Research Hypothesis This study is undertaken to validate our research
hypothesis that implementation of Sandwich (delayed start antagonist)protocol
will improve outcomes in IVF/ICSI cycles in POSEIDON poor responders as it has advantages
of both GnRH antagonist protocol & long GnRH agonist protocol. Sandwich
protocol results in better synchronised follicular response leading to lesser
cycle cancellation rate and more number of mature oocytes. It gives the
opportunity to use dual trigger and requires less total gonadotrophin
requirement compared to long GnRH agonist protocol.
Aim: To compare the
efficacy of sandwich (delayed start GnRH antagonist) protocol with conventional
antagonist stimulation protocol in terms of IVF outcomes in POSEIDON poor
responders.
Primary objective:To
compare the efficacy of sandwich (delayed start GnRH antagonist ) protocol with
conventional antagonist stimulation protocols
in POSEIDON poor responders in terms of
oocyte yield.
Secondary objectives: To
compare the efficacy of sandwich (delayed start GnRH antagonist) protocol with
conventional antagonist protocol in POSEIDON poor responders in terms of
• Total
dose of gonadotrophins required
• Duration of controlled ovarian
stimulation
• Peak serum estradiol (E2) &
progesterone (P4) on the day of trigger
• FORT/Follicular output rate
• Endometrial thickness on the day of
OPU
• Number of mature oocytes (MII)
retrieved
• Fertilization rate
• Cleavage rate
• Total number of embryos
• Embryo grading
• Cycle cancellation rate
• Clinical pregnancy rate per embryo
transfer
• Live birth rate (LBR)
• Miscarriage rate
Materials and methods - Study design: Open label, randomized controlled trial, parallel design allocation
where Sandwich(delayed start antagonist)
protocol (Study group A) will be compared individually with conventional GnRH antagonist protocol (Study
group B).This study will be registered in the Clinical Trial Registry of India
(CTRI).
Study population: Infertile
women undergoing IVF/ICSI cycles
Place of study: ART
(Assisted Reproductive Technology) centre, Department of Obstetrics and
Gynecology, AIIMS, New Delhi.
Duration of study: From
date of ethical clearance to July 2026
Study groups:
1)Study group A: Infertile women undergoing
Sandwich(delayed start antagonist
protocol)
2)Study group B: Infertile women undergoing
conventional GnRH antagonist protocol
Sample size:patients
(45 patients in each study group)
Sample size calculation: primary objective of this study is to compare the oocyte
yield between the Sandwich (delayed start antagonist protocol) and the
conventional GnRH antagonist protocol in POSEIDON poor reponders. Previous
study by Al-Jeborry et al(2020)(28) reported the average number of oocyte yield from GnRH
antagonist protocol in POSEIDON poor responders
as 2.8±2.32 . With a significance level of 0.05, power of 80% and an
estimated 10% loss to follow up, a minimum of 45 subjects per group is required
if we assume that there will be improvement of 1.5 units.A total 90 patients
will be enrolled for present study.
Statistical analysis :
The data will be presented using descriptive statistics. Qualitative data will
be displayed as frequency and percentages, while quantitative data will be
shown as either mean ± SD for normally distributed data, or median (Min-Max)
for non-normally distributed data. Categorical variables will be analyzed using
either the Chi square or Fisher exact test. Differences between groups will be
observed using the independent T test or One-way ANOVA, assuming normality of
data, or the Mann Whitney U test or Kruskal Wallis test if normality of data
cannot be assumed. Other appropriate analyses will be performed as needed to
meet the objectives at the time of analysis. Statistical significance will be
defined as a p value of <0.05.
Inclusion criteria:
• Unexpected poor responders who belong to
POSEIDON 1 (Age < 35 years, AMH ≥ 1.2ng/ml and / or
AFC ≥ 5, Previous ovarian response yielding <4 oocytes in subgroup 1a and
4-9 oocytes in subgroup 1b)
POSEIDON 2 (Age ≥ 35 years, AMH ≥ 1.2ng/ml and / or AFC ≥
5, Previous ovarian response yielding <4 oocytes in subgroup 2a and 4-9 oocytes in subgroup 2 b)
• Expected poor responders who belong to
POSEIDON 3 ( Age < 35 years , AMH <1.2ng / ml and / or AFC < 5 ) and
POSEIDON 4 ( Age
≥ 35 years , AMH <1.2ng / ml and / or AFC < 5 )
Exclusion criteria:
• Anatomical and pathological abnormalities in the uterus
• Endocrine disorders such as thyroid dysfunction,
hyperprolactinemia and diabetes mellitus
• h/o tumour in hypothalamus and pituitary,
Hypogonadotropic hypogonadism
• Azoospermia in male partner
• Endometriosis, h/o previous adnexal surgeries
• Recurrent miscarriage and recurrent implantation
failure
• BMI ≥
Recruitment: Infertile
women attending the out-patient department and IVF Clinic will be screened
according to the inclusion and exclusion criteria. Eligible candidates will be informed
about the study and informed written consent will be taken from the couple
after explaining the detailed plan, purpose and duration of the study in their
own understandable language. The couples refusing to participate in the trial
shall be treated at par with all other ongoing IVF/ICSI cycles at the center.
Their decision to refuse participation in this study shall not affect their IVF
treatment in any way.
