomization program stratified by center (to avoid 
bias). The randomization number will be assigned to each subject included in the study, as well 
as their corresponding group. The randomization program will be set up by the Inti Inc., Taiwan. 
For example, the randomization process for a subject attending the initial clinical site in Taiwan: 
Subject code 
Randomization number 
Group 
TW01-001 
1 
Control 
TW01-002 
2 
Study 
TW01-003 
3 
Study  
TW01-004 
4 
Control 
TW01-005 
5 
Control 
TW01-006 
6 
Study 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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(b) Subjects will undergo the hormone replacement therapy (HRT) in a frozen embryo transfer 
(FET) cycle. The HRT treatment cycle will be performed following medical criteria and in 
accordance with the usual practice of the clinic and the doctors. Ideally, the subjects in the 
control and study groups should follow identical drug prescription program.  
(c) Endometrial receptivity test by oraTM:  
1) Study group subjects will undergo blood sampling for the oraTM test on the fifth day of 
progesterone administration in a mock cycle (120 ± 3 hours after the first progesterone 
injection); the control group subjects will undergo blood sampling for the oraTM test and 
frozen embryo transfer at the standard time (120 ± 3 hours after the first progesterone 
injection) for data collection.  
2) The collected blood samples will be processed into plasma by the researchers, and these 
samples will then be sent to the Inti Service Laboratory in Taiwan for an endometrial 
receptivity test. The results, indicating the receptivity timing as determined by oraTM, will be 
provided 10 days later. The results include: 
a. 
Receptive Phase: At the time of blood draw, it is the optimal Window of Implantation 
(WOI) for embryo implantation. It is recommended to perform embryo implantation at 
the sampling time point. 
b. 
Pre-Receptive: At the time of blood draw, it is before the optimal Window of 
Implantation (WOI). The endometrium is not yet ready for embryo implantation. It is 
suggested to delay the embryo implantation window by 24 hours. 
c. 
Post-Receptive: At the time of blood draw, the endometrium has passed the optimal 
time for embryo implantation. It is recommended to advance the embryo transfer time 
by 24 hours. 
3) Any subject whose blood sample does not provide adequate information to recommend timing 
for FET will be withdrawn from the study.  
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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(d) Frozen embryo transfer   
On the day of embryo transfer, one of the subject’s vitrified, euploid blastocysts will be thawed, 
and the subject will undergo single embryo transfer. The frozen embryo transfer in the study 
group should follow the exact same drug prescriptions and dosage without deviation from 
the mock cycle.   
1) If the subject is assigned to the control group, a single embryo transfer will be performed on 
the subsequent cycle after randomization. The transfer timing follows the standard HRT 
protocol at 120 ±3 hours post initiation of progesterone. 
2) If the subject is assigned to the study group, a single embryo transfer will be performed on the 
HRT cycle after the mock cycle. The transfer timing is based on the implantation window 
indicated by oraTM test results.   
(e) Results confirmation  
1) Approximately 10 days following implantation, a serum hCG concentration will be detected. 
2) Around 6 weeks after estimated gestational age, an ultrasound will be performed to assess the 
presence of a gestational sac, providing an estimate of clinical pregnancy. 
3) Around 12 weeks after estimated gestational age, an ultrasound will be performed to assess 
the presence of a fetal heartbeat, providing an estimate of ongoing pregnancy. 
4) Around 20 weeks after estimated gestational age, live birth will be evaluated. 
5) Abortion and miscarriage rates would be calculated. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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Fig. 1 Flowchart of the clinical trial 
 
5.7. Schedule of Activities 
This project is expected to be implemented for 6-15 months for individual sites depending on the 
allocated subject size. 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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6. 
Risk and benefit analysis 
The execution process of this study follows the standard procedures of in vitro fertilization (IVF), except for 
the blood specimen collection for endometrial receptivity testing. Rigorous standard operating procedures 
have been established for the specimen collection process, specimen storage, and specimen transportation. 
Only relatively sensitive subjects may experience discomfort during blood specimen collection, but 
noticeable improvement is observed after a period of rest. 
 
