Evaluate the Effectiveness of Progestin-Primed Versus GnRH Antagonist Protocols in Vietnamese Women Undergoing In-vitro Fertilization: A Randomized Controlled Trial
Phase: NA
Conditions: IVF
Sponsor: Hanoi Medical University

STUDY PROTOCOL FOR EVALUATE THE EFFECTIVENESS OF 
PROGESTIN-PRIMED VERSUS GNRH ANTAGONIST PROTOCOLS IN 
VIETNAMESE WOMEN UNDERGOING IN-VITRO FERTILIZATION 
 
PROTOCOL ID: 9720105 
DOCUMENT DATE: December 15, 2023 
 
Author list: Than Trong Thach1*, Le Duc Thang2, Nguyen Ha Ngoc Thien Thanh3, 
Duong Thi Ngoc Chau1, Le Thai Thanh Khue1, Nguyen Manh Ha4, Le Hoang2 
Affiliation: 1University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 
City, Vietnam; 2Tam Anh General Hospital, Hanoi, Vietnam; 3An Sinh Hospital, Ho Chi 
Minh City, Vietnam; 4IVF and Tissue Engineering Center, Hanoi Medical University 
Hospital, Hanoi, Vietnam 
Corresponding author: Thach Than Trong 
Email: thachthan007@gmail.com 
ORCID ID: 0000-0003-1746-7267 
Phone: +84908400040 
Address: Binh Thanh District, Ho Chi Minh City, Vietnam 
 
 
 
 

BACKGROUND 
Controlled Ovarian Stimulation (COS) plays a significant role in the cycle of In Vitro 
Fertilization (IVF) or Intra-Cytoplasmic Sperm Injection (ICSI). Premature luteinizing 
hormone (LH) surge is the main reason for cycle cancelation during COS (1). Two 
principal methods of pituitary suppression are employed to delay the onset of LH peak in 
the COS cycle: (1) prolonging the administration of a gonadotropin-releasing hormone 
agonist (GnRH-a) before the implementation of COS in a long-acting agonist regimen (2) 
immediate pituitary suppression with a gonadotropin-releasing hormone antagonist 
(GnRH-ant) in a short-acting antagonist regimen (2). Recently, with the successful 
development of embryo freezing and thawing techniques, a new COS protocol was 
proposed using progestin as a "primer" (Progestin-Primed Ovarian Stimulation – PPOS) in 
the act of inhibiting the LH peak and preventing ovulation occurrence. In 2015, Kuang et 
al. first reported this protocol and demonstrated efficacy in preventing premature 
luteinization (3). The PPOS protocol is dominant due to its patient-friendly benefits: oral 
administration, convenience, and lower cost. Several studies have highlighted the potency 
of PPOS in prohibiting premature LH surge and promoting positive pregnancy outcomes 
compared to classical COS regimens in infertile women with normal ovarian reserve 
(NOR) or those with polycystic ovary syndrome (PCOS) (4-11). 
An important factor in determining the effect of progesterone (stimulatory or inhibitory) 
on pre-ovulatory gonadotrophin secretion, or even its synergistic or antagonistic effect with 
estrogen, is the timing of administration, the rate of administration, and P4/E2 hormone 
ratio. Previous studies still have not had consensus; some studies show that at the end of 
the follicular phase, progesterone concentration increases slightly due to the secretion of 
granulosa cells of pre-ovulatory antral follicles, causing a slight increase in LH 
concentration, proving the role of progesterone's stimulating role on gonadotropins (12); 
However, the LH peak only achieve when progesterone is administered after estrogen has 
previously been primed. On the other hand, high levels of progesterone from early in the 
menstrual cycle have been shown to suppress LH peaking (13), with its primary role being 

to inhibit follicle development and subsequent inhibition of ovulation, which is the 
contraceptive basis of progestin-only contraceptives. Recently, it has not been possible to 
use a single hypothesis related only to estradiol, progesterone, gonadotrophin, GnRH, 
kisspeptin, and the time to start taking progestogen to explain the mechanism of LH peak 
appearance and ovulation induction. DYG is a potential alternative progestin for the PPOS 
protocol in ART (4, 10); it has a high selectivity for progesterone receptors with potent 
progestogenic activity. In contrast to other progestins, DYG has no clinically relevant 
agonistic or antagonistic action on the androgen, estrogen, and glucocorticoid receptors 
and only mild antimineralocorticoid features. Unlike natural progesterone, dydrogesterone 
has good oral bioavailability; therefore, it may reduce the side effects of progestins (14-
16). However, few studies compared the PPOS protocol's efficacy with DYG and GnRH-
antagonist protocols.  In this RCT, we compared the effects of two protocols, PPOS using 
DYG and GnRH-ant, on the ovarian response and clinical outcomes in patients undergoing 
IVF or ICSI. 
METHODS AND ANALYSIS 
Objectives 
This trial aims to compare the efficacy and safety of the PPOS protocol to the GnRH 
antagonist protocol in patients undergoing IVF procedures. 
Design of the trial 
This was an open-label, randomized controlled trial conducted at the Assisted 
Reproduction Center of Tam Anh General Hospital between January 2023 and December 
2024. The study aimed to estimate the efficacy of the intervention (PPOS protocol) 
compared to a control group receiving a gonadotropin-releasing hormone (GnRH) 
antagonist protocol. Inclusion criteria were women aged 20-45 years undergoing IVF. 
Exclusion criteria included failure to complete ovarian stimulation, systemic diseases like 
renal failure or lupus, uterine abnormalities, random-start controlled ovarian stimulation 
cycles, and preimplantation genetic testing for aneuploidies. The study details were 
explained to all participants, and informed consent was provided. This study was approved 

