Dydrogesterone Primed Ovarian Stimulation Versus Fixed Gonadotropin Releasing Hormone Antagonist Protocol for Oocyte Accumulation in Low Ovarian Reserve Patients: A Randomized Controlled Trial
Phase: NA
Conditions: Diminished Ovarian Reserve
Sponsor: Tam Anh TP. Ho Chi Minh General Hospital

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EXHIBIT A 
CLINICAL STUDY PROTOCOL 
 
Title: 
Dydrogesterone primed ovarian stimulation versus fixed gonadotropin-
releasing hormone antagonist protocol for accumulation of oocyte in 
patients with low ovarian reserve: A randomized controlled trial 
Protocol Number:  
DYDR-C22-0313 
National Clinical Trial (NCT) 
Identified Number: 
NCT05847283 
Sponsored by: 
Tam Anh TP. Ho Chi Minh General Hospital Joint Stock Company 
Funded by: 
Abbott Company  
Principal Investigator: 
Nhu H Giang, MD, MCE 
Assisted Reproductive Technilogy Unit 
Tam Anh TP. Ho Chi Minh General hospital 
2B Pho Quang 
Tan Binh District 
Ho Chi Minh city  
Viet Nam 
Tel: +84 793 231 721 
Version Number:   
Version 3.0 
 
 
 
 
 
 
 
August 9th 2024 
 
 

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1 
TABLE OF CONTENTS 
SUMMARY OF CHANGES FROM PREVIOUS VERSION: ..................................................................................... 4 
1. 
STATEMENT OF COMPLIANCE ................................................................................................................ 6 
2. 
PROTOCOL SUMMARY .......................................................................................................................... 6 
2.1. 
Summary ..................................................................................................................................... 6 
2.2. 
Synopsis ....................................................................................................................................... 7 
2.3. 
Schema ........................................................................................................................................ 9 
2.4. 
Schedule of activities (SOA) ........................................................................................................ 10 
3. 
INTRODUCTION AND RATIONALE ........................................................................................................ 12 
4. 
OBJECTIVES ......................................................................................................................................... 13 
4.1. 
Primary objectives: .................................................................................................................... 13 
4.2. 
Secondary objectives: ................................................................................................................ 13 
5. 
STUDY DESIGN .................................................................................................................................... 14 
6. 
STUDY POPULATION ............................................................................................................................ 16 
6.1. 
Inclusion criteria ........................................................................................................................ 16 
6.2. 
Exclusion criteria ........................................................................................................................ 16 
7. 
STUDY INTERVENTION ......................................................................................................................... 16 
7.3. 
Study intervention administration ............................................................................................. 17 
7.3.1. 
Ovarian stimulation ...................................................................................................................... 17 
7.3.2. 
Oocyte retrieval and cryopreservation ......................................................................................... 18 
7.3.3. 
Oocyte thawing and ICSI .............................................................................................................. 18 
7.3.4. 
Embryo cryopreservation ............................................................................................................. 19 
7.3.5. 
Endometrium preparation and embryo transfer .......................................................................... 19 
7.4. 
Study intervention follow-up ..................................................................................................... 20 
7.4.1. 
Ovarian hyperstimulation syndrome assessment. ....................................................................... 20 
7.4.2. 
Pregnancy outcome follow-up ..................................................................................................... 21 
8. 
OUTCOME MEASUREMENTS ............................................................................................................... 21 
9. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT ............................................................ 23 
9.1. 
Discontinuation of study intervention ........................................................................................ 23 
9.2. 
Participant discontinuation/withdrawal from the Study ............................................................. 23 
9.3. 
Lost to follow-up ........................................................................................................................ 24 
10. 
STUDY ASSESSMENT AND PROCEDURES .......................................................................................... 24 
10.1. 
Feasibility of Study ..................................................................................................................... 24 
10.2. 
Safety and other assessments .................................................................................................... 24 
11. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................................................... 24 
11.1. 
Adverse Events and adverse drug reactions ................................................................................ 24 
12. 
STATISTICAL CONSIDERATIONS ....................................................................................................... 27 
12.1. 
Sample size determination ......................................................................................................... 27 

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12.2. 
Randomization ........................................................................................................................... 27 
12.3. 
Statistical analyses ..................................................................................................................... 27 
12.3.1. 
Characteristics of patients ....................................................................................................... 27 
12.3.2. 
Primary outcome ..................................................................................................................... 28 
12.3.3. 
Secondary outcome ................................................................................................................. 28 
12.3.4. 
Missing data and sensitivity analysis ...................................................................................... 28 
12.3.5. 
Data and safety monitoring board .......................................................................................... 28 
12.3.6. 
Planed interim analyses ........................................................................................................... 28 
13. 
ETHICAL CONSIDERATION ............................................................................................................... 29 
13.1. 
Regulation statement ................................................................................................................. 29 
13.2. 
Recruiment and consent ............................................................................................................ 29 
13.3. 
Privacy ....................................................................................................................................... 29 
14. 
ADMINISTRATIVE ASPECTS AND PUBLICATION ............................................................................... 29 
14.1. 
Handling and storage of data and documents ............................................................................ 29 
14.2. 
End of study report .................................................................................................................... 29 
14.3. 
Public disclosure and publication policy ..................................................................................... 30 
15. 
REFERENCES ................................................................................................................................... 31 
 
 
 
 

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3 
GLOSSARY AND ABBREVIATIONS 
ICH GCP 
International Conference on Harmonisation Good Clinical Practice 
CFR 
Code of Federal Regulations 
IND 
Investigational New Drug 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
DOR 
Diminish ovarian reserve 
DPOS 
Dydrogesterone-primed ovarian stimulation 
PPOS 
Progestin-primed ovarian stimulation 
IVF 
In vitro fertilization 
ART 
Assisted reproductive technology 
FET 
 
Frozen embryo transfer 
RCT 
Randomized clinical trial  
ICSI 
 
Intra Cytoplasmic Sperm Injection 
DYG 
Dydrogesterone 
MIP 
Microzined progesterone  
MPA 
Medroxyprogesterone acetate 
AE 
Adverse event 
SAR 
Serious adverse event 
NATIONAL DI & ADR CENTRE 
National centre of Drug information and adverse drug reactions monitoring  
RTAC 
Reproductive Technology Accreditation Certification 
OHSS 
Ovarian hyperstimulation syndrome 
 
 
 

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SUMMARY OF CHANGES FROM PREVIOUS VERSION: 
 
Changed 
sections 
Previous version: 
 Protocol version 2.1 
Update version:  
Protocol version 3.0 
Reason of change form 
earlier version  
Study 
Population 
Inclusion criteria: 
● Women’s age between 18 and 
37 years  
● AFC ≤5 and/or AMH  ≤1.2 
ng/ml 
● Agree to perform single frozen 
blastocyst embryo transfer 
Exclusion criteria: 
● Oocyte recipient 
● Indication of preimplantation 
genetic testing 
● Known allergic reactions to 
medications in the Study 
(progesterone products, GnRH 
antagonist….) 
● Basal FSH above 15mIU/mL. 
● Have contraindications of ART 
treatment (e.g. critical or 
acute diseases)  
● Retrieved sperm 
● Repeated Implantation failure 
(had more than three failed 
embryo transfers with good 
quality embryos) 
● Inability to comply with the 
study procedures 
Inclusion criteria: 
● Women’s age between 18 and 
37 years  
● AFC ≤5 and/or AMH  ≤1.2 
ng/ml 
● Agree to perform single frozen 
blastocyst embryo transfer 
Exclusion criteria: 
● Oocyte recipient 
● Indication of preimplantation 
genetic testing 
● Known allergic reactions to 
medications in the Study 
(progesterone products, GnRH 
antagonist….) 
● Basal FSH above 15mIU/mL. 
● Have contraindications of ART 
treatment (e.g. critical or 
acute diseases)  
● Retrieved sperm 
● Repeated Implantation failure 
(had more than three failed 
embryo transfers with good 
quality embryos) 
● 
Inability to comply with the 
study procedures 
● 
Patients with a history of 
thyroid cancer who are on 
hormone 
replacement 
therapy or those diagnosed 
with thyroid diseases at the 
time of eligibility assessment 
After the SAE case related to 
thyroid cancer, DSMB and IRB 
have reviewed and stated that 
current evidence suggests the 
strong possibility that there is 
no 
link 
between 
the 
treatment being used in the 
trial and thyroid cancer. 
To reduce any possible risk for 
current 
and 
prospective 
participants 
with 
thyroid 
disease in the study, the 
DSMB and IRB recommended 
that it should be excluded 
participants 
with 
current 
indications 
of 
thyroid 
diseases.  
We update the exclusion 
criteria 
according 
to 
the 
recommendations. 
Study 
Duration 
Estimated Study Start Date (First 
patient in): April, 2023 
Study Start Date (First patient in): 
June, 22th, 2023 
- As of August 22, 2024, the 
study 
has 
pre-screened 