7. 
Statistical considerations 
7.1. Sample size calculation 
The sample size calculation for the two-armed endpoint suggests that obtaining data from 650 
participants (325 subjects for each group). This sample size is adequate to detect a 10% difference in 
clinical pregnancy outcomes between groups given an alpha level of p <0.05 and a power of 0.8 and 
using 50% anticipated LB in the control arm (based on current success rates among euploid embryo 
transfers conducted with standard timing protocol). Accounting for 10-20% dropout rate, the goal is 
to enroll 800 subjects in total. 
7.2. Data Evaluation and Statistical Considerations 
(a) The outcome of clinical pregnancy and live birth rate, etc. per transfer will be compared between 
the study and control groups by chi-square analysis.  
(b) The quantitative outcomes such as gestational age and BMI, etc. will be compared between 
treatment groups by the Mann-Whitney U test. 
7.3. Data Management 
(a) Data management organization and procedures 
1) Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents must be reviewed by study personnel 
and data entry staff, which will ensure that they are accurate and complete. 
2) CRFs are provided for each subject in printed or electronic format. Source documentation 
must be available for the following to confirm data collected in the CRF. The sponsor will 
review CRFs for accuracy and completeness; any discrepancies will be resolved with the 
investigator or designee, as appropriate. 
(b) Electronic data validation, verification, and protection procedures 
After upload of the data into the study database they will be verified for accuracy and consistency 
with the data sources 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
Confidential and Proprietary                                                                                                                                                                                                Page 17 of 21 
8. 
Adverse events (AE), Adverse reactions and medical device deficiency  
During and following a subject's participation in the study, the investigator/institution should ensure 
that adequate medical care is provided to a subject for any adverse events, including clinically 
significant laboratory values, related to the trial. The investigator/institution should inform a subject 
when medical care is needed for intercurrent illness(es) of which the investigator becomes aware. 
 
In the event medical care to a subject is required, the medical care given to, and medical decisions 
made on behalf of, subjects should always be the responsibility of a qualified physician or, when 
appropriate, other healthcare providers. 
8.1. Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence, unintended disease or injury 
in subjects, users or other persons, that is considered a change from baseline or pre-study status, 
whether or not related to the investigational medical device. 
Any pre-existing medical condition or symptoms present in a subject will not be considered an Adverse 
Event in this study, unless it worsens because of this study.  
All Adverse Events (AEs) will be reported on an AE Case Report Form and will include the following: 
Date/time of onset, description of the event, the duration of the event, the severity of the event, 
assessment of the relation of the event to the study device and procedure, description of action taken 
(if any) and the event outcome. 
8.2. Serious Adverse Events 
A Serious Adverse Event (SAE) is defined as an adverse event that is anticipated or unanticipated and 
which reasonably suggests that one of the manufacturers’ devices has or may have caused or 
contributed to a death or serious injury.  
A Serious Adverse Event is an Adverse Event that led to: (a) death, (b) serious deterioration in the 
health of the subject that either resulted in a (i) life-threatening illness or injury or (ii) permanent 
impairment of a body structure or a body function, or (iii) in-patient or prolonged hospitalization or 
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function or (c) fetal distress, fetal death or a congenital 
abnormality or birth defect.  
These events are typically reportable to health authorities. Serious Adverse Events will be reported to 
the Sponsor within 24 hours of knowledge of the event. 
 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
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9. 
Regulatory, Ethical and Study Oversight Considerations 
9.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
(a) Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines 
(b) Applicable Good Clinical Practice (GCP) Guidelines 
(c) Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, and other relevant documents must be submitted to an 
IRB/IEC by the investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
subjects. 
The investigator will be responsible for the following: 
(a) Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC. 
(b) Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures; and 
(c) Providing oversight of the conduct of the study at the site and adherence to requirements of ISO 
14155:2020, the IRB/IEC, or all other applicable local regulations. 
9.2. Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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9.3. Informed Consent Process 
(a) The investigator or designee must obtain written informed consent before any clinical study 
related activity takes place.  The investigator or designee will explain the nature of the study to 
the subject and answer all questions regarding the study. 
(b) Subjects must be informed that their participation is voluntary. Subjects will be required to sign a 
statement of informed consent that meets the requirements of ISO 14155:2020, local regulations, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
(c) The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
(d) A copy of the ICF(s) must be provided to the subjects. 
9.4. Data Protection 
(a) Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
(b) The subject must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the subject. All data used in the analysis and reporting of this evaluation will be used in a manner 
without identifiable reference to the study p subject. 
(c) The subject must be informed that his/her medical records may be examined by auditors or other 
authorized personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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9.5. Data Quality Assurance 
(a) All subject data relating to the study will be recorded on Case Report Forms (CRFs). The 
Investigator/researcher is responsible for verifying that data entries are accurate and correct by 
physically signing the CRF. 
(b) The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
(c) The Investigator must permit study-related monitoring (if applicable), audits (if applicable), 
IRB/IEC review, and regulatory agency inspections and provide direct access to source data 
documents. 
(d) Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
(e) The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
(f) The Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
(g) Study monitors will perform ongoing source data verification to confirm that data entered the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of subjects are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, GCP, and all 
applicable regulatory requirements. 
(h) Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 2 years after study completion unless local regulations or 
institutional policies require a longer retention period.  
(i) No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written notification 
to the Sponsor. 
9.6. Source Documents 
(a) Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
(b) Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 