by the Ethics Committee of Hanoi Medicine University, decision number 842, dated July 
7, 2023. 
Eligibility criteria 
Eligible patients must meet all inclusion criteria, and no listed exclusion criteria exist. 
Inclusion criteria 
Women meeting the sample selection criteria are as follows: (1) Women aged 20 to 45; (2) 
Infertility due to male factors, fallopian tube factors, or unknown causes; (3) Undergoing 
IVF in one COS cycle and intended to apply either GnRH antagonist protocol or PPOS 
protocol; (4) Voluntary participation in research. 
Exclusion criteria 
Women who met any of the following criteria were excluded: (1) Any contraindications to 
ovarian stimulation and IVF/ICSI treatment; (2) Hyperprolactinemia or other endocrine 
diseases; (3) Those who took hormone drugs within the past three months; (4) Suffering 
from systemic diseases such as kidney failure, lupus erythematosus, depression, etc.; (5) 
Abnormal structure of the uterine cavity; (6) Patients with endometriosis or cancer; (7) 
Random-start cycles; (8) Oocyte donation cycles; (9) Perform embryo biopsy. 
Recruitment of study participants 
Infertile patients come for examination at the Assisted Reproduction Center of Tam Anh 
General Hospital, Hanoi, and the Assisted Reproduction and Graft Technology Center of 
Hanoi Medical University. In the basic infertility examination process at the hospital, the 
clinicians will consider the patient's inclusive and exclusive criteria. The clinicians will 
contact a research team member if the inclusive criteria are met. A research team member 
or hospital physician will invite the patient to participate, advise on the study procedure 
and the benefits and risks of participating, and answer any patient questions (Appendix 2). 
If the patients agree to participate, they will consent to participate in the trial (Appendix 3). 
Each participant will be randomly assigned to the treatment group using the PPOS protocol 
or the control group using the GnRH-ant regimen. 

Sample size estimation 
The sample size was estimated to optimize the precision of non-inferiority testing. This 
statistical inference is based on a Negative Binomial (NBI) regression model, which aims 
to compare the average number of retrieved oocytes (or MII oocytes) between two distinct 
groups, as described by Cundill and Alexander (2015) (17). The following formula 
encapsulates the estimation process: 
√𝑁 = 
𝑍
!" $ %& !
'! ( !
)! * & !
+"( !
+!*( ,"#$% !
+" & !
'"( !
)_!*( !
+!& !
'!( !
)!*
𝑙𝑜𝑔 (𝜇.) −𝑙𝑜𝑔 (𝜇!) − 𝛿
  
Where: 
N represents the aggregate sample size, with each unit being a cycle or patient. 
𝜇. and 𝜇! denote the average outcome values in the control group (GnRH_ant regimen) 
and treatment group (PPOS regimen), respectively. The outcome might be the count of 
retrieved oocytes or MII oocytes. 
𝑄. and 𝑄! are the allocation ratios for the control and treatment groups, respectively. They 
represent the proportion of the total sample size that should be allocated to each group. In 
our research, both Q0 and Q1 were set to 0.5. 
𝑘. and 𝑘! are the dispersion parameters of the NBI distribution for the control and treatment 
groups, respectively. 
𝛿 is the non-inferiority margin (in log scale), signifying the minimum clinically or 
practically significant difference. 
𝑍/ is the critical value, or pth percentiles of a standard normal distribution 
α is the Type I error, set at 0.05, and β is the Type II error, set at 0.2 (corresponding to a 
statistical power of 0.8). 

From January 1st to October 10th, 2022, at Tam Anh Hospital, 804 patients underwent 
ovarian stimulation. We observed average retrieved oocyte counts of 11.2 and 11.4 and 
average mature oocyte counts of 7.62 and 7.54 in the PPOS and GnRH-ant groups, 
respectively. We engaged in a simulation process with these observations, utilizing the 
formula to determine potential sample size values. We let μ0 and μ1 span an interval from 
6 to 12 units, while the difference between the groups ranged from -1.5 to 1.5 units. The 
non-inferiority margin remained constant at log(1.5) units. The results from this simulation 
are illustrated in Figure 1. According to this result, we concluded that a sample comprising 
200 patients (split equally between the groups) would be required. This size ensures that 
no difference in the number of retrieved or MII oocytes between the PPOS and control 
group would exceed 1.5 units. 
Randomization Process 
We apply a stratified randomization process to ensure unbiased allocation of participants 
to GnRH-ant and PPOS treatment arms. The process is designed and executed using Python 
programming language. Initially, each participant will be assigned a unique identification 
(ID) constructed from a combination of uppercase letters (A-Z) and numbers (0-9), with 
customizable ID lengths. Concurrently, each participant is categorized based on the 
"POSEIDON" criterion, a categorical stratification variable with four potential categories: 
P1, P2, P3, and P4. Participants are allocated to these strata by a predefined probability 
distribution of 14.86%, 25.39%, 15.99%, and 43.76%, respectively. This distribution was 
derived from the actual distribution of POSEIDON categories among patients who 
underwent IVF treatment at Tam Anh Hospital during 2020-2022. Within each 
"POSEIDON" stratum, participants are randomized equally across the two treatment 
groups (GnRH-ant or PPOS protocol). The process ensures that if there's an odd number 
of units in a stratum, the extra unit is randomized within the stratum rather than across the 
entire dataset.  

Treatment method 
Ovarian stimulation protocols 
Controlled ovarian hyperstimulation commenced on the second day of the menses utilizing 
recombinant follicle-stimulating hormone (Follitrope, LG Chem, South Korea) at dosages 
between 150-300 international units (IU) per day. Initial gonadotropin dosages were 
determined per patient based on baseline parameters, including age, AMH, baseline FSH, 
body mass index (BMI), antral follicle count (AFC), and titrated subsequently per 
folliculogenesis response. In the gonadotropin-releasing hormone (GnRH) antagonist 
protocol group, pituitary suppression began on stimulation day six via daily 0.25 milligram 
GnRH antagonist administration (ganirelix or cetrorelix). In the progestin-primed ovarian 
stimulation (PPOS) group, 30mg/day of dydrogesterone was initiated on cycle day 2 
through to trigger day. Serum luteinizing hormone (LH) levels were quantified on 
stimulation days one, six, and eight alongside trigger day using competitive 
electrochemiluminescence immunoassays via Cobas analyzer. Once dominant follicles 
reached ≥20 mm diameter or ≥ 3 follicles met 18 mm threshold, final oocyte maturation 
was induced. Depending on ovarian hyperstimulation risk, either 0.2 mg triptorelin 
(Diphereline, Ipsen Pharma Biotech, France) alone was administered for high-risk patients 
or a Dual trigger consisting of 2000 IU hCG (IVF-C, LG Chem, South Korea) combined 
with 0.2 mg triptorelin (Diphereline, Ipsen Pharma Biotech, France) was used for the 
remaining patients. Oocyte retrieval via transvaginal aspiration was performed 
approximately 36 hours later. 
 