Randomization: Eligible
candidates will be randomized into Sandwich(delayed start antagonist) protocol
or GnRH antagonist protocol group. Mixed block randomization method will
be used. Computer generated random number list will be generated by using
nQuery software and the participants will be allocated into one of the three
groups. Allocation of the patients into one of the two groups will be done by
sequentially numbered opaque sealed envelope. The envelopes will be prepared by
a person not associated with the conduct of the study. The envelopes will be
sequentially opened. This randomization and allocation to the two groups will
be done by a part of the team of investigators who are not involved in the
treatment procedure of the participants. This randomization and allocation
process will ensure blinding and minimize bias in the study.
Intervention: Before a
patient is recruited for IVF, a detailed clinical history including menstrual
history, previous obstetric history including history of pregnancy losses,
history of prior treatment taken for infertility, details of previous IVF
cycles (if available) will be recorded on a predesigned proforma. Detailed
examination including general physical examination and gynecological
examination will be done.
She will undergo baseline blood investigations including
serum luteinizing hormone (LH), follicle stimulating hormone (FSH) levels,
anti-mullerian hormone (AMH), thyroid stimulating hormone (TSH) and prolactin
levels. Baseline transvaginal ultrasound (TVS) will be done on day 2-5 of the
menstrual cycle to see for antral follicle count (AFC) and 3D
ultrasound on day 14-16 of the menstrual cycle for
uterine cavity evaluation, endometrial thickness and to rule out any other
pelvic pathology. If any uterine pathology is suspected, the participants will
undergo hysteroscopy. Semen analysis and semen culture of the partner will also
be done prior to recruitment.
Patient will undergo stimulation protocol as per
randomization.
In the Study Group A (Sandwich protocol), patients will receive Tab.Estradiol valerate (Tab
Estrabet) 2mg bd from midluteal phase
(day 21) of previous cycle till the onset of menses/ the day of starting
GnRHantagonist. GnRH antagonist (Injection Cetrotide 0.25mg/d) will be started
on day2 and continued for 7 days. Gonadotropins
{Injection recombinant FSH (Gonal F) subcutaneously and Injection Human
Menopausal Gonadotrophin(HMG )intramuscularly} will be initiated from the next
day in the ratio of 2:1 after confirmation of downregulation (Serum estradiol
< 50 pg/ml, no dominant follicle & endometrial thickness <4mm on
TVS). The dose of gonadotrophin will be decided depending on patient’s age, BMI
(body mass index), AMH (Anti mullerian hormone), AFC(Antral follicle count)
and/or ovarian response in previous cycles (if available). The dose will be
adjusted based on ovarian response. GnRH antagonist (Injection Cetrorelix) 0.25
mg/day subcutaneously will be started when the lead follicle is ≥13mm and will be continued up to &
including the day of trigger. Recombinant LH 75IU will be added from the day of
starting GnRH antagonist till the time of trigger.
In the Study Group B (GnRH Antagonist protocol), patients
will receive patients will receive Tab.Estradiol valerate (Tab Estrabet) 2mg bd
from midluteal phase (day 21) of previous cycle till the onset of menses/the
day of starting GnRH antagonist. Gonadotropins {Injection recombinant FSH
(Gonal F) subcutaneously and Injection Human Menopausal Gonadotrophin (HMG
)intramuscularly} will be initiated from the next day in the ratio of 2:1 after
confirmation of downregulation (Serum estradiol < 50 pg/ml, no dominant
follicle & endometrial thickness <4mm on TVS). The dose of gonadotrophin
will be decided depending on patient’s age, BMI (body mass index), AMH (Anti
mullerian hormone), AFC(Antral follicle count) and/or ovarian response in
previous cycles (if available). The dose will be adjusted based on ovarian
response. GnRH antagonist (Injection Cetrorelix) 0.25 mg/day subcutaneously
will be started when the lead follicle is
≥13mm and will be continued up to & including the day of trigger.
Recombinant LH 75IU will be added from the day of starting GnRH antagonist till
the time of trigger.
For both the protocols, the criteria for final follicular
maturation trigger will be at least 2 follicles with diameter ≥17 mm.Dual trigger((Injection recombinant hCG 250mcg
subcutaneously and Leuprolide 1mg subcutaneously) will be used. Oocytes will be
retrieved with flushing 34-36 hours post ovulation trigger Routine IVF or ICSI
will be performed, as appropriate. Freshly ejaculated sperm samples will be
prepared by double density gradient centrifugation and each oocyte will be
inseminated with 55,000 sperm or ICSI performed depending on the patient
profile.Then both the gametes will be incubated at 37 °C, 5% O2 and 6% CO2 in
the conventional incubator. Day 3 fresh
double embryo transfer will be performed under ultrasound guidance if
<3 embryos are obtained. If ≥3 good grade embryos are obtained, we will
consider day 5 fresh blast transfer.
Luteal phase support will be maintained until 12 weeks of gestation or
until the day of pregnancy test if negative.
Follow up:
Beta hCG and urine pregnancy test will be performed on
day 16 in our laboratory and progesterone will be continued up to 12 weeks of
gestation in a normal intrauterine pregnancy and discontinued in case of a
biochemical pregnancy or no pregnancy. Clinical pregnancy rates will be
calculated as per transvaginal ultrasound performed at 6-7 weeks showing one or
more gestational sacs with fetal cardiac activity. Clinical pregnancy rate includes
ectopic pregnancy as well.
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