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Changed 
sections 
Previous version: 
 Protocol version 2.1 
Update version:  
Protocol version 3.0 
Reason of change form 
earlier version  
Estimated Primary Completion 
Date (Last patient in): April, 2025 
Estimated Study Completion Date: 
April, 2026 
Estimated Primary Completion 
Date (Last patient in): May, 2027 
Estimated Study Completion Date: 
December, 2027 
2364 patients, of which 
2071 patients failed pre-
screening, 
293 
patients 
were screened, and 272 
patients were recruited. 
- The pre-screening failure 
rate is high, so to ensure the 
recruitment 
of 
the 
approved number of 730 
patients, the research team 
requested an extension of 
the 
study 
period 
to 
December 2027. 
- For 
the 
difficulties 
in 
recruiting patients into the 
study and slow recruitment 
progress, we have updated 
study timeline.  
- We also update Study Start 
Date was June, 22th 2023, 
which was actually later 
than the initial estimated 
date (April 2023) for two 
months.  
Visit 12 
Visit 12: (Day 163  ± 7 – Clinical 
pregnancy 
confirmation): 
 
A 
transvaginal 
ultrasound 
examination will be performed to 
determine the pregnancy defined 
as the presence of fetal heartbeats 
at gestation week 7 ± 1. 
Visit 12: (Day 163  ± 7 – Clinical 
pregnancy 
confirmation): 
 
A 
transvaginal 
ultrasound 
examination will be performed to 
determine the pregnancy defined 
as the presence of at least one 
gestational sac at gestation week 7 
± 1. 
Update typo error on page 16 
of 46 - Visit 12 
 
 
 

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1. STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), applicable Vietnamese Code of Federal Regulations (CFR), Terms and Conditions of Award. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place without 
prior agreement from the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor, 
funding agency, and documented approval from the Institutional Review Board (IRB), except where necessary 
to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct of this Study 
have completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted 
to the IRB for review and approval. Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented in the Study. All changes to the consent form will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants who 
provided consent, using a previously approved consent form. 
2. PROTOCOL SUMMARY 
2.1. Summary 
One of the barriers in patients with diminished ovarian reserve (DOR) is the significantly reduced number of 
oocytes resulting in fewer oocytes collected and embryos formed. Many ovarian stimulation strategies have 
been proposed to improve oocyte or embryo quantity which is oocyte accumulation could be a potential option 
with a comparable success rate and reasonable cost. Dydrogesterone-primed ovarian stimulation (DPOS) 
protocol effectively blocks the Luteinizing hormone (LH) surge in IVF. It favors segment ART cycles such as FET, 
oocyte donor, fertility preservation, and oocyte accumulation set. The protocol is more user-friendly and 
cheaper than the GnRH antagonist regimen regarding LH suppression during ovarian stimulation. Initial evidence 
suggests that oocyte quantity and quality are comparable with other ovarian stimulation regimens. However, 
data related to the PPOS protocol has not been well documented. There has not been an RCT with a large sample 
size and well-designed to provide more substantial evidence. A randomized trial to compare the effectiveness 
of PPOS and GnRH antagonist protocol in IVF is urgently needed. 
The randomized, open-label, multi-center trial will be conducted at IVFTA HCM – Tam Anh TP. Ho Chi Minh 
General Hospital and IVFTA HN – Tam Anh General Hospital, Vietnam. Patients will be randomized, using a 
computer-generated randomization list in a 1:1 ratio, to either the DPOS group or the GnRHanta group after 
assessing eligibility and signing informed consent. Randomization will be centrally controlled by a data scientist 
without involvement in any treatment procedure. After randomization, the patients will be administered human 
Menopausal Gonadotrophin (HMG) 225 IU/day (IU/d) via intramuscular injection on the 2nd - 4th menstrual 
day. In the intervention arm, women will receive oral Dydrogesterone 10mg (Duphaston 10mg) t.i.d daily from 
the first day of ovarian stimulation until final oocyte maturation. In the control arm, GnRH antagonist (Ganirelix 
0.25mg) subcutaneously once daily from day 5 of ovarian stimulation will be administered till the day of final 
oocyte maturation. Oocyte cryopreservation will be applied to collect at least 7 ± 1 oocytes. In the last ovarian 

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stimulation cycle, the fresh oocytes and all thawed oocytes will be fertilized by ICSI. The freeze-all strategy will 
be applied in both arms, and single blastocyst frozen embryo transfer will be performed in the next menstrual 
cycle. 
The ongoing pregnancy rate of patients in IVFTA HCM was 45.0% in the Antagonist IVF stimulation group. To 
show or refute that hypothesis: no significant difference in ongoing pregnancy rates when using DPOS protocol 
(40 - 42%), we need 657 patients to produce a two-sided 95% confidence interval for the difference in population 
proportions with a width that is equal to 5% (margin = 5.0%, alpha = 5.0% and power = 80%). Considering a 10% 
loss to follow-up and protocol violation, we plan to recruit 730 participants (365 per arm). The primary endpoint 
is the ongoing pregnancy rate after the first completed transfer. Secondary endpoints are ovarian stimulation, 
embryo culture characteristics, drop-out rate, and DPOS and GnRH antagonist protocol safety. 
All analyses will be performed on an intention-to-treat basis using the R statistical package 
2.2. Synopsis 
Title: 
Dydrogesterone primed ovarian stimulation versus fixed gonadotropin-releasing 
hormone antagonist protocol for accumulation of oocyte in patients with low 
ovarian reserve: A randomized controlled trial 
Objectives: 
 
Primary objective:  
To compare the ongoing pregnancy rate per patient in low ovarian reserve patients 
after accumulation oocyte cycles with either dydrogesterone primed ovarian 
stimulation (DPOS) or gonadotropin-releasing hormone antagonist (GnRHanta) 
protocol 
 
Secondary objectives: 
1. To compare the characteristics of ovarian stimulation between DPOS and 
GnRHanta protocol, including LH, Estradiol, and Progesterone profile (Day 
1, day 5, and day 8 of ovarian stimulation, final oocyte maturation day, and 
12 hours after the final oocyte maturation injection), premature LH rate, 
the duration of ovarian stimulation the total dose of FSH and the number 
of ovarian stimulation cycles.  
2. To compare the outcomes of the ovarian stimulation between DPOS and 
GnRHanta protocol, including number of cumulus-oocyte complexes, 
number of MII oocytes, oocyte survival rate, fertilization rate, embryo-
cleavage rate, blastocyst rate, top-quality blastocyst rate, blastocyst 
survival rate, implantation rate, positive pregnancy rate, clinical pregnancy 
rate, early miscarriage rate, multiple pregnancy rate, ectopic pregnancy 
rate.  
3. To compare the drop-out rate of DPOS and GnRHanta protocol in 
accumulation oocyte cycles of patients with low ovarian reserve 

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4. To assess the safety of DPOS and GnRHanta protocol in accumulation 
oocyte cycles of patients with low ovarian reserve. 
5. To compare the quality of life during ART treatment based on the WHO-
BRIEF questionnaire 
Endpoints: 
 
Primary endpoint: The ongoing pregnancy rate in the first frozen embryo transfer 
cycle. 
Secondary endpoint: LH, Estradiol, and Progesterone profile (Day 1, day 5, and day 
8 of ovarian stimulation, final oocyte maturation day, and 12 hours after the final 
oocyte maturation injection), premature LH rate, the duration of ovarian 
stimulation and the total dose of FSH, the number of ovarian stimulation cycles, 
number of cumulus-oocyte complexes, number of MII oocytes, oocyte survival rate, 
fertilization rate, embryo-cleavage rate, blastocyst rate, top-quality blastocyst rate, 
blastocyst survival rate, implantation rate, positive pregnancy rate, clinical 
pregnancy rate, early miscarriage rate, multiple pregnancy rate, ectopic pregnancy 
rate, drop-out rate, OHSS rate, and adverse events. 
 
Study Population: 
Couples who undergo IVF treatment at ART Unit – Tam Anh General TP. Ho Chi Minh 
(IVFTA HCM) and ART Unit – Tam Anh General hospital (IVFTA HN) fulfill the 
inclusion and exclusion criteria  
Inclusion criteria: 
● 
Women’s age between 18 and 37 years  
● 
AFC ≤5 and/or AMH  ≤1.2 ng/ml 
● 
Agree to perform single frozen blastocyst embryo transfer 
Exclusion criteria: 
● 
Oocyte recipient 
● 
Indication of preimplantation genetic testing 
● 
Known allergic reactions to medications in the Study (progesterone 
products, GnRH antagonist….) 
● 
Basal FSH above 15mIU/mL. 
● 
Have contraindications of ART treatment (e.g. critical or acute diseases)  
● 
Retrieved sperm 
● 
Repeated Implantation failure (had more than three failed embryo 
transfers with good quality embryos) 
● 
Inability to comply with the study procedures 