Laboratory protocol 
Oocyte-cumulus complexes were incubated for 2 hours in G-IVF medium (Vitrolife) using 
Origio benchtop incubators to complete nuclear maturation. After removing cumulus cells, 
denuded oocytes were evaluated under an inverted microscope to validate the achievement 
of metaphase II status, while degenerate, large, or severely dysmorphic oocytes were 
excluded. Intracytoplasmic sperm injection (ICSI) was executed 3-4 hours post-retrieval 
by experienced embryologists. Resultant zygotes were cultured in continuous single media 

(Fujifilm Irvine Scientific) within tri-gas incubators (37°C, 5% O2, 6% CO2) until day 3. 
Strict morphological criteria were enforced, only retaining normally fertilized two 
pronuclei zygotes while eliminating abnormal multinuclear embryos. Cleavage-stage 
quality was graded at 67-69 hours per Istanbul consensus based on cell number, 
fragmentation, multinucleation, and uniformity. On post-ICSI day 3, embryologists 
counseled patients on pursuing blastocyst culture versus cryopreservation. The 
morphology of the blastocysts was evaluated using the Gardner and Schoolcraft grading 
system, and embryos meeting the criteria of 3-6 AA/AB/BA blastocysts or 1-2 AA/AB 
embryos were classified as good quality. 
 
Outcome measurements 
Primary outcomes 
The primary outcome is the success rates, including maturation, fertilization, and 
probabilities of achieving Day 3 and Day 5 embryos.  
Secondary outcomes 
The secondary outcome is the process of the evolution of LH levels in the PPOS group.  
We transferred the cryopreserved embryo in the next cycle after the stimulation cycle. 
Perform quantitative hCG test 10 days or 13 days after S5 or S3 embryo transfer: (1) If 
there is a positive hCG test (>5 mIU/ml), the pregnancy will continue to be monitored; (2) 
Negative hCG test (<5 mIU/ml), we determined the outcome to be a failure in the first 
embryo transfer, and the study ended. 
Cancel cycles 
The cycle is canceled for COS cycles where no follicles are larger than 12 mm after ten 
days of ovarian stimulation. The characteristics of the canceled cycle (starting dose, total 
gonadotropin doses, COS days, LH, E2, and P4 measurements) are still recorded in the 
data collection table. The patient will have COS performed again in the next cycle. 

Safety endpoints 
The safety endpoints include the incidence of moderate or severe OHSS, miscarriage rates, 
ectopic pregnancy, and the complications of oocyte retrieval. Ovarian hyperstimulation 
syndrome (OHSS) is due to the excessive response of the ovaries to ovarian stimulation. 
OHSS is an uncommon complication (1 - 5% per cycle) and dangerous during ovarian 
stimulation. According to the American Society for Reproductive Medicine (ASRM) in 
2016, OHSS is commonly classified into mild, moderate, severe, and critical based on 
symptoms, ovarian size, ascites, and haemoconcentration (Hct). Mild OHSS is diagnosed 
when presenting abdominal bloating, mild abdominal pain, and ovarian size < 8cm. 
Moderate OHSS is diagnosed by the ultrasonographic presence of ascites, ovarian size of 
8-12 cm, with Hct >41%, and increased white blood cell count (>15 x 109/L). Severe OHSS 
is defined as clinical ascites (occasionally pleural effusions), Oliguria, hematocrit>45%, 
hypoproteinemia, and ovarian size usually >12 cm. Critical OHSS is diagnosed by tense 
ascites or large pleural effusions, hematocrit>55%, white blood cell count >25 x 109/L, 
oliguria/anuria, thromboembolism, acute respiratory distress syndrome, and so on. 
Complications of oocyte retrieval: (1) Vaginal bleeding: After completing the oocyte 
retrieval, the patient will have a speculum placed to examine the vagina. If bleeding is seen 
at the needle puncture site, the clinician will use gauze to press on the bleeding site and 
wait about 5 minutes. After that, the clinician checks again; if there is still bleeding, the 
clinician will sew the needle puncture site. (2) Bladder hemorrhage: caused by the needle 
piercing the egg through the bladder, with the primary symptom being red urine. Most 
cases will not require intervention. Patients should drink plenty of water, and in some cases, 
hemostatic drugs or antibiotics may be considered. If red urine persists or has blood clots 
in the bladder, washing the bladder could be regarded, and a cystoscopy could be 
performed to stop the bleeding. (3) Internal bleeding due to ovarian cyst rupture: After 
oocyte retrieval, if the patient has symptoms: abdominal pain (lower abdomen, one side or 
both sides, can spread to the shoulders), abdominal examination shows tenderness and 
reflexes abdominal wall, pain when touch pouch of Douglas or lethargy, fatigue, pale skin. 
The patient will be monitored for vital signs (pulse, blood pressure, temperature, SpO2), 

and an ultrasound will be performed to check the ovaries, fluids, and abdominal cavity. At 
the same time, we will take blood to test for red blood cell index, hemoglobin, and 
hematocrit. If the patient's vital signs are stable, the amount of abdominal fluid is low, and 
the hematocrit is > 30%, the patient will be using hemostatic medication; the vital signs 
and hematocrit are monitored to determine whether the bleeding continues. When there are 
hemodynamic changes, or the hematocrit continues to decrease below 30%, the patient 
undergoes laparoscopic surgery to find the bleeding site in the ovary and cauterize the 
bleeding. (4) Infection at the egg retrieval site: infrequent, with symptoms such as fever, 
lower abdominal pain, pain on one side of the pelvis with increased white blood cells, and 
increased CRP. The patient will be treated with broad-spectrum antibiotics according to 
the hospital protocol. 
The method of data collection 
Personnel: This includes one main researcher and three associates. 
Tools: Conducted using data collection table (Appendix 1) 
Data collection plan: The data collection process corresponding to each step of the 
research process, shown in detail in Figure 2.3, is expected to occur over 18 months 
(from January 1, 2023, to June 30, 2024). 
 