 
 
CLINICAL STUDY PROTOCOL 
Title: Multi-national, multi-center randomized controlled trial to 
evaluate the clinical utility of non-invasive endometrial receptivity 
test (oraTM) in patients with implantation failure 
Doc. No. ORA-PTL-2024-01 
Version 
1.0 
Date 
2024/01/10 
 
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(c) Source documents may include original documents, data, and records e.g. hospital records, 
clinical/office charts, laboratory notes, etc. 
(d) If study data is recorded directly on the CRFs (i.e., no prior written or electronic record of data), 
it is source data. 
9.7. Study and Site Closure 
The Sponsor and/or designee reserves the right to pause enrollment, to close the study site or terminate 
the study at any time for any reason at the sole discretion of the sponsor. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
(a) Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, the sponsor's procedures, or GCP guidelines. 
(b) Inadequate recruitment of subjects by the investigator 
(c) Discontinuation of further study intervention development 
9.8. Insurance 
This trial/study is not covered by human subject liability insurance. 
10. 
References 
1. Achache, H., & Revel, A. (2006). Endometrial receptivity markers, the journey to successful embryo 
implantation. Human Reproduction Update, 12(6), 731–746. 
2. Ruiz-Alonso, M., Blesa, D., & Simón, C. (2012). The genomics of the human endometrium. Biochimica 
Et Biophysica Acta (BBA) - Molecular Basis of Disease, 1822(12), 1931–1942.  
3. Doyle, N., Jahandideh, S., Hill, M. J., Widra, E., Levy, M. J., & Devine, K. (2022). Effect of Timing by 
Endometrial Receptivity Testing vs Standard Timing of Frozen Embryo Transfer on Live Birth in 
Patients Undergoing In Vitro Fertilization. JAMA, 328(21), 2117. 
4. Chen, M., Hsu, A., Lin, P. C., Chen, Y., Wu, K., Chen, K., Wang, T., Yi, Y., Kung, H., Chang, J., Yang, 
W., Lu, F., Guu, H., Chen, Y., Chuan, S., Chen, L., Chen, C. H., Yang, P. E., & Huang, J. Y. (2023). 
Development of a predictive model for optimization of embryo transfer timing using Blood-Based 
microRNA expression profile. International Journal of Molecular Sciences, 25(1), 76.