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● 
Patients with a history of thyroid cancer who are on hormone replacement 
therapy or those diagnosed with thyroid diseases at the time of eligibility 
assessment 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
Site enrolling:  
- 
IVFTA HCM (Tam Anh TP. Ho Chi Minh General hospital) 
- 
IVFTA HN (Tam Anh General hospital)  
IVFTA HCM has a volume of about 1700 - 2000 cycles per year. Of these, 67% of 
patients were under 37 years old, and 45% had a low ovarian reserve. Frozen 
embryo transfer is 97% of all cycles. The embryo and gamete cryopreservation 
system at IVFTA-HCM is well established for cryopreservation requirements in 
oocyte accumulation strategy. Quality management was applied with RTAC's code 
of practice.  
Description of Study 
Intervention: 
After written consent is obtained, the patient will undergo ovarian stimulation from 
the second-fourth day of menstruation after randomization to either arm: 
1. Intervention arm: Women will receive oral Dydrogesterone 10mg 
(Duphaston 10mg) t.i.d daily from the first day of ovarian stimulation till 
the day of final oocyte maturation. 
2. Control arm: Women will receive GnRH antagonist (Ganirelix 0.25mg) once 
subcutaneously daily from day 5 of ovarian stimulation till the day of final 
oocyte maturation  
The hMG will be started from day 2 to day 4 in both groups. Oocyte 
cryopreservation will be applied to collect at least 7 ± 1 oocytes (including frozen 
and fresh oocytes). In the last ovarian stimulation cycle, the fresh oocytes and all 
thawed oocytes will be fertilized by ICSI. Freeze all strategy will be applied in both 
arms, and a single frozen embryo transfer will be performed in the next menstrual 
cycle. 
Study Duration: 
Study Start Date (First patient in): June, 2023 
Estimated Primary Completion Date (Last patient in): May, 2027 
Estimated Study Completion Date: Dec, 2027 
Participant Duration: 
 
 
 
2.3. Schema 

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2.4. Schedule of activities (SOA) 
Stage 
Procedure 
Before 
Ovarian 
stimulation 
(OS) 
OS cycle (repeated in 2 - 3 OS cycles) 
Embryo 
culture 
Endometrium 
preparation 
Embryo 
transfer 
day 
Pregnancy 
testing 
Pregnancy follow-up 
1st 
Day 
of OS 
5th 
Day 
of OS 
8th 
Day 
of OS 
Trigger 
day 
12h 
after 
the 
trigger 
shot 
OPU 
day 
7th week  
of 
pregnancy 
12th week 
of 
pregnancy 
Visiting 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Visit 13 
Pre-screening 
Information providing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pre IVF testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Ultrasound  
 
X  
  
  
  
  
  
  
 
  
  
  
  
AMH  
 
X 
  
  
  
  
  
  
 
  
  
  
  
Pre-anesthesia testing and examination 
 
 X 
  
  
  
  
  
  
 
  
  
  
  
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
Randomization 
  
X 
 
 
 
 
  
  
 
  
  
  
  
Ovarian 
stimulation 
FSH 
 
X 
 
 
 
 
 
 
 
 
 
 
 
LH 
  
X 
X 
X 
X 
X 
  
  
 
  
  
  
  
E2 
  
X 
X 
X 
X 
X 
  
  
 
  
  
  
  
P4 
  
X 
X 
X 
X 
X 
  
  
 
  
  
  
  
Ultrasound for OS 
  
X 
X 
X 
X 
 
  
  
 
  
  
  
  
OPU 
  
  
  
  
 
  
X 
  
 
  
  
  
  
Oocyte cryopreservation 
  
  
  
  
 
  
X 
  
 
  
  
  
  

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Stage 
Procedure 
Before 
Ovarian 
stimulation 
(OS) 
OS cycle (repeated in 2 - 3 OS cycles) 
Embryo 
culture 
Endometrium 
preparation 
Embryo 
transfer 
day 
Pregnancy 
testing 
Pregnancy follow-up 
1st 
Day 
of OS 
5th 
Day 
of OS 
8th 
Day 
of OS 
Trigger 
day 
12h 
after 
the 
trigger 
shot 
OPU 
day 
7th week  
of 
pregnancy 
12th week 
of 
pregnancy 
Visiting 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Visit 13 
Embryo 
culture 
Oocyte thawing (in the last OS cycle) 
  
  
  
  
 
  
X 
  
 
  
  
  
  
ICSI (in the last OS cycle) 
  
  
  
  
 
  
 X 
 
 
  
  
  
  
Embryo assessment 
  
  
  
  
 
  
  
X 
 
  
  
  
  
Embryo cryopreservation 
  
  
  
  
 
  
  
 X 
 
  
  
  
  
Embryo 
transfer 
Ultrasound for ET 
  
  
  
  
 
  
  
  
X 
 
 
  
  
Embryo thawing 
  
  
  
  
 
  
  
  
 
X  
  
  
  
Embryo transfer 
  
  
  
  
 
  
  
  
 
 X 
  
  
  
Follow-up 
bhCG testing 
  
  
  
  
 
  
  
  
 
  
X  
 
  
Ultrasound for Pregnancy Monitoring 
  
  
  
  
 
  
  
  
 
  
  
X  
X 
QOL 
WHO-BRIEF 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Report 
Adverse event review and evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete the case report form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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3. INTRODUCTION AND RATIONALE 
Even when assisted reproductive techniques are offered, ovarian stimulation still is a significant challenge in 
reproductive medicine. Diminished ovarian reserve (DOR) is often associated with poor ovarian stimulation 
response, a high cancellation rate, and a significant decline in pregnancy rate during in vitro fertilization (IVF) cycle. 
Among infertile women, diminished ovarian reserve (DOR) incidence ranges from 6% to 64% at different ages. Based 
on data of 181,536 fresh, autologous ART cycles reported to SART by US clinics in 2004 and 2011 (1), the prevalence 
of LOR patients increased from 19 to 26% from 2004 to 2011, and it relates to poor IVF outcomes and low pregnancy 
rate for these patients (2,3). Unfortunately, the prevalence of DOR has also increased by 42% among patients 
younger than 40 years old (1). DOR is associated with a decrease in oocyte number and quality and contributes to a 
decrease in the clinical pregnancy rate and live birth rate and an increase in the miscarriage rate (4). Various studies 
showed the live birth rate per cycle of 11.1%, 11.4%, and 6.7%, according to ART-register data in the United Kingdom, 
Canada, and Egypt (5–7). Chang et al. found that young patients with DOR had significantly decreased rates of 
biochemical pregnancy, clinical pregnancy, and embryo implantation but increased rates of miscarriage compared 
to young patients without DOR (8).  
Several cohort and meta-analysis studies showed that the number of oocytes retrieved for in vitro fertilization (IVF) 
positively predicts ART treatment (9–11). The appropriate number of oocytes was reported to be between 6 and 15 
for optimizing the live birth rate (9,12). If fewer oocytes are retrieved, the live birth delivery rate decreases (9,13). 
Unfortunately, one of the barriers in patients with DOR is the significantly reduced number of oocytes resulting in 
fewer oocytes collected and embryos formed. S.J. Morin et al. (2018) reported that the number of oocytes collected 
in the DOR group (6 oocytes [2-10]) decreased significantly compared to the non-DOR group (14 oocytes [8-19]) (P 
< 0.001). The number of usable blastocysts was also significantly lower in the DOR group than in the non-DOR group 
(2 embryos [0-3] vs. 4 embryos [1-8]), while the cycles with no usable blastocyst increased significantly (17.0% vs. 
5.3%; P< 0.001) (14). 
Many ovarian stimulation strategies have been proposed to improve oocyte or embryo quantity to increase the 
chances of embryo transfer and pregnancy outcomes (15,16). Cobo et al. (2012) reported an oocyte storage strategy 
in LOR patients showing the cumulative live-birth rate was higher in the accumulation group 36.4% (95% CI, 30,3 – 
42%) than in the fresh group 23.7% (19.9 – 27.4%, P < 0.05) with significant lower embryo-transfer cancellation rate 
(9.1% of accumulation group vs. 34% of the fresh group) (17). The accumulation of oocytes from several ovarian 
stimulation cycles is currently possible with the aid of novel vitrification technologies. Therefore, the strategy could 
potentially increase the number of embryos with comparable success rates and reasonable costs (17–19).  
The Progesterone priming ovarian stimulation (PPOS) protocol could be a potential treatment in an oocyte 
accumulation setting to reduce the financial burden and stress. Progesterone with high concentrations has long been 
shown to block the LH surge. Its inhibiting role on follicular growth has been the foundation of progestin-only 
contraceptives, which, after prolonged use, suppress follicular growth and thus block ovulation (20,21). The 
generation of the LH surge is suggested by two periods: one oestradiol-dependent (early follicular phase) and one 
oestradiol-independent (late follicular phase) which the signal is transmitted to the GnRH neurosecretory system 
following the release of the LH surge. If the pituitary gland is exposed to Progesterone for an extended period, 
Progesterone downregulates its receptors in the pituitary gland (22), inhibiting the pituitary release of LH. 
Progesterone is essential in inhibiting the estrogen-dependent LH surge pathway (23). Progesterone also involves 