Research variables 
Independent variable 
Table 1 Independent variables 

Variable 
name 
Define 
Type 
Scale/encoding 
Unit 
How to 
collect 
Treatment 
grouping 
One of 2 groups: 
Intervention 
group: 
using PPOS protocol. 
Control group: using 
GnRH-ant regimen 
Qualitative, 
binary 
0 = control group 
(GnRH-ant regimen) 
1 
= 
Intervention 
group 
(PPOS 
regimen). 
 
According 
to medical 
records 
Time 
Time point for LH 
quantification 
Discrete 
qualitative 
1 = S6 
2 = S8 
3 = ovulation day 
 
According 
to medical 
records 
Sampling 
location 
Center/hospital 
where samples were 
collected. 
There is significant 
clustering of the data 
and may contribute to 
random effects on the 
observed results. 
Discrete 
qualitative 
1,2,3...: 
number 
corresponding 
to 
each 
hospital/reproduction 
center 
 
 
 
 
Covariations 
Table 2 Covariates 

Variable 
name 
Define 
Type 
Scale/encoding 
Unit 
How to collect 
A. Characteristics of the study population 
Age 
Time 
is 
calculated in 
calendar years 
from the date 
of birth on the 
wife's ID card 
to the date of 
participation 
in the study 
Continuous 
variables 
[20 – 45] 
Years 
old 
Administrative 
information 
from medical 
records 
Height 
Height at the 
time 
of 
selection 
for 
the 
study, 
accurate to 0.5 
cm 
Continuous 
dosing 
[150, 165.5, … 
172] 
cm 
Direct 
measurement 
Weight 
Body weight 
at the time of 
selection 
for 
the study 
Continuous 
variables 
[45, ... 55... 60] 
kg 
Direct 
measurement 

Variable 
name 
Define 
Type 
Scale/encoding 
Unit 
How to collect 
BMI 
The patient's 
body 
mass 
index, 
according 
to 
the formula: 
BMI=Weight 
(kg)Height 
(m)2 
Continuous 
variables 
[19.1 … 23.4 
…] 
kg/m2 
Secondary 
data, 
calculated 
from 
height 
and weight 
Infertility 
period 
Time 
from 
when 
you 
wanted 
to 
have a baby 
and did not 
use 
contraceptives 
until you were 
selected 
for 
the study 
Continuous 
variables 
[twelfth …] 
month 
Interview and 
record 
in 
medical 
records 
Causes 
of 
infertility 
Is the cause of 
the 
patient's 
infertility 
Identification 
0 = Male factor 
1 = Fallopian 
tube factor 
 
Based 
on 
diagnosis 
recorded 
in 

Variable 
name 
Define 
Type 
Scale/encoding 
Unit 
How to collect 
2 = POR 
3 = Ovulatory 
disorders 
4 = Unknown 
cause 
medical 
records 
AFC 
Number 
of 
ovarian 
follicles 
measuring 2 - 
10mm 
on 
transvaginal 
ultrasound on 
day 2 of the 
menstrual 
cycle 
Discrete 
quantification 
[2 … 4 …] 
ovarian 
follicles 
Test 
results/medical 
records 
AMH 
Patient's 
AMH 
concentration 
before 
IVF 
(up 
to 
3 
months) 
Quantitative, 
continuous 
[0.5,1,2, …] 
ng/ml 
Test 
results/medical 
records 

Variable 
name 
Define 
Type 
Scale/encoding 
Unit 
How to collect 
B. Characteristics of the in vitro fertilization cycle 
Gonadotropin 
starting dose 
The first dose 
of 
gonadotropin 
(FSH + hMG) 
is 
administered 
during 
the 
ovarian 
stimulation 
cycle 
Identification 
0. 150 
1. 225 
2. 300 
3. 375 
 
IU 
Take 
notes 
from medical 
records 
Total 
gonadotropin 
dose 
Total number 
of 
FSH 
+ 
hMG 
drug 
units injected 
for 
ovarian 
stimulation 
Quantitative, 
continuous 
[1800, …] 
IU 
Take 
notes 
from medical 
records 
COS time 
Number 
of 
days of FSH + 
hMG 
injection 
Quantitative, 
continuous 
[8, … ] 
day 
Take 
notes 
from medical 
records 

Variable 
name 
Define 
Type 
Scale/encoding 
Unit 
How to collect 
Number 
of 
days 
using 
GnRH-ant 
Actual 
number 
of 
days 
of 
GnRH-ant use 
in the GnRH-
ant subgroup. 
Quantitative, 
continuous 
[4, … ] 
day 
Take 
notes 
from medical 
records 
 
Primary outcomes of the study (dependent variable) 
Table 3 Dependent variables in the study 
Variable name 
Define 
Type 
Scale/encoding 
Unit 
How to 
collect 
A. 
Ovarian stimulation results 
Expected 
number 
of 
oocytes 
 
Expected number 
of oocytes to be 
collected: 
number 
of 
oocytes with size 
≥ 12 mm on the 
day of ovulation. 
Quantitative, 
discrete 
[0,1,2,3…] 
oocytes Recorded 
from 
medical 
records 
Number 
of 
oocytes obtained 
Number 
of 
oocytes obtained 
Quantitative, 
discrete 
[0,1,2,3…] 
oocytes Recorded 
from 

