Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT05071339 |
Other study ID # |
0013-21-ASF |
Secondary ID |
|
Status |
Recruiting |
Phase |
Phase 4
|
First received |
|
Last updated |
|
Start date |
April 1, 2021 |
Est. completion date |
March 1, 2023 |
Study information
Verified date |
October 2021 |
Source |
Assaf-Harofeh Medical Center |
Contact |
Michal Youngster, MD |
Phone |
+972506430111 |
Email |
michalyo[@]gmail.com |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
In the study the investigators would like to examine the effect of GnRH antagonist
administration at the beginning of the follicular phase in patients presenting with high
baseline estradiol levels of 200 pmol/L or above with a leading follicle of 11-13 mm. In the
unit's practice, patients presenting for cycle initiation with a leading follicle > 10 in the
presence of E2 > 200 pmol/L (54 pg/ml) are deferred and receive a priming antagonist protocol
in their sequential cycle. The aim of this intervention is to suppress FSH levels at the
beginning of the cycle thus preventing estradiol secretion of the leading follicle. This may
contribute to better synchronization of the remaining antral follicles cohort and allow for a
better cycle outcome instead of cancellation or one-month postponement. As previous studies
using GnRH antagonist pre-treatment prior to GT initiation for synchronization purposes
demonstrated positive results (including different patient population) , no deleterious
effects are expected.
Description:
During the late luteal phase, parallel to the corpus luteum demise, FSH levels gradually
increase in order to preserve antral follicles from atresia. Early antral follicles show
different sensitivity to FSH possibly contributing to the establishment of the dominant
follicle by starting their development earlier than others. Previous studies indicated larger
follicles are more sensitive to FSH then smaller ones, thus respond to lower levels of FSH.
The premature gradual exposure to FSH may accelerate the development of the larger follicle
and accentuate size discrepancies observed during controlled ovarian hyperstimulation (COH).
During COH exogenous gonadotropins are expected to influence early antral follicle growth to
simultaneously reach functional and morphological maturation. Significant size discrepancy at
the time of HCG administration may result in a larger fraction of immature oocytes, reducing
the number of embryos and the pregnancy rate.
Since baseline FSH levels are higher in older and poor responder patients, early antral
follicles are exposed to higher levels of FSH thus size discrepancies are observed more
frequently, contributing to higher cancellation rates and reducing furthermore pregnancy
rates.
Several protocols have been established to overcome early antral follicle exposure to FSH.
Estradiol priming for 7 days in the late luteal phase prior to GT stimulation achieved FSH
suppression and resulted in size discrepancy reduction and better cycle outcome (higher
number of mature oocytes, embryos and pregnancy rates). A meta-analysis demonstrated reduced
cycle cancellation rate and higher clinical pregnancy rate. GnRH antagonist priming, also by
reducing FSH levels in the late luteal phase, resulted in coordination of early antral
follicular size. These priming protocols require preplanning and a relatively predictable
menstrual cycle in order to start the priming supply in the late luteal phase. Poor responder
patients and those in-between IVF treatment cycles may not have regular menses or may be
waiting for pregnancy test results, thus do not represent optimal potential candidates for a
priming protocol.
Several studies have investigated the outcome of GnRH antagonist supplementation at the
beginning of the menstrual cycle prior to GT stimulation. The delayed start protocol which
combines estradiol priming followed by GnRH antagonist for 7 days at the beginning of menses
prior to GT administration to further synchronize antral follicles improved ovarian response
in poor responders and reduced cycle cancellation rate with no significant effect on
pregnancy rates. A preliminary study investigated the effect of three day administration of
GnRH antagonist at the beginning of the follicular phase prior to GT stimulation in normal
responders regardless of baseline hormonal levels and found a trend towards increase in
clinical pregnancy rate, and similar profiles of early embryo development, compared to
standard fixed GnRH antagonist protocol.