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slow-down pulsatility of luteinizing hormone in the pituitary gland and hypothalamus (24). Based on the mechanism, 
the effect was gradually applied to ovarian stimulation. Various studies show that Progestin-primed ovarian 
stimulation (PPOS) effectively blocks the LH surge in IVF (25–27). Compared with the GnRH antagonist protocol, 
Chen et al. (2020) showed that the incidence of premature LH surge in the PPOS group was lower than that in the 
antagonist group (0 vs. 5.88%, P < 0.05) (20). PPOS favors segment ART cycles such as FET, oocyte donor, fertility 
preservation, and oocyte accumulation set. In DOR patients, ovarian could be simulated in multiple processes to 
obtain more oocytes for the increasing number of embryos (17). However, numerous stimulation cycles can stress 
LOR patients as they undergo several procedures, injections, and financial burdens. Instead, the PPOS might be more 
user-friendly and cheaper than the GnRH antagonist regimen regarding LH suppression during ovarian stimulation 
(27,28).  
Many PPOS protocols have been proposed in which the three most agents include Dydrogesterone (DYG), 
Microzined Progesterone (MIP), and Medroxyprogesterone acetate (MPA) (20). There were no important 
differences between the three PPOS protocols in terms of ovarian stimulation response as well as pregnancy 
outcomes(20,21,29). MIP seems to be of unusual choice because of its vaginal administration. DYG 20 – 30 mg/day 
has shown to be effective in preventing early LH surge (30,31), although MPA 10 mg/day exerts a more substantial 
suppression on endogenous LH than DYG (31). However, excessive inhibition of LH levels in the poor response group 
relates to poor outcomes, and LH supplementation even is indicated in women (32,33). Notably, the extensive 
worldwide use of DYG for the treatment of threatened and recurrent miscarriage, as well as for the luteal phase 
support in infertile patients, also suggests its long-term safety (21). Ovarian Stimulation (DPOS) may be an effective 
and safe protocol in the DOR population. 
Nevertheless, data related to the PPOS protocol has not been well documented, including DPOS. More and more 
centers in China are using the protocol because it is simpler and cheaper (26,34–36). Initial evidence suggests that 
oocyte quantity and quality are comparable with other ovarian stimulation regimens (20,21,27). Based on 
retrospective studies, the rate of euploid embryos and the live birth rate were similar in the PPOS group compared 
with the control group (37,38). However, there has not been an RCT with a large sample size and well-designed to 
provide more robust evidence. A randomized trial to compare the effectiveness of DPOS and GnRH antagonist 
protocol in IVF is urgently needed. 
 
4. OBJECTIVES  
4.1. Primary objectives:  
• 
To compare the ongoing pregnancy rate per patient in low ovarian reserve patients after accumulation oocyte 
cycles with either dydrogesterone primed ovarian stimulation (DPOS) or fixed gonadotropin-releasing hormone 
antagonist (GnRHanta) protocol 
4.2. Secondary objectives: 
• 
To compare the characteristics of ovarian stimulation between DPOS and GnRHanta protocol, including LH, 
Estradiol, and Progesterone profile (Day 1, day 5, and day 8 of ovarian stimulation, final oocyte maturation day, 
and 12 hours after the final oocyte maturation injection), premature LH rate, the duration of ovarian 
stimulation and the total dose of FSH, the number of ovarian stimulation cycles.  

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• 
To compare the outcomes of the ovarian stimulation between DPOS and GnRHanta protocol, including number 
of cumulus-oocyte complexes, number of MII oocytes, oocyte survival rate, fertilization rate, embryo-cleavage 
rate, blastocyst rate, top-quality blastocyst rate, blastocyst survival rate, implantation rate, positive pregnancy 
rate, clinical pregnancy rate, early miscarriage rate, multiple pregnancy rate, ectopic pregnancy rate.  
• 
To compare the drop-out rate of DPOS and GnRHanta protocol in accumulation oocyte cycles of patients with 
low ovarian reserve 
• 
To assess the safety of DPOS and GnRHanta protocol in accumulation oocyte cycles of patients with low ovarian 
reserve. 
• 
To compare the quality of life during ART treatment based on WHO-BRIEF questionnaire 
5. STUDY DESIGN  
 
This  open-label, randomized, controlled, multi-center clinical trial compares the efficacy and safety of the oral 
Dydrogesterone primed ovarian stimulation versus fixed gonadotropin-releasing hormone antagonist protocol 
for accumulating oocytes in patients with low ovarian reserve.  
- 
Study Type: Interventional (Clinical Trial)  
- 
Estimated Enrollment: 730 participants (365 per arm) 
- 
Allocation: Randomized  
- 
Intervention Model: Parallel Assignment  
- 
Masking: Open-label 
- 
Primary Purpose: Treatment  
- 
Official Title: Dydrogesterone primed ovarian stimulation versus fixed gonadotropin-releasing hormone 
antagonist protocol for accumulation of oocyte in patients with low ovarian reserve: A randomized 
controlled trial 
The Study will be conducted according to the following scheme: 
Pre-screening  
• 
Visit 1 (Day – 180 to 1):  The patients who have IVF indication will undergo a physical examination - including 
vitals sign, a gynecological exam; a review of their medical history and contaminant medication, a 
transvaginal ultrasound and baseline routine tests (blood tests – including AMH, cervical cancer screening 
– Pap's smear and HPV, breast ultrasound…).  Potentially eligible couples will be given the information sheet 
about the Study during their first consultation 
Screening and Enrollment 
• 
Visit 2 (Day 1:  the first day of OS cycle -  Ovarian stimulation (OS) starts on the 2nd – 4th of mense):  
o 
The patients undergo a  transvaginal ultrasound to access Antral Follicle Count, ovaries and uterus. 
o 
Laboratory tests (blood tests, urine test and ECG) will be taken for pre-anesthesia examination; in 
addition, the hormone values include FSH (follicle-stimulating hormone) – only for the first OS 
cycle, E2 (Estradiol), LH (luteinizing hormone), P4 (Progesterone) and AMH if the result is not 

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available within 6 months. A pre-anesthesia examination will ensure the patient is eligible for the 
oocyte retrieval procedure.  
o 
Screening for eligibility will be performed by treating physicians.  
o 
Eligible participants will be invited to a full discussion with investigators about the Study and given 
the informed consent form. Patients will be given a period (3-4 hours) during anesthesia testing to 
understand the information and decide whether they agree to participate in the Study. The 
investigators will obtain written informed consent from all couples before enrolment. To maximize 
retention in the trial, a consultation will be available to couples to ensure they understand the 
procedures well and to address any questions or complaints that arise during the Study. 
Treatment period: The patient will be treated with an oocyte accumulation strategy, and estimated ovarian 
stimulation cycles range from two to four cycles to collect at least 7 ± 1 oocytes. 
For the first ovarian stimulation cycle: 
• 
Visit 2 (Day 1:  the first day of OS cycle -  Ovarian stimulation (OS) starts on the 2nd – 4th of mense): After 
informed consent is obtained, the patient will be indicated randomly with one of the following regimens:  
Group I: oral DYG (Duphaston) 10mg t.i.d from the first day of OS to the day of final oocyte maturation 
Group II: GnRH antagonist (Ganirelix 0.25 mg) will be initiated on the fifth day of OS to the day of final 
oocyte maturation 
• 
Visit 3 (1st cycle - Day 5 of OS): Transvaginal ultrasound and blood sampling (for hormone check-up) will be 
performed. 
• 
Visit 4 (1st cycle - Day 8 of OS): Transvaginal ultrasound and blood sampling (for hormone check-up) will be 
performed. 
• 
Visit 5 (1st cycle - Day 10 ± 2 of OS): Transvaginal ultrasound and blood sampling (for hormone check-up) 
will be performed. A final oocyte maturation injection will be performed. 
• 
Visit 6 (1st cycle - Day 11 ± 2 of OS): blood sampling (for hormone check-up) will be performed after 12 
hours of final oocyte maturation injection. 
• 
Visit 7 (1st cycle - Day 12 ± 2 of OS): Oocyte retrieval and oocyte cryopreservation will be performed. AE/SAE 
will be recorded routinely. 
For the following ovarian stimulation cycle (s): the patient will be stimulated with the previous OS protocol. The visits 
of the patient will be repeated as the first OS cycle.  
For the last ovarian stimulation cycle: Based on the aim to collect at least 7 ± 1 oocytes, the clinician will determine 
the last ovarian stimulation cycle on the day of final oocyte maturation. It is defined as a cycle in that the total 
number of frozen and expected fresh oocytes are at least 7 ± 1 oocytes. The patient will be stimulated with the 