Variable name 
Define 
Type 
Scale/encoding 
Unit 
How to 
collect 
after 
aspiration 
under 
the 
guidance 
of 
transvaginal 
ultrasound. 
medical 
records 
Number of MII 
oocytes 
Number 
of 
ovarian follicles 
at metaphase II 
(MII) 
stage 
obtained 
after 
aspiration under 
the guidance of a 
transvaginal 
ultrasound probe 
Quantitative, 
discrete 
[0,1,2,3…] 
oocytes Recorded 
from 
medical 
records 
Number 
of 
fertilized 
oocytes 
Number 
of 
oocytes with 2 
pronuclei 
appearing 
after 
about 
18-20 
hours 
after 
performing ICSI 
Quantitative, 
discrete 
[0,1,2,3…] 
oocytes Recorded 
from 
medical 
records 

Variable name 
Define 
Type 
Scale/encoding 
Unit 
How to 
collect 
Number 
of 
embryos N3 
Number of N3 
embryos 
obtained 
after 
fertilization 
Quantitative, 
discrete 
[0,1,2,3…] 
Embryo Recorded 
from 
medical 
records 
Number 
of 
embryos N5 
Number of N5 
embryos 
obtained 
after 
fertilization 
Quantitative, 
discrete 
[0,1,2,3…] 
Embryo Recorded 
from 
medical 
records 
No embryos 
The condition of 
eggs not being 
able 
to 
create 
embryos 
after 
IVF/ICSI 
Binary 
0 = No 
1 = Yes 
 
Recorded 
from 
medical 
records 
Cancel cycle 
The COS cycle is 
canceled 
according to the 
criteria in section 
2.5.3 
Binary 
0 = No 
1 = Yes 
 
Recorded 
from 
medical 
records 
Ovarian 
hyperstimulation 
(OHSS) 
Is a treatment-
induced 
complication of 
Binary 
0 = No 
1 = Yes 
 
Monitor 
and record 
from 

Variable name 
Define 
Type 
Scale/encoding 
Unit 
How to 
collect 
physiological 
ovarian 
hyperstimulation, 
characterized by 
symptoms 
of 
varying degrees 
as described in 
section 2.6. 
medical 
records 
OHSS level 
The severity of 
OHSS 
is 
classified 
according to the 
standards 
in 
section 2.6 
Qualitative 
0 = Mild 
1 = Average 
2 = Severe 
3 = Critical 
 
Monitor 
and record 
from 
medical 
records 
B. Describe the progression of LH hormone 
Average 
LH 
concentration 
LH concentration 
was 
measured 
repeatedly 
on 
days S6, S8 and 
the day to initiate 
oocyte 
Quantitative, 
continuous 
[… 1,1 … ] 
IU/L 
Recorded 
from 
medical 
records 

Variable name 
Define 
Type 
Scale/encoding 
Unit 
How to 
collect 
maturation 
and 
induce ovulation. 
Note: From these primary variables, secondary outcomes can be determined, for example: 
ratio of MII oocytes / total number of aspirated oocytes; ratio of retrieved oocytes/expected 
total number of oocytes; ratio of fertilized oocytes/total number of oocytes collected, etc. 
 
Statistical analysis plan 
Data analysis and visualization were done using the R programming language (ver 4.3.1). 
The following analytic procedure was applied to evaluate multiple outcomes across 
successive stages of a controlled ovarian stimulation procedure: (1) For the count data 
outcomes, such as the number of retrieved oocytes and number of maturated (MII) oocytes, 
their distribution was described using median and 5th to 95th percentiles. The adjusted 
effect of the PPOS regimen on these outcomes will be evaluated by a Negative Binomial 
(NBI) regression analysis; (2) The success rates, including maturation rate, fertilization 
rate, probabilities of achieving Day 3 and Day 5 embryos, as well as their transferability, 
were also described as median and 5th to 95th percentiles. The effectiveness of the PPOS 
protocol compared to GnRH-ant on the probability of success was evaluated as adjusted 
risk difference (aRD) and odds ratio (aOR) via a binomial regression model; (3) To achieve 
a precise estimation of the PPOS protocol’s effect, adjustment for multiple baseline and 
procedural factors such as maternal age, AFC, baseline levels of AMH, LH, trigger method, 

total FSH dose and length of stimulation was applied to regression analysis. The 
plausibility of each adjusted factor was confirmed based on data visualization and 
statistical analysis of the relationship between that factor and the targeted outcome. NBI 
and binomial regression models were fitted using the GAMLSS package (18). Confidence 
intervals for the marginal effects were determined by the delta method (19). Statistical 
inferences were based on null hypothesis testing at the significance level 0.05. 
ETHICS IN RESEARCH 
During IVF/ICSI, preventing premature luteinization is an essential part of COS ovarian 
stimulation. Among the current COS regimens, the antagonist COS regimen is the most 
commonly used regimen because it helps shorten ovarian stimulation time and is patient-
friendly by reducing the amount of exogenous gonadotropin drugs required. injection and 
reduce treatment costs. However, the effectiveness in preventing LH surge is still quite 
variable. Recently, the PPOS regimen was born with the purpose of inhibiting the LH peak 
and preventing ovulation from occurring. Still, it has proven to be advantageous when the 
progestin route of administration is oral, meeting patient friendliness because of the 
reduction in the worry of having to inject too much medicine during the COS cycle. At the 
same time, progestin is also much cheaper than subcutaneous GnRH-ant. It should be noted 
that, until now, no regimen is optimal in effectiveness for all subjects. This also contributes 
to ensuring fairness and ethics in research. When participating in the study, patients are 
fully counseled about ovarian stimulation drugs, the IVF procedure, and the risks of 
complications that may occur during IVF, such as bleeding. vagina at the oocyte retrieval 
site, internal bleeding due to ovarian cyst rupture or infection at the aspiration site, ovarian 
hyperstimulation syndrome, possibility of cycle cancellation, fertilization rate, clinical 
pregnancy, and study progress ( 0. Patients also know which regimen they will use when 
undergoing ovarian stimulation (open-label). When agreeing to participate in the study, the 
patient will sign a consent form to participate in the study ( 04). All patient information is 
encrypted and confidential, used only for research purposes, not for any other purpose.  

