Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03895099 |
| Other study ID # |
RANDOS |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
September 4, 2020 |
| Est. completion date |
October 30, 2023 |
Study information
| Verified date |
November 2023 |
| Source |
Centre Hospitalier Intercommunal Creteil |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Oocyte donation is a cumbersome and demanding procedure, involving an injectable hormonal
treatment for an average duration of 12 days, according to the protocols, 1 to several daily
injections. The objective of this study is to show that treatments can be simplified without
reducing the number of oocytes that have been punctured, by blocking the luteinizing hormone
(LH) surge by using oral progesterone and by limiting the number of injections of
gonadotropins using corifollitropin alpha, regardless of the start date of the pacing
protocol during a natural cycle.
Description:
Medically assisted procreation can help infertile patients with a panel of techniques adapted
to various causes of infertility. In most cases, these techniques use patients' own gametes.
However, despite the medical advances, it is still impossible today to regenerate gametic
cells when they have disappeared from the gonads. Especially for women with premature ovarian
failure, the only feasible option is to receive oocytes from a third-party donor. In France,
the principle of free and anonymous applies to the donation and no compensation is allowed
outside the reimbursement of expenses incurred. Oocyte donors are women volunteers who agree
to undergo heavy medical treatment to help other women, without any other consideration so
that the recognition of their donation. It is important for these women to minimize the risks
involved, to simplify and minimize ovarian stimulation treatments, which are generally
injections and to offer maximum flexibility, without reducing the quality of the donation.
The advent of oocyte and embryo vitrification has opened up new opportunities for
reproductive scientists to improve the practice and results of IVF attempts. It is now
established that vitrification of whole oocyte cohorts does not compromise, and may even
improve, the results of IVF attempts. In addition, it is now clear that progesterone
modulates the frequency of Gonadotropin-Releasing Hormone (GnRH) pulses and can strongly
inhibit the pulsatile secretion of GnRH and LH and thereby inhibit the LH peak induced by
increased plasma concentrations of GnRH and LH. estradiol. And, in the context of oocyte
donation, the deleterious effects of ovarian stimulation on endometrial receptivity have no
impact: the increase in progesterone levels during stimulation is not a concern in this group
who will not benefit from an embryonic transfer.
Initially, progesterone stimulation protocols were performed during the luteal phase as part
of the urgent preservation of fertility in cancer patients. The first European feasibility
study was conducted and published in 2013 in normotensive patients. While the preliminary
findings were not optimistic, many publications, from 2013, showed that this luteal strategy
is effective without the addition of a GnRH antagonist, but imposes a freeze all strategy. In
all these studies, whether it is luteal phase stimulation schemes, strategies of 2
consecutive stimulations, in the follicular and then luteal phase, or random-start
stimulation protocol, the quality of the oocytes does not seem to be impacted, with identical
implantation and birth rates in the control groups (conventional ovarian stimulation). The
state of health of newborns and malformation rates are also identical to those of
conventional protocols.
Although luteal phase endogenous progesterone levels appear to be sufficient to block the LH
surge, recent publications have also shown the efficacy of exogenous progesterone, which can,
without compromising the oocyte's competence, replace the use of an agonist or antagonist
during the follicular phase. The advantages are oral administration and the reduction of
potential costs, without any secondary effect on the competence of oocytes.
Different progestins were used. Kuang et al (2015) report the first randomized study studying
an exogenous progestogen-based ovarian stimulation protocol using medroxyprogesterone acetate
(MPA). Compared to a standard short protocol, with embryonic vitrification in both groups,
the number of mature oocytes and the number of frozen embryos, the implantation and pregnancy
rates after thawed embryo transfers were not significantly different. The same group
published between 2015 and 2017, 4 studies validating micronized progesterone as an effective
oral alternative to treatment with GnRH agonists for the prevention of premature LH surge
during controlled ovarian stimulation for intracytoplasmic sperm injection (IVF-ICSI).
Recently, the same group compared dydrogesterone and micronized progesterone with the same
results. More recently, another progestogen, desogestrel, has been used in addition to
corifollitropin alpha in an oocyte donation program, compared to a conventional antagonist
protocol. The authors reported the same number of oocytes in both groups, with better
tolerance of treatment in the desogestrel group. In the same way as for luteal phase
stimulation protocols, exogenous progestin-exogenous ovarian stimulation protocols have
similar neonatal outcomes, compared to "standard" protocols, for birth weight, gestational
age, and Congenital malformation rate.
The use of luteal phase or follicular phase stimulation protocols with progestins could
rapidly develop in the context of oocyte donation where no embryo transfer is performed. A
single published study reports 13 MPA-blocked oocyte donor (PPO) cycles compared to
counter-protocol donation cycles. This retrospective study found a significant difference in
favor of the progestin-primed ovarian stimulation (PPOS) protocol for the number of oocytes
retrieved. The duration of ovarian stimulation, the number of units of gonadotropins needed
were not different from one group to another. No peak of LH was observed in the PPOS group.
These PPOS protocols have many advantages for these women wishing to donate their oocytes:
improved flexibility (donors can choose the date of their oocyte retrieval, without cycle
constraint), better acceptance with fewer injections, and lower cost. In addition, the use of
Corifollitropin Alpha (CTA) improves patient comfort by reducing the number of injections (1
instead of 7), without altering the quality and number of oocytes. In addition, these
protocols allow the initiation of ovulation by injection of GnRH agonists, drastically
reducing the risk of hyperstimulation syndrome and contributing to the safety of donors. A
retrospective study (proof of concept study) published in 2018 shows that the joint use of a
PPOS and CTA gives satisfactory results, while being acceptable ("patient friendly").
To improve donor comfort and validate the use of progestogen-blocking ovarian stimulation
protocols, this protocol combining the use of corifollitropin alpha and blocking the
preterm-mediated progestogen LH peak is an innovative and promising approach, without impact
neither on quantity nor on oocyte quality.
Our study (proof of concept) aims to validate the use of PPOS in oocyte donation, and to show
that these stimulation protocols can be started whatever the phase of the menstrual cycle.
The assumptions are:
- The number of oocytes retrieved is not significantly different, regardless of the start
date of treatment during the menstrual cycle.
Exogenous progestin therapy effectively blocks the LH surge during ovarian stimulation.
- It is possible to significantly reduce the number of injections during controlled ovarian
stimulation for oocyte donors and the cost to society, without decreasing the effectiveness
of ovarian stimulation.