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previous OS protocol. The visits of the patient will be repeated as the first OS cycle. However, the frozen oocytes of 
the previous OS cycle  will be thawed. All fresh and thawed oocytes will be fertilized by ICSI at Visit 7. 
• 
Visit 8: (Day 77 ± 7 – Embryo culture report): The patient will receive a Blastocyst embryo culture report 
and decide whether embryo cryopreservation or not. 
• 
Visit 9: (Day 90 ± 7 – Endometrial preparation): Endometrial preparation will start on the 2nd – 4th of 
mense.  
• 
Visit 10: (Day 109 ± 7 – Embryo transfer): Progesterone will be started when endometrial thickness reaches 
8 mm or more for 6 - 7 days. Embryo transfer will be performed under ultrasound.  
• 
Visit 11: (Day 121 ± 7): On day 11, after embryo transfer, subjects will have a routine pregnancy test (serum 
β-hCG) to confirm the subject ́s biochemical pregnancy 
• 
Visit 12: (Day 163  ± 7 – Clinical pregnancy confirmation):  A transvaginal ultrasound examination will be 
performed to determine the pregnancy defined as the presence of at least one gestational sac at gestation 
week 7 ± 1 .  
• 
Visit 13 (Day 198 ± 7 - End of treatment): A transvaginal ultrasound examination will be performed to 
determine the Ongoing pregnancy, defined as fetal heartbeats at gestation week 12 ± 1 . 
6. STUDY POPULATION 
Patients come for examination and treatment at ART Unit – Tam Anh TP. Ho Chi Minh General hospital (IVFTA HCM) 
and Tam Anh General hospital (IVFTA HN) 
6.1. Inclusion criteria 
• 
Woman age ≤ between 18 and 37 years  
• 
AFC ≤ 5 and/or AMH ≤  1.2 ng/ml 
• 
Agree to perform freeze-all strategy and single frozen blastocyst embryo transfer  
6.2. Exclusion criteria 
● 
Oocyte recipient 
● 
Indication of preimplantation genetic testing 
● 
Known allergic reactions to medications in the Study (progesterone products, GnRH antagonist….) 
● 
Basal FSH above 15mIU/mL. 
● 
Have contraindications of ART treatment (e.g. critical or acute diseases)  
● 
Retrieved sperm 
● 
Repeated Implantation failure ( ≥ 3 failed embryo transfers with good-quality embryos) 
● 
Inability to comply with the study procedures. 
● 
Patients with a history of thyroid cancer who are on hormone replacement therapy or those diagnosed 
with thyroid diseases at the time of eligibility assessment 
7. STUDY INTERVENTION 
7.1. Pre-screening  

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At Visit 1, the couples with IVF indication will undergo a physical examination - including vitals signs, a gynecological 
exam; a review of their medical history and contaminant medication, a transvaginal ultrasound, and baseline routine 
tests. The blood tests include total blood count, blood group, AMH (within 6 months), TSH, FT4, Anti-TPO, HIV, HCV, 
HBsAg, Syphilis, Tuberculosis, Rubella, Chlamydia PCR, Pap's smear and HPV, breast ultrasound.  Potentially eligible 
couples will be given the information sheet about the Study during their first consultation (Visit 1).  
7.2. Screening and Enrollment 
The patients will be checked for inclusion criteria on the second - fourth menstrual day (Visit 2). Laboratory tests 
(blood tests, urine test and ECG) will be taken for pre-anesthesia examination; in addition, the hormone values 
include FSH (follicle-stimulating hormone) – only for the first OS cycle, E2 (Estradiol), LH (Luteinizing hormone), P4 
(Progesterone) and AMH if the result is not available within 6 months. A pre-anesthesia examination will be 
performed to ensure that the patient is eligible for the oocyte retrieval procedure.  
On the day (Visit 2), sscreening for eligibility will be performed by treating physicians.  If the patients are eligible, we 
will invite them to a full discussion about the Study and give the informed consent form. We will inform verbal and 
written consent and explain the relevant information such as study context, objectives, and data collection 
procedure. Patients will be given a period (3-4 hours) during anesthesia testing to understand the information and 
decide whether they agree to participate in the Study. The investigators will obtain written informed consent from 
all couples before enrolment. To maximize retention in the trial, a consultation will be available to couples to ensure 
they understand the procedures well and to address any questions or complaints that arise during the Study.  
When there is an eligible participant to be enrolled in the Study, clinicians from the specific site will enter the study 
data management center to get the allocation of patients according to a computer-generated randomization list in 
a 1:1 ratio, with a variable block size of 2, 4, 6 or 8. After randomization, if a participant wishes to change her assigned 
protocol in the first cycle, she will be considered a crossover but analysed in the group she was assigned (intention-
to-treat). However, if she wishes to change the assigned protocol from the second ovarian stimulation cycle or 
transfer more than one embryo after randomization, it will be considered a protocol violation and excluded from 
the analysis. Due to the type of interventions, this Study will be label-opened to clinicians who perform ovarian 
stimulation, oocyte retrieval, and embryo transfer.  
7.3. Study intervention administration 
7.3.1. 
Ovarian stimulation 
At Visit 2, eligible patients will be randomized to the DPOS group or GnRH antagonist group: 
For DPOS arm (Group I): Patients will be co-administered with Human Menopausal Gonadotrophin (HMG) 225 
IU/day (IU/d) via intramuscular injection and oral DYG (Duphaston) 30mg/d from menstrual cycle day 2 - 4 (CD2 – 
CD4)  (Visit 2) to the day of final oocyte maturation (Dual trigger with Ovitrelle 250 mcg and Diphereline 0,2mg). 
For GnRH antagonist arm (Group II): In the fixed GnRH antagonist protocol, daily s.c. administration of GnRH 
antagonist (Ganirelix 0.25 mg) will be initiated on the 5th day of stimulation. HMG 225 IU will be administered daily 
from menstrual cycle day 2 - 4 (CD2 – CD4) (Visit 2), and follicular monitoring will be performed after 4 days of 

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injections. Treatment with HMG and GnRH antagonist will continue daily until the day when final oocyte maturation 
is triggered (Dual trigger with Ovitrelle 250 mcg and Diphereline 0,2mg) 
Follicular development will be monitored by ultrasound scanning and measurement of LH, E2 and P4 on Day 5 (Visit 
3) and Day 8 (Visit 4). Scanning and hormonal measurement will be repeated depending on the size of the follicles. 
A dual trigger with Ovitrelle 250 mcg and Diphereline 0,2mg will be used when at least one leading follicles of 17 
mm (Visit 5). After 12 hours of final maturation injection, hormonal measurement also will be performed (Visit 6).   
7.3.2. 
Oocyte retrieval and cryopreservation 
After 36 hours of final maturation injection (Visit 7), all follicles greater than 12mm in diameter will be aspirated. In 
the low ovarian reserve group, oocyte cryopreservation will be applied to collect at least 7 ± 1 oocytes. The patient 
will be stimulated with the previous OS protocol for the following ovarian stimulation cycle. The visits of the patient 
will be repeated as the first OS cycle.  
Oocytes will be received after 36 hours post-hCG. Then, the cumulus-oocyte complexes (COCs) will be cultured for 
2 hours in a CXCM medium (Irvine, USA) (37oC, CO2 6%, O2 5%). After 2 hours, the oocytes will be denuded, and the 
presence of the first polar body will assess oocyte maturity.  
Matured oocytes will be frozen by vitrification (CRYOTEC® Method) (39). Firstly, the oocytes will be balanced in an 
equilibration solution (ES). When the shape of the oocyte fully recovers, it will be transferred to a Vitrification 
Solution (VS) with a minimum equilibrium (the limit time is 15 min). The oocyte will be exposed to a vitrification 
solution by maintaining the same mixture of cryoprotectants but double-concentrated for 50 – 60 seconds. Loading 
takes place within the next 10 seconds by placing oocytes on the device contained in the minimum volume—
immediately plunging into liquid nitrogen-induced vitrification. Three oocytes maximum will be loaded per device 
container. Oocytes were stored in liquid nitrogen tanks for a variable storage time.  
7.3.3. 
Oocyte thawing and ICSI 
For the last ovarian stimulation cycle, based on the aim to collect at least 7 ± 1 oocytes, the clinician will determine 
the last ovarian stimulation cycle on the day of final oocyte maturation. It is defined as a cycle in that the total 
number of frozen and expected fresh oocytes is more than seven. The patient will be stimulated with the previous 
OS protocol. The visits of the patient will be repeated as the first OS cycle. However, the frozen oocytes of the 
previous OS cycle will be thawing; all fresh and frozen oocytes will be fertilized by ICSI at Visit 7. 
For the fresh oocyte, the oocytes will be received after 36 hours post-hCG. Then, the cumulus-oocyte complexes 
(COCs) will be cultured for 3 hours in a CXCM medium (Irvine Scientific., USA) (37oC, CO2 6%, O2 5%). After 3 hours, 
the oocytes will be denuded, and oocyte maturity will be assessed by the presence of the first polar body and 
continued to culture for another hour before ICSI. 
The thawing process will follow the CRYOTEC® Method (39). After removing the liquid nitrogen, the oocytes will be 
transferred immediately into the 37oC thawing solution (TS) within 1 minute. Then the oocyte will be transferred to 
a diluent solution (DS) for 3 minutes at room temperature. The warming procedure will be completed using two 
washes (one lasting 5 minutes, the other 1 minute) in the buffer solution at room temperature. After warming, 
oocytes were placed under standard culture conditioners at 6%CO2 and atmospheric at 37oC for 2 hours before the 
intracytoplasmic sperm ịnjection. After warming, the survival oocyte is evaluated. Warmed oocytes are considered 