 
Patient and public involvement 
Patients and the public are not involved in the trial process. 
 
SUMMARY OF THE RESEARCH IMPLEMENTATION PROCESS 
Table 4 Summary of the research implementation process 
Time 
Research stages 
Sample 
selection 
Random 
grouping 
After randomization 
After 
examination 
Third day of 
menstruation 
Ovarian 
stimulation 
Oocyte 
aspiration 
Fertilization 
and embryo 
culture 
Embryo 
transfer 
Monitor 
Sample selection 
 
Receiving patients 
x 
 
 
 
 
 
 
Examination 
x 
 
 
 
 
 
 
Basic testing 
x 
 
 
 
 
 
 
Sign consent 
x 
 
 
 
 
 
 
Random grouping 
 
x 
 
 
 
 
 
Intervention 
 
PPOS regimen 
 
 
 
GnRH-anta regimen 
 
 
 
Sampling and 
outcome 
assessment 
 

Time 
Research stages 
Sample 
selection 
Random 
grouping 
After randomization 
After 
examination 
Third day of 
menstruation 
Ovarian 
stimulation 
Oocyte 
aspiration 
Fertilization 
and embryo 
culture 
Embryo 
transfer 
Monitor 
Anthropometry and 
physiological status 
x 
 
 
 
 
 
 
Characteristics of 
KTBT 
 
 
x 
 
 
 
 
Main outcome 
 
Pregnancy 
progresses 
 
 
 
 
 
 
x 
Secondary 
outcomes 
 
Expected number of 
oocytes, number of 
oocytes recovered, 
number of MII 
oocytes, cycle 
cancellation 
 
 
 
x 
 
 
 
Number of fertilized 
ovules, N3, N5 
embryos, no 
embryos 
 
 
 
 
x 
 
 
OHSS 
 
 
 
x 
 
 
 

Time 
Research stages 
Sample 
selection 
Random 
grouping 
After randomization 
After 
examination 
Third day of 
menstruation 
Ovarian 
stimulation 
Oocyte 
aspiration 
Fertilization 
and embryo 
culture 
Embryo 
transfer 
Monitor 
Average LH 
concentration 
 
 
x 
 
 
 
 
 

FIGURE 
 
 
Figure 1 Results from the simulation estimate the sample size.  

Note: According to this result, a sample comprising 200 patients (split equally between the 
groups) would be required. This size ensures that no difference in the number of retrieved 
or MII oocytes between the PPOS and control group would exceed 1.5 units. 
 
Figure 2 Flowchart of the participant allocation 
 
 

APPENDIX 
APPENDIX 1 
DATA COLLECTION TABLE 
STUDY 
COMPARISON OF FERTILISATION RESULTS BETWEEN TWO OVARIAN 
STIMULATION PROTOCOLS WITH PROGESTIN AND ANTAGONIST IN VIETNAM 
POPULATION 
 
DATA COLLECTION TABLE 
 
I. PATIENT INFORMATION 
Hospital: 
 
File number: 
 
First and last name: 
 
Date of birth: [ ][ ] / [ ][ ] / [ ][ ][ ][ ] (Day Month Year) 
Phone number: 
 
Phone number (husband or other relative): 
 
PROTOCOL used: [ ] PPOS  [ ] GnRH-ant  
II. DATA COLLECTION 
A. BACKGROUND INFORMATION 
Code 
Question 
Reply 
Note 
A1 
 Date of birth 
[ ][ ] / [ ][ ] / [ ][ ][ ][ ] 
 

Code 
Question 
Reply 
Note 
Day month Year 
A2 
 Height 
[ ][ ][ ] cm 
 
A3 
 Weight 
[ ][ ],[ ]kg 
 
A4 
 Infertility period 
[ ][ ][ ] month 
 
A5 
 
Causes of infertility1 
[ ] 0. Male factor 
[ ] 1. Fallopian tube factor 
[ ] 2. POR 
[ ] 3. PCOS 
[ ] 4. Unknown cause 
 
Day 2 - 3 of menstrual cycle 
A6 
 AMH 
[ ][ ],[ ] ng/ml 
 
A7 
 AFC2 
[ ][ ] 
 
 
B. OVARIAN STIMULATION PROCESS 
(S1 start date: [ ][ ] / [ ][ ] / [ ][ ][ ][ ]) 
Code 
Question 
Reply 
Note 
B1  
First dose of 
gonadotropins 
[ ] 150 IU [ ] 225 IU [ ] 300 IU [ ] 375 IU 
 
B2  
Day 
E2 concentration 
(pg/ml) 
P4 concentration 
(ng/ml) 
LH concentration 
(IU/L) 
 
1If multiple causes coexist, choose the most dominant cause 
2Ovarian follicle size 2 - 10 mm 

Code 
Question 
Reply 
Note 
[ ][ ] / [ ][ ] 
(Day S6) 
[ ][ ][ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ] / [ ][ ] 
(Day S8) 
[ ][ ][ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ] / [ ][ ] 
(Trigger) 
[ ][ ][ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
B3  
Total gonadotropin 
dose 
[ ][ ][ ][ ] IU 
 
B4  COS time 
[ ][ ] day 
 
B5  
Number of days 
using GnRH-ant3 
[ ][ ] day 
 
B6  Early LH peak 
[ ] 0. No [ ] 1. Yes (on date ) 
 
B7  
Number of 
cancellation cycles 
[ ][ ] 
 
 
B'. OVARIAN STIMULATION PROCESS 
(S1 start date: [ ][ ] / [ ][ ] / [ ][ ][ ][ ]) 
 (For canceled cycles) 
 