Patients not receiving priming protocol that are planned for an antagonist protocol usually
start their stimulation on day 2-3 of menses. A baseline Ultrasound and hormonal blood test
are performed to determine adequacy of cycle start. In a long agonist protocol, gonadotropin
stimulation begins after confirming that effective pituitary downregulation has been achieved
(serum estradiol level <30-40 pg/mL, no follicles >10 mm in diameter). In an antagonist
protocol cut offs may be defined according to the clinical observations and expectations of
each individual program. There have been reports of estradiol level cut-offs between 56pg/ml
and 80pg/ml with an average of 35pg/ml. In a prospective randomised trial Patients who
presented with an elevated day 3 E2 >80 pg/mL in a cycle before IVF-ET had a higher
cancellation rate and achieved a lower PR independent of FSH level.
In summary, several studies have proposed the use of different priming modalities in order to
suppress the early rise of FSH at the late luteal stage, including the use of estrogen and
GnRH-antagonist. No study examined the effect of these modalities on women with follicular
and hormonal levels suggesting early recruitment and beginning of development of the leading
follicle.
Study aim: In this study the investigators would like to examine the effect of GnRH
antagonist administration at the beginning of the follicular phase in patients presenting
with high baseline estradiol levels of 200 pmol/L or above (<350) with a leading follicle of
10-13 mm. In the unit's practice, patients presenting for cycle initiation with a leading
follicle > 10 in the presence of E2 > 200 pmol/L (54 pg/ml) are deferred and receive a
priming antagonist protocol in their sequential cycle. The aim of this intervention is to
suppress FSH levels at the beginning of the cycle thus preventing estradiol secretion of the
leading follicle. This may contribute to better synchronization of the remaining antral
follicles cohort and allow for a better cycle outcome instead of cancellation or one-month
postponement. As previous studies using GnRH antagonist pre-treatment prior to GT initiation
for synchronization purposes demonstrated positive results (including different patient
population) , no deleterious effects are expected.
Materials and Methods: This is a proof-of-concept pilot study. Patients will be recruited at
the reproductive medicine unit of Shamir Medical Center, Israel.
Study population: Patients undergoing controlled ovarian hyper stimulation at the IVF unit,
Shamir medical center. Planned recruitment of 15 patients.
Sample size: This is a proof of concept pilot study to evaluate the feasibility and potential
effectiveness of the intervention. A sample size of 15 patients will allow detecting the
potential for use of cycles that would have been cancelled using standard protocols. As the
comparator is mandatory cancellation, i.e. 0% use of cycles, this sample size is sufficient.
Study protocol:
Patients treated at the IVF unit at Shamir Medical Center planned for an antagonist cycle
will undergo blood test and US exam at day 2-3 of their menstrual cycle. Patients will be
recruited if a leading follicle > 10mm is shown in the presence of E2 200-350pmol/L.
Following the initial US exam in the morning, if a follicle 10-13 mm will be demonstrated,
the patient will receive a form explaining that the protocol may be changed according to
blood test results with three possible options: 1. Continuation with the original protocol 2.
Cancellation 3. Change in protocol as part of a research if the patient agrees to
participate. As patients undergo blood draws in the morning, with results available in the
afternoon, the initial recruitment will be performed over the phone with signed informed
consent received at the following clinic visit.
Patients will receive a verbal explanation over the phone and following verbal consent will
start GnRH antagonist injections [Cetrotide (cetrolix) or Orgalutran (ganirelix) - depending
on their primary prescription] for 3-5 days by which time a second blood test (for estradiol,
progesterone, LH and FSH) and US exam will be performed.
- If estradiol levels have decreased to < 200 pmol/L then ovarian stimulation according to
the original patient's protocol will be started.
- If estradiol levels have increased above 5%, the cycle will be cancelled.
- If estradiol levels have slightly decreased but still above 200 or increased in less
than 5% then GnRH antagonist for 3 more days will be prescribed. After these 3 days if
estradiol levels have decreased to < 200, ovarian stimulation according to the original
patient's protocol will be started. If estradiol levels are > 200 then cycle will be
cancelled.
When treatment is continued, the previous leading follicle will be separately followed.
Treatment outcomes will be recorded, including the number of large and small follicles,
number of mature oocytes of expected mature oocytes and number of embryos. Leading follicle
outcome will be recorded separately. In patients with a previous or a subsequent cycle with
similar GT dosages, cycle outcomes will be compared to the cycle with the intervention.
Risks to subjects: No anticipated risks over regular stimulation protocol side effects.
Statistical analyses: Descriptive statistics will be used.