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'morphologically surviving' if there is no dark/degenerated or contracted ooplasm and no cracked zona pellucida. 
Oocytes with an abnormal oolemma or ooplasm at the time of ICSI should not be excluded (40) 
Semen samples will be obtained by masturbation after 3–5 days of ejaculatory abstinence. After the samples are 
liquefied at room temperature, a semen analysis will follow the WHO (2021) guidelines (41). The density gradient 
procedure will use the Isolate (Irvine Scientific., USA) discontinuous density gradient. Briefly, one aliquot of liquefied 
semen will be loaded onto 40%, and 80% gradients (each 1.0 ml) with the 80% fraction at the bottom of a 15 ml tube 
and then will be centrifuged at 300 g for 10 min at room temperature. After centrifugation, the sperm pellet will be 
washed twice in 3 ml of pre-warmed MHMC [Irvine Scientific., USA] and centrifuged for 5 min at 300 g. The 
supernatant will be discarded, and the final pellet will be resuspended in a pre-warmed MHMC medium. 
Intracytoplasmic sperm injection (ICSI) is performed at 40 hours post-hCG for both the fresh and frozen oocytes and 
continues to culture in the CXCM medium (Irvine Scientific., USA) (37oC, CO2 6%, O2 5%).  Once injected, oocytes 
were placed in the individual wells. Wells will be filled with 20ul of CXCM medium (Irvine, USA) (37oC, CO2 6%, 
O2 5%).  Fertilization check at 17±1 hours post-ICSI and only normally fertilized zygotes show two pronuclei (2PN) 
are continued to culture to day 3. The morphology of culture embryos will be assessed at 68±1 hours, 116±2 hours, 
and 140 ± 2 hours after injection. The evaluated parameters include cell number, symmetry, and percentage of 
fragmentation for cleavage day 3.  Cleavage day 3 embryos with greater than 6 blastomeres will be considered day 
3 embryos. All embryos are continued to culture until day 5. 
On day 5, the quality of blastocysts will depend on the expansion of the blastocoele cavity and the integrity of both 
the inner cell mass and trophectoderm cells.   Embryos are categorized into four grades (Grade 1: AA, AB, BA, Grade 
2: BB, Grade 3: BC, CB, and Grade 4: others). The highest-graded blastocysts with a blastocoel expansion greater 
than 3 (42) are vitrified (CRYOTEC® Method). The slow-growing embryos (the blastocoel expansion lesser than 3, 
cleaved embryos) continue to culture to day 6.   
On day 6, the blastocysts are assessed and vitrified similarly to day 5 embryos. Freeze all in both arms, then the 
frozen embryo will be transferred in the next cycle. 
7.3.4. 
Embryo cryopreservation 
At Visit 8, after 5-6 days of culture, all embryos are cryopreserved by vitrification ( one embryo/container) using 
CRYOTEC® Method. We will be frozen blastocysts that have the expansion of grade 3 or more, and the quality of the 
inner cell mass and trophectoderm cells have grade B or C (not used for CC). The procedures for oocytes will be 
similar to those described above, such as the vitrification step, loading, and storage. Firstly, the embryos will be 
balanced in an equilibration solution (ES). When the shape of the embryos is fully recovered, they will be transferred 
to a Vitrification Solution (VS) with a minimum equilibrium (the limit time is 15 min). The embryos will be washed in 
the VS2 well and spread onto the Cryotec (one blastocyst/Cryotec). After freezing, the containers will be stored in 
liquid nitrogen. 
7.3.5. 
Endometrium preparation and embryo transfer 
At Visit 9, all patients undergoing FET will receive oral estradiol valerate (Valiera®; Laboratories Recalcine) 6 mg/day 
from the 2nd to 4th day of menses for 6 days. The endometrial thickness will be monitored from day six onwards. 
From day 8-9 of menses, the estradiol dose could be adjusted to 12mg/day according to the development of the 

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endometrium. Progesterone will be started when endometrial thickness reaches 8 mm or more. Patients will receive 
micronized Progesterone (Cyclogest® 400mg; Actavis) at the dose of 400mg twice daily (morning and evening) plus 
dydrogesterone (Duphaston 10mg) at the dose of 10mg twice daily (morning and evening). Estradiol valerate  will 
be decreased to 4 - 8mg/day when starting Progesterone. A single embryo will be thawed on the day of embryo 
transfer after six or seven days of Progesterone, depending on day-5 or day-6 embryo. After thawing, surviving 
embryos will be transferred into the uterus under ultrasound guidance. Estradiol and Progesterone will be continued 
until the day of the pregnancy test. If the pregnancy test is positive, the patients will continue to use 800 mg 
micronized Progesterone or 800 mg micronized Progesterone plus 20 mg dydrogesterone until 7 weeks of gestation. 
The blastocyst will be thawed on embryo transferring day (Visit 10) according to the CRYOTEC® Method. After 
warming, the survival blastocyst is evaluated. Blastocyst cryo-survival be defined as at least 75% of cells perceived 
to be intact after thawing (40). After thawing, the embryo will be cultured in a CXCM medium (37oC, CO2 6%, O2 5%). 
The embryo will be transferred to the uterus two hours later under ultrasound. 
7.3.6. 
Quality of life assessment 
These participants completed questionnaires, which included a standardized quality of life measure (World Health 
Organisation Quality of Life -- Brief Assessment (WHOQoL-BREF)). The WHOQoL-BREF assesses four domains of 
quality of life: 1) physical 2) psychosocial 3) social relationships, and 4) environment.  
The total score will be converted to a 100-point scale (according to WHO guidelines). The questionnaire will be 
assessed at two points: 
• 
On the Day 2 of menstruation in the first cycle (Visit 1) 
• 
On the day of the final maturation injection of last OS cycle (Visit 6 of the last cycle) 
 
7.4. Study intervention follow-up 
7.4.1. 
Ovarian hyperstimulation syndrome assessment. 
In low ovarian reserve patients, the risk of OHSS is rare. However, following oocyte retrieval, if the number of 
collected oocytes is more than 20 with an hCG trigger, they will be managed according to the OHSS management 
policy of IVFTA HCM. In short, the high-risk patient will be documented and educated regarding symptoms and when 
to seek further help. Clinical examination on the Day 3 and Day 5 of embryo culture in person is mandatory for all 
high-risk OHSS cases (Visit 8).  
OHSS diagnosis accords with RCOG guideline 2016. The category of OHSS severity is listed in Table 1. Outpatient 
management is applied for women with mild and moderate OHSS. Hospital admission will be considered when 
having severe or critical OHSS symptoms requiring paracentesis. Severe OHSS is an SAE and will be reported.  
Table 1. Category of Ovarian hyperstimulation syndrome severity 
Category 
Features 
  
Mild 
Abdominal bloating 
Mild abdominal pain 
Ovarian size usually < 8 cm3 
Moderate 
Moderate abdominal pain 
Nausea ± vomiting 
Ultrasound evidence of ascites 

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Ovarian size is usually 8 - 12 cm3 
Severe 
Clinical ascites (± hydrothorax). 
Oliguria (< 300 ml/day or < 30 ml/hour) 
Hematocrit> 45% 
Hyponatraemia (Na⁺/ máu < 135 mmol/l) 
Hypo-osmolality (osmolality < 282 mOsm/kg) 
Hyperkalaemia (K⁺ > 5 mmol/l) 
Serum Albumin (< 35 g/l) 
Ovarian size usually> 12 cm 
Critical  
Tense ascites/ large hydrothrorax 
 Hct > 55% 
White cell count > 25 000/ml 
Oliguria/ Anuria 
Thromboembolism 
ARDS (Acute Respiratory Distress Syndrome) 
Note: Hct = haematocrit; WBC = white blood cell; CrCl = creatinine clearance; Cr = creatinine; Na+ = 
sodium; K+ =potassium 
Ovarian size may not correlate with the severity of OHSS in cases of assisted reproduction because of the 
effect of follicular aspiration  
7.4.2. 
Pregnancy outcome follow-up 
Serum hCG will be measured 11 days after embryo transfer (Visit 11), and if positive, an ultrasound scan of the 
uterus will be performed at gestational weeks 7 (Visit 12) and 12 (Visit 13). At 11–12 weeks of gestation, participants 
will be referred to the IVFTA HCM - Tam Anh TP. Ho Chi Minh General hospital and IVFTA – Tam Anh General hospital 
for prenatal care. For those who cannot participate in the prenatal care program at Tam Anh TP. Ho Chi Minh General 
hospital or Tam Anh General hospital, for any reason, will contact the participants via telephone/email to collect 
data. We also ask these participants to scan the results of each visit in every contact. 
8. OUTCOME MEASUREMENTS 
The primary endpoint is ongoing pregnancy after the first embryo transfer. Ongoing pregnancy is defined as 
pregnancy with a detectable heart rate at 12 weeks' gestation or beyond after the completion of the first transfer. 
Cycles in which no blastocyst is available for transfer will be considered failures. Several fertility outcomes, 
characteristics, and outcomes of the ovarian stimulation, patient safety, drop-out rate, and quality of life during 
oocyte accumulation will be assessed as secondary endpoints. Full details and definitions are provided in Table 2. 
 