3For the GnRH-ant protocol group 

Code 
Question 
Reply 
Note 
B'1  
First dose of gonadotropins 
[ ] 150 IU [ ] 225 IU [ ] 300 IU 
[ ] 375 IU 
 
B'2  
Day 
E2 concentration 
(pg/ml) 
P4 concentration 
(ng/ml) 
LH concentration 
(IU/L) 
[ ][ ] / [ ][ ] 
(Day S6) 
[ ][ ][ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ] / [ ][ ] 
(Day S8) 
[ ][ ][ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ] / [ ][ ] 
(Trigger) 
[ ][ ][ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
[ ][ ],[ ][ ] 
B'3  Total gonadotropin dose 
[ ][ ][ ][ ] IU 
 
B'4  COS time 
[ ][ ] day 
 
B'5  
Number of days using GnRH-
ant4 
[ ][ ] day 
 
B'6  Early LH peak 
[ ] 0. No 
[ ] 1. Yes (on date) 
 
 
C. RESULTS OF EMBRYORA AVOLUTION AND INFERTILATION 
(Date of oocyte retrieval [ ][ ] / [ ][ ] / [ ][ ][ ][ ]) 
 
4For the GnRH-ant regimen group 

Code 
Question 
Reply 
Note 
C1  
Expected number of 
oocytes 
[ ][ ] 
 
C2 S
Number of oocytes 
obtained 
[ ][ ] 
 
C3  Number of MII oocytes 
[ ][ ] 
 
C4  Number of fertilized ovules 
[ ][ ] 
 
C5  Number of blanks 
[ ][ ] 
 
C6  Number of embryos N3 
[ ][ ] 
 
C7  Number of embryos N5 
[ ][ ] 
 

APPENDIX 2 
RESEARCH INFORMATION SHEET FOR PATIENTS 
 
I. INFORMATION ABOUT RESEARCH 
Study name: " COMPARISON OF FERTILISATION RESULTS BETWEEN TWO 
OVARIAN 
STIMULATION 
PROTOCOLS 
WITH 
PROGESTIN 
AND 
ANTAGONIST IN VIETNAM POPULATION." 
Researcher and contact information 
Main implementer: Doctor. Than Trong Thach 
Contact phone: +84908.40.00.40 
Email: thachthan007@gmail.com 
Research sponsor: This research was not sponsored by any individual or entity. The 
person conducting the research pays for the necessary expenses of the research 
themselves. 
II. RESEARCH PURPOSES 
Progestin-primed ovarian stimulation regimen (using Dydrogesterone as a "primer" for 
the COS cycle) compared to a conventional ovarian stimulation regimen (GnRH-ant and 
gonadotropin) in Vietnamese women. performed in vitro fertilization. 
III. REASON FOR INVITING TO PARTICIPATE IN THE STUDY 
You were invited to participate in this study because you were treated with in vitro 
fertilization and met the above study inclusion criteria. You need to carefully read and 
understand the content provided in this information sheet. Before you decide to 

participate in this study, you will be carefully explained about the research objectives 
and procedures, and you can also ask questions if necessary. After you are satisfied and 
understand this study and want to participate, you will sign a voluntary commitment to 
participate. 
IV. RESEARCH PROCESS 
Step 1: Invite to participate in the study 
When you come for a check-up at the Artificial Reproductive Technology Center of Tam 
Anh General Hospital, Hanoi, the doctor will review the standards after performing basic 
surveys of the infertility examination process. receive and eliminate her. If you meet the 
sample selection criteria, your doctor will invite you to participate, advise you on the 
research process, the benefits and risks of participating, and answer your questions. If 
you agree to participate, you will sign consent to participate in the study. 
Step 2: Randomize groups 
After signing consent to participate in the study, she will be randomly assigned to 1 of 2 
study subgroups (PPOS regimen group or GnRH-ant regimen group). You will know 
which group you are in. The doctor will collect some of your information into a data 
collection table. 
Step 3: Stimulate the ovaries and monitor follicle development 
First, you will be injected with ovarian stimulation medication starting on the 2nd or 3rd 
day of your menstrual cycle (called stimulation day S1). From day 5 onwards, the doctor 
will adjust or maintain the drug dose according to the response of the ovaries until 
ovulation is stimulated. The doctor will monitor the response of the ovaries by 
transvaginal ultrasound to measure the size of ovarian follicles, and the concentration of 
estradiol (E2), LH, and progesterone (P4) in the serum will be measured on the morning 

of S5, S8, and ovulation induction day. To prevent a premature LH peak, for the GnRH-
anta protocol, you will receive a subcutaneous injection of 0.25 mg of Cetrorelix 
(Cetrotide; Merck Serono) once daily from S5, along with ovarian stimulation 
medication until the day before. when ovulation is triggered. For the PPOS protocol, 
she will receive Dydrogesterone (DYG) 10mg, 1 pill x 3 times/day from S1 and 
continuously every day until the day of oocyte retrieval. When there are more than 2 
ovarian follicles with a diameter greater than 17 mm, she will inject oocyte maturation 
medication with Triptoreline 0.2mg (Diphereline; Ipsen) or hCG 10,000 IU (IVF C 5000; 
LG) or recombinant hCG DNA 250 mcg (Ovitrelle; Merck Serono), and oocyte retrieval 
was performed 36 – 38 hours later. For stimulation cycles where no follicles are larger 
than 15 mm after 7 days of ovarian stimulation, the cycle is canceled. She will still have 
ovarian stimulation done again in the next cycle. 
Step 4: Oocyte retrieval, fertilization, and embryo culture 
The doctor will perform transvaginal oocyte retrieval 36 - 38 hours after the injection of 
medication to trigger oocyte maturation. After aspiration, the eggs will be fertilized by 
intracytoplasmic sperm injection (ICSI). Embryos will be cultured until day 3 or day 5 
(depending on the number of embryos and the clinician's decision) and then completely 
frozen. 
Step 5: Monitor the patient after oocyte retrieval 
After aspiration, you will be monitored and treated for the following complications. 
These are complications that can occur with any IVF process. 
- Vaginal bleeding: After the oocyte retrieval is completed, a speculum will be 
placed to examine the vagina. If bleeding is seen at the needle puncture site, the doctor 
will use gauze to press on the bleeding site and wait for a while. 5 minutes. After that, 