 
 
Table 2. Secondary endpoints and their definition 
 
Secondary endpoints 
Definition 
LH, Estradiol and progesterone 
profile 
LH, Estradiol, and progesterone level are measured on day 1, day 5, and 
day 8 of ovarian stimulation, final oocyte maturation day, and 12 hours 
after the final oocyte maturation injection 
Rate of premature LH surge 
Premature LH surge (PLS) is increased serum LH more than twice the 
baseline or more than 15 mIU/ml 

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The rate of Premature LH surge is defined as number of PLS appearances 
per number of ovarian stimulation cycles 
Duration of ovarian stimulation 
Number of ovarian stimulation days (from the first day of FSH injection to 
final oocyte maturation injection day) 
The total dose of FSH 
A number of international units of HMG are administrated during ovarian 
stimulation 
Number 
of 
Cumulus-oocyte 
complex (COCs) 
Number of Cumulus-oocyte complexes after oocyte retrieval 
Number of MII oocyte 
Number of MII oocytes after denuding 
Number of survival oocyte 
Number of survival oocytes after thawing  
Fertilization rate per oocyte 
inseminated/injected  
Fertilisation is defined as the appearance of two PN at 17±1 hour per 
inseminated/injected  
Embryo-cleavage rates 
Number of embryos on Day 3 after ICSI day 
Blastocyst rate 
Numbers of embryos on Day 5 and Day 6 after ICSI 
Number of survival blastocyst 
Number of survival embryos on Day 5 and Day 6 after thawing 
Top-quality blastocyst rate 
Numbers of embryos on Day 5 and Day 6 with good quality after ICSI 
Positive pregnancy test 
A positive pregnancy test is defined as a serum hCG level greater than 25 
mIU/mL 11 days after the first transfer  
Implantation rate 
Implantation rate is defined as the number of gestational sacs per 
number of embryos transferred 3 weeks after the first transfer  
Biochemical pregnancy 
Biochemical pregnancy is defined as a pregnancy diagnosed only by the 
detection of beta hCG in serum or urine 
Miscarriage 
Complete loss of clinical pregnancy at 12 weeks of gestation 
Multiple pregnancy rate 
Multiple pregnancy rate is explained as two or more gestational sacs or 
positive heartbeats by transvaginal sonography 5 weeks after embryo 
placement 
Ectopic pregnancy rate 
Ectopic nidation of pregnancy confirmed by sonography or laparoscopy at 
12 weeks of gestation 
OHSS 
Ovarian hyperstimulation is diagnosed according to RCOG guideline 2016 
Known Adverse events regarding 
medications 
Adverse events regarding medications according to local information 
products - including: 
• 
Duphaston: Abdominal pain, bloating, severe headache, dizziness, 
depression, hot flushes, abnormal vaginal discharge, joint pain, 
urinary problems or nausea, fatigue or extreme tiredness, 
somnolence or sleepiness, vaginal hemorrhage, pruritus (severe 
itching of the skin). 
• 
Orgalutran: redness, pain or swelling at injection site, headache, 
nausea, tiredness. 

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• 
Diphereline: nausea, tiredness, mood changes, depression, 
redness, swelling, pain and /or bruising at the injection site, 
swelling of the hands and feet (edema) muscle and bone pain, 
pain in arms and legs, dizziness, headache, impotence, loss of 
libido. 
• 
Ovitrelle: injection site, headache, vomiting, nausea (feeling 
sick), abdominal (belly) pain, abdominal distension (feeling of 
bloating) 
• 
Valiera: Headache, nausea, breast pain, abdominal cramp, 
bloating, vaginal spotting. 
• 
Cyclogest: Abdominal distension (swelling in the abdomen), 
abdominal pain, constipation, sleepiness, tiredness, hot flush, 
breast pain. 
• 
IVF-M: Headache, injection site pain, injection site allergic 
reaction, abdominal pain, abdominal cramps or nausea. 
Drop-out 
Drop-out is defined as any patient discontinuing the Study or the 
investigator withdrawing them from the Study for any reason. 
Quality of life score 
Quality of life is assessed by Vietnamese WHO-BRIFE questionnaire 
 
9. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
9.1. Discontinuation of study intervention 
Discontinuation from DPOS study does not mean discontinuation from the treatment, and remaining study 
procedures should be completed as indicated by the study protocol.  Suppose a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment. In that case, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically relevant 
finding will be reported as an adverse event (AE). 
9.2. Participant discontinuation/withdrawal from the Study 
Participants are free to withdraw from the Study at any time upon request. 
An investigator may discontinue or withdraw a participant from the Study for the following reasons: 
● 
Pregnancy that is not from an embryo transfer cycle 
● 
Significant study intervention non-compliance  
● 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the Study would not be in the best interest of the participant 
● 
Disease progression which requires discontinuation of the study intervention 
● 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation 

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The reason for participant discontinuation or withdrawal from the Study will be recorded on the Case Report Form 
(CRF). Subjects who sign the informed consent form and are randomized but do not receive the study intervention 
may be replaced. Subjects who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the Study, will not be replaced. 
9.3. Lost to follow-up 
A participant will be considered lost to follow-up if she fails to return for scheduled visits and is unable to be 
contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
● 
The site will attempt to contact the participant, reschedule the missed visit, counsel the participant on the 
importance of maintaining the assigned visit schedule, and ascertain if the participant wishes to and/or 
should continue in the Study. 
● 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter to 
the participant's last known mailing address or local equivalent methods). These contact attempts should 
be documented in the participant's medical record or study file.  
● 
Should the participant continue to be unreachable, she will be considered to have withdrawn from the 
Study with a primary reason of loss to follow-up. 
10. STUDY ASSESSMENT AND PROCEDURES 
10.1. 
Feasibility of Study 
IVFTA-HCM is a recognised center in Vietnam with high volume and modern equipment. IVFTA-HCM has a volume 
about 1700 - 2000 cycles per year. Of these, 67% of patients under 37 years old and 45% had a low ovarian reserve. 
Frozen embryo transfer is 97% of all cycles. The embryo and gamete cryopreservation system at IVFTA-HCM is well-
established for freezing requirements in the oocyte collection strategy. RTAC code of practice was applied in quality 
management.  
10.2. 
Safety and other assessments 
The investigator will inform subjects and the reviewing accredited medical research ethics committee if anything 
occurs, based on which it appears that the disadvantages of participation may be significantly greater than was 
foreseen in the research proposal. The Study will be suspended pending further review by the accredited medical 
research ethics committee, unless suspension would jeopardize the subjects' health. The investigator will take care 
that all subjects are kept informed 
 
11. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
11.1. 
Adverse Events and adverse drug reactions 
Adverse events (AE) are defined as any undesirable experience occurring to a subject during the trial, whether or 
not considered related to the intervention.  

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An adverse drug reaction (ADR) is defined as an appreciably harmful or unpleasant reaction resulting from an 
intervention related to the use of a medicinal product; adverse effects usually predict hazard from future 
administration and warrant prevention, or specific treatment, or alteration of the dosage regimen, or withdrawal of 
the product 
11.2. 
Reporting of adverse events  
11.2.1. AE Recording 
All adverse events reported spontaneously by the subject or observed by the investigator or their staff will be 
recorded. Any AE should be recorded on the Adverse Events form in the CRF and source documents. In every visiting, 
AE/SAE will be recored by subject or observed by medical staff. The AE/SAE related medication also will be asked 
routinely in the oocyte pick-up day (Visit 7) of every ovarian stimulation cycle.  
AEs will be collected from the time the subject signed the study specific informed consent until the last visit (Visit 
13) according to the pregnancy outcomes (the primary endpoint is the ongoing pregnancy). 
 
11.2.2. AE assessment  
Each AE is to be evaluated by the investigator for duration, severity, seriousness and causal relationship to the 
investigational drug. The action taken with study drug, the concomitant treatment/therapy introduced and the 
outcome, and as well as whether the event led to study termination will also be recorded. 
 
Severity  
The severity of the AE should be characterized as "“mild, moderate or severe"” according to the following definitions:  
-  Mild events are usually transient and do not interfere with the subject’s daily activities.  
-  Moderate events introduce a low level of inconvenience or concern to the subject and may interfere with 
daily activities.  
-  Severe events interrupt the subject's usual daily activity.  
 
Drug-Event Relationship  
The causal relationship between the study drug and the AE should be characterized according to the following:  
-  Unrelated – there is not a reasonable possibility that the study drug caused the AE.  
-  Unlikely – suggests that only a remote connection exists between the study drug and  
the event. Other conditions, including concurrent illness, progression or expression of  
the disease state or reaction to concomitant medication, appear to explain the AE.  
-  Possible – suggests that the association of the AE with the study drug is unknown,  
however, the event is not reasonably supported by other conditions.  
-  Probable – suggests that a reasonable temporal sequence of the AE with drug administration exists and, in 
the Investigator's clinical judgment, it is likely that a causal relationship exists between the drug administration 
and the AE, and other conditions (concurrent illness, progression or expression of the disease state, or 
concomitant medication reactions) do not appear to explain the AE.  

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Outcome 
The outcome of the adverse event should be classified according to the following definitions:  
-  Recovered / resolved: the event has resolved (no further symptoms are present and no treatment is being 
received by the subject).  
-  Recovered / resolved with sequelae: the event has resolved but there may be lingering effects present (e.g., 
a scar following a cut or abrasion).  
-  Fatal: the subject died as a result of the event. This code should only be used for the event that caused the 
death, not any event that was present at the time of the subject’s death. Fatal events require immediately 
reporting to the Sponsor (or an authorized representative).  
-  Unknown: may only be used in the event that the subject is lost to follow-up and no reliable data can be 
obtained.  
11.2.3. AE reporting 
All of AE will be reported to the Instituional Review Board of Tam Anh TP. Ho Chi Minh General hospital and Ethical 
Committee for Biomedical Research on Human Subjects of Vietnamese Ministry of Health in periodic reports.  
11.2.4. AE follow-up 
All AEs occurring during the Studystudy are to be followed up in accordance with good medical practice until resolved 
or judged no longer clinically significant, or if a chronic condition, until fully characterized. All follow-up results are 
to be reported to the Instituional Review Board of Tam Anh TP. Ho Chi Minh General hospital.  
11.3. 
Serious Adverse Events  
11.3.1. Definition 
A serious adverse event (SAE) is any untoward medical occurrence or effect, at any dose, that:  
• 
results in death;  
• 
is life threatening (at the time of the event);  
• 
requires hospitalization or prolongation of existing inpatients’ hospitalization;  
• 
results in persistent or significant disability or incapacity;  
• 
is a congenital anomaly or birth defect;  
• 
is considered an important medical event (an event that may not be immediately life- threatening or result 
in death or hospitalization, but based on medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  
 
11.3.2. Reporting SAE 

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Any SAE, whether or not related to the study drug, must be reported immediately (within 24 hours of the 
investigator’s awareness of the event) by telephone or email to Instituional Review Board of Tam Anh TP. Ho Chi 
Minh General hospital . Pregnancy in a study subject is not considered an adverse event. Serious complication of 
pregnancy are considered as a SAE. 
Fatal or life-threatening SAEs must be reported urgently within 07 workdays of investigator’s awareness of the event. 
Other SAEs must be reported within 15 workdays. The reports will be sent to Agency of Science, Technology and 
Training, Ethical Committee for Biomedical Research on Human Subjects of Vietnamese Ministry of Health   and 
National centre of Drug information and adverse drug reactions monitoring (National DI and ADR center). 
 
Investigator shall report adverse events that occur during the course of the Study directly to the competent 
regulatory authorities as required by and in accordance with the Applicable Law 
 
12. STATISTICAL CONSIDERATIONS 
12.1. 
Sample size determination 
The ongoing pregnancy rate of patients in ART center – Tam Anh HCM hospital was 45.0% in the Antagonist IVF 
stimulation group. To show or refute that hypothesis: no significant difference in ongoing pregnancy rates when 
using DPOS protocol (40 - 42%) (43–45), we need 657 patients to produce a two-sided 95% confidence interval for 
the difference in population proportions with a width that is equal to 5% (margin = 5.0%, alpha = 5.0% and power = 
80%). Considering a 10% loss to follow-up and protocol violation we plan to recruit 730 participants (365 per arm). 
12.2. 
Randomization 
After signed informed consent, patients will be randomly assigned in a 1:1 ratio to receive one protocol: Antagonist 
or DPOS. Randomization will be centrally controlled by a data scientist, who is not involved in any treatment 
procedure. When there is an eligible participant to be enrolled in the Study, clinicians from the specific site will enter 
the study data management center to get the allocation of patients according to a computer-generated 
randomization list in a 1:1 ratio, with a variable block size of 2, 4, 6 or 8. Apart from randomization, patients will be 
followed up and treated according to the protocol at each center. 
12.3. 
Statistical analyses 
Statistical analysis will be conducted according to the ITT principle, in which all randomized women will be conducted 
for the comparison of primary outcomes between treatment groups. The per-protocol analysis may be conducted, 
but these results would be considered reference only. All tests will be two-tailed, and differences with p–value < 
0.05 will be considered statistically significant. The statistical software used was R, version 4.0.5 (R Foundation for 
Statistical Computing). We will develop a detailed statistical analysis plan that will be completed before data–lock. 
12.3.1. Characteristics of patients 
Patient's characteristics will be shown through descriptive analysis, and the balance between the two arms will be 
assessed. For continuous variables, the normality test will be estimated using frequency histograms and the 

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Shapiro's test. If the parameters are normally distributed, they will be presented as mean with standard deviation 
(SD) and compared using Student's t-tests or ANOVA tests. If the parameters are non-normally distributed, their 
medians and inter-quantile ranges (IRQs) will be reported, and non-parametric tests will be utilized to test the 
distribution of these variables. For categorical variables, data will be shown by the proportions of the two arms, and 
they will be compared using Pearson's chi-square test or Fisher's exact test where appropriate. In addition, we will 
also report the numbers of recruitment, participants lost to follow-up, protocols violation, and other relevant 
descriptive data. 
12.3.2. Primary outcome 
The primary outcome, ongoing pregnancy rate will be compared using Pearson's chi-square test or Fisher's exact 
test for unadjusted analysis. We will also compute the unadjusted risk ratio (RR) and its 95% confidence interval 
(95% CI). In the event of a prominent imbalance of potential confounders between arms, we will perform 
multivariable Log-Binomial or Poisson Regression with a robust variance estimate to compute adjusted RR and its 
95% CI. 
12.3.3. Secondary outcome 
For continuous variables, results will be shown as mean (SD) and between-group differences will be considered using 
Student's t-test. For dichotomous outcomes, relative risk (RR) and 95% confidence interval (CI) values will be 
calculated. 
12.3.4. Missing data and sensitivity analysis 
Missing values regarding baseline characteristics, we will first perform an analysis by excluding missing values; we 
will then perform multiple imputations to impute missing values and conduct subsequent analysis to estimate the 
robustness of the findings. For the loss of follow-up and protocol violation, we will attempt sensitive analyses to 
explore the effect of these factors on the trial findings. 
12.3.5. Data and safety monitoring board 
An independent Data and Safety Monitoring Board (DSMB) will be established to review and interpret data 
generated from the Study and to review revisions of the protocol before their implementation. Its primary objectives 
are to ensure the safety of study subjects and the integrity of research data. The DSMB advises on research design 
issues, data quality and analysis, and research participant protections for the Study. 
The DSMB will hold regular conference calls to review the protocol concerning ethical and safety standards, monitor 
the safety of the trials, monitor the integrity of the data concerning the original study design, and provide advice on 
study conduct. The DSMB will review the progress of the trial, adjudicate adverse events, and decide on any 
premature closure of the Study. The DSMB consists of three members. Voting members consist of individuals who 
are impartial, independent of the investigator(s), and who have no financial, scientific, or other conflicts of interest 
with the Study. 
12.3.6. Planed interim analyses 

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The interim analysis will be performed by an independent statistician who will not be directly involved in the Study, 
after the completion of data collection of the first 366 randomized patients. In interim analyses, data will be assessed 
for safety, efficacy, and futility. Safety will be assessed in terms of serious adverse events. The interim analysis will 
be conducted using a two-sided significant test with the Haybittle–Peto spending function and a type I error rate of 
5% with stopping criteria of p <0.001. According this report, the DSMB will guide whether to stop or continue the 
Study. 
13. ETHICAL CONSIDERATION 
13.1. 
Regulation statement 
The Study will be conducted according to the principles of the Declaration of Helsinki (World Medical Association 
Declaration Of Helsinki Ethical Principles for Medical Research Involving Human Subjects Version Edinburgh, 
Scotland, October 2000, with Note of Clarification on Paragraph 29 added by the WMA General Assembly, 
Washington 2002 end Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 2004) and 
in accordance with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, regulations 
and Acts. 
The National Review Board approved protocol V 2.1 on February 16th, 2023, with No: 28/CN-HĐĐĐ  
The National Review Board approved the amended protocol V3.0 on October 22nd, 2024, with No: 237/CN- HĐĐĐ 
13.2. 
Recruiment and consent 
The investigator must explain to each subject the nature of this Study, its purpose, procedures, expected duration 
and the potential risks and benefits involved in study participation along with any discomfort it may entail. Each 
subject must be informed that participation in the Study is voluntary and that withdrawal of consent will not affect 
her right to the most appropriate medical treatment or affect the doctor's relationship. 
Informed consent will be given by means of a standard written statement. It will be written so as to be easily 
understood by the subject. The subject will be given the time to read and understand the statement herself before 
signing her consent and dating the document. The subject will be provided with a copy of the written statement 
once signed. 
Patients randomized to the DOPS group will be paid fees associated with medication. 
13.3. 
Privacy 
Participating subjects will be assigned a 5-digit number. This personal code will be on all forms retrieved from 
participants 
14. ADMINISTRATIVE ASPECTS AND PUBLICATION 
14.1. 
Handling and storage of data and documents 
Data will be collected using a questionnaire and the Microsoft excel software. Data monitoring will be done by the 
principal investigator, based at Tam Anh TP. Ho Chi Minh General hospital. Data handling will be done anonymously, 
with only the patient code available to the local investigator. Patients will be asked for informed consent.  
14.2. 
End of study report 

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At the end of the study, a final report of Study results will be sent to the National and Local Institutional Review 
Board.  
14.3. 
Public disclosure and publication policy 
No specific arrangements will be made between any sponsors and the investigator concerning the public disclosure 
and publication of the research data. The principal investigator will publish the results of the Study as soon as 
appropriate. 

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