the doctor checks again, and if there is still bleeding, he can consider injecting hemostatic 
medicine. 
- Bladder hemorrhage rarely occurs due to the needle piercing the egg through the 
bladder, with the main symptom being red urine. Most cases will not require 
intervention. You will be told to drink plenty of water, and in some cases, hemostatic 
medication or antibiotics may be considered. If red urine persists or there are blood clots 
in the bladder, bladder irrigation, and cystoscopy can be performed to stop the bleeding. 
- Internal bleeding due to ovarian cyst rupture: After oocyte retrieval, if there are 
symptoms of abdominal pain (lower abdomen, one side or both sides, can spread to the 
shoulders), lethargy, or fatigue, you will be examined and Perform tests to diagnose. 
Subsequent treatment will be performed according to the hospital's protocol. 
- Infection at the egg retrieval site: very rare, with symptoms such as fever, lower 
abdominal pain, and pain on one side of the pelvis, and blood tests are performed to 
determine infection. After that, she will be treated with broad-spectrum antibiotics 
according to the hospital protocol. 
- Ovarian hyperstimulation syndrome is due to excessive response of the ovaries to 
ovarian stimulation. This is an uncommon complication (1 - 5% in one cycle) but is a 
dangerous complication during ovarian stimulation. You may have symptoms such as 
abdominal pain, nausea, vomiting, difficulty breathing, rapid weight gain, and decreased 
urination. Depending on the level of symptoms and tests, it can be divided into levels: 
mild, moderate, severe and critical; and she will be monitored and treated according to 
the hospital's protocol. 
Step 6: Embryo transfer and confirmation of pregnancy 
You will have frozen embryos transferred in the next cycle and a quantitative hCG test 
will be performed 10 days or 13 days after N5 or N3 embryo transfer: (1) If the hCG test 
is positive (> 5 mIU/ml), the pregnancy will continue to be monitored; (2) If the hCG 

test is negative (< 5mIU/ml), the outcome is determined as failure in the first embryo 
transfer and the study ends. She will still continue to undergo IVF according to the 
hospital's protocol. 
V. RESPONSIBILITIES OF RESEARCH SUBJECTS WHEN PARTICIPATING 
IN RESEARCH 
You need to follow the instructions of your doctor and midwife and complete all steps 
in the treatment and research process as described above because of the study's possible 
risks and side effects. When performing IVF, you will have risks and side effects of IVF 
treatment, such as: 
1) Complications of the oocyte retrieval process, such as vaginal bleeding, internal 
bleeding due to ovarian cyst rupture, bladder bleeding, and infection at the retrieval site: 
rarely occur; you will be evaluated by a doctor. , monitor and treat if there is a risk or 
this condition occurs as in step 5 of the research process 
2) Ovarian hyperstimulation is when the ovaries respond greatly to ovarian 
stimulation drugs. Ovarian hyperstimulation can cause bloating, abdominal pain, and 
polymembranous effusion. Your doctor will evaluate your condition, monitor and treat 
you if there is a risk or this condition occurs, as in step 5 of the research process. 
3) Cycle cancellation: a condition in which no ovarian follicles are larger than 12 
mm after ten days of ovarian stimulation. Your condition will be evaluated with canceled 
cycles, and your ovaries will be stimulated again in the next cycle. 
4) Embryo transfer but negative pregnancy test results: due to the nature of the study, 
only data is recorded on the first embryo transfer, so if the pregnancy test result is 
negative, the study will end, but you will still be able to continue fertilization treatment. 
Test tube sperm according to hospital protocol. 
VII. BENEFITS OF PARTICIPATING IN RESEARCH 

You will be thoroughly explained and monitored throughout the in vitro fertilization 
treatment process. 
VIII. INFORMATION SECURITY 
Your information will be kept confidential in your medical record. When collecting data, 
all personal information will be encrypted, stored separately, and used only for research 
purposes. 
IX. DO NOT PARTICIPATE IN RESEARCH 
The choice to participate in the study is yours and voluntary. If you have been accepted 
into the study but change your mind, you can withdraw from the study at any time. She 
will still be cared for and treated like a routine in vitro fertilization case. 
X. COSTS OF TREATMENT AND COSTS OF RESEARCH 
You will not be paid for participating in the research. You will still pay the cost of COS 
injections and the cost of performing in vitro fertilization as in normal treatment cases, 
according to hospital regulations. 
XI. CONTACT 
If you have any questions about the study, please contact Dr. Than Trong Thach at 
+84908 400 040 or by email at thachthan007@gmail.com. 
 

APPENDIX 3 
CONSENT TO PARTICIPATE IN RESEARCH 
Research name 
“COMPARISON OF FERTILISATION RESULTS BETWEEN TWO OVARIAN 
STIMULATION PROTOCOLS WITH PROGESTIN AND ANTAGONIST IN 
VIETNAM POPULATION. " 
Researcher and contact information 
Main researcher: Dr. Than Trong Thach 
Contact Phone: +84908.40.00.40 
Email: thachthan007@gmail.com 
 
I voluntarily participated in this study. I have read and clearly understood the purpose and 
procedure of the research. The study was explained clearly; I had time to ask questions 
about the study, and I was satisfied with all the answers. 
 
 
_________________________ 
       
 
Name of study participant   
Signature  
 
 
Date 
 
Confirmation of the person conducting the research 

I, the undersigned, commit to fully explaining research information to research participants 
and ensuring that research participants clearly understand the purpose, procedures, risks, 
and benefits of participating in the study. 
 
 
 
_________________________ 
       
 
Name of person conducting research  
 
Signature  
 
 
Date 
 
 

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