Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders

Comparison of the Cumulative Number of Oocytes Obtained With 2 Controlled Ovarian Hyperstimulations (COH) Within the Same Cycle With FertistartKit® (DUOSTIM) Versus 2 Conventional COH in Poor Ovarian Responders Undergoing IVF. Bistim Study

During ovarian stimulation, all the follicles grow under the action of FSH, only the selected follicles and with the faster growth are taken. However during this stimulation, other smaller follicles are also recruited and sensitized, which may increase the selection of follicles available on the follicular wave following. In patients with weak reserve this potentiation has a great interest, and the sequence of 2 stimulations on the same cycle could make it possible to obtain a larger number of oocytes and embryos, thus giving a better chance of delivery than on 2 distinct cycles of stimulation. However, this is preliminary data that needs to be confirmed with a randomized controlled trial. In this population of poor prognosis, the use of FSH-associated LH activity may optimize the ovarian response to stimulation, particularly the combination containing placental HCG (Fertistartkit®) that obtaining a slightly higher number of oocytes than highly purified HMG (Menopur®).

Study Overview

• Status: Completed
• Conditions: Fertility Disorders
• Intervention / Treatment: Drug: DUOSTIM; Drug: Conventional stimuli

Detailed Description

Ovarian stimulation is an essential prerequisite for any in vitro fertilization attempt (IVF) to optimize the chances of delivery per cycle. These depend in the first place on the age of the patients and secondly on the number of oocytes collected. There is a strong correlation between these two factors, the ovarian reserve diminishing with age. In older patients or patients with decreased reserve, however, the number of oocytes collected remains a prognostic factor for the chances of delivery.

At the present time, there is no validated intervention that would bring a significant interest on the number of oocytes obtained in the group of bad responder patients. However, it is a very heterogeneous population whose definition has been proposed only recently, the Bologna criteria and questioned by a new proposal from the Poseidon group. The latter is more focused on the prognosis of success, differentiating patients with a diminished reserve (count of antral follicles CFA <5 and / or AMH <1.2 ng / ml) from those with an "unexpected" bad response. As the profiles are better defined, it is easier to determine the impact of a strategy in a specific group.

Recent clarifications on the ovarian cycle and folliculogenesis have shown that several waves of follicular development coexist on the same cycle and that it is perfectly possible to obtain a follicular development with a luteal phase equivalent oocyte quality, compared to conventional stimulations performed in the follicular phase. The main constraint of luteal phase stimulation is the lack of possibility of fresh transfer due to non-synchronization with the endometrium. This constraint is today secondary given the evolution of conservation techniques with the development of embryonic and oocyte vitrification.

On the other hand, there is a differential dependence of FSH follicles, their sensitivity depending on the number of FSH receptors and their duration of exposure to FSH. During ovarian stimulation, all the follicles grow under the action of FSH, only the selected follicles and with the faster growth are taken. However during this stimulation, other smaller follicles are also recruited and sensitized, which may increase the selection of follicles available on the follicular wave following. In patients with weak reserve this potentiation has a great interest, and the sequence of 2 stimulations on the same cycle could make it possible to obtain a larger number of oocytes and embryos, thus giving a better chance of delivery than on 2 distinct cycles of stimulation. However, this is preliminary data that needs to be confirmed with a randomized controlled trial. In this population of poor prognosis, the use of FSH-associated LH activity may optimize the ovarian response to stimulation, particularly the combination containing placental HCG (Fertistartkit®) that obtaining a slightly higher number of oocytes than highly purified HMG (Menopur®).

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bruges, France
    • Polyclinique Jean Villar
  • Créteil, France, 94000
    • Chi Creteil
  • Marseille, France
    • Cabinet Médical Carré Saint Giniez
  • Montpellier, France
    • Polyclinique Saint Roch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 41 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Women from 20 to 41 years old
• CFA <5 and / or AMH <1, 2 ng / ml
• 19 ≤ BMI ≤ 32
• Supports IVF or ICSI
• If antecedent IVF / ICSI, number of oocytes collected <4
• Attack rank (puncture with transfer) <3
• Affiliation to the general social security scheme and benefiting from 100% infertility

Exclusion Criteria:

• Confirmed ovarian insufficiency (amenorrhea)
• FSH> 20 IU / l or CFA <1
• Puncture rank> 3
• Azoospermia or cryptozoospermia
• Against indication to ovarian stimulation
• Presence of a cyst of indeterminate etiology, ovarian, uterine or mammary carcinoma, hypothalamic or pituitary tumors
• Hypersensitivity to any of the medicines in the protocol
• Moderate or severe pathology of renal or hepatic function
• Evolutionary thromboembolic accidents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DUOSTIM; (stim 1) flexible antagonist protocol with pre-treatment with estrogen (S1 between J1 and J8 under E2) and stimulation with Fertistartkit® 300 IU / d; triggering by rHCG (Ovitrelle®250μg) and puncture at 36h; oocyte freezing; (stim 2) resumption of stimulation only by Fertistratkit® 300 IU / day from the day after the puncture; introduction of Progestan® 7 days later to avoid menstruation during the second puncture; triggering with rHCG and second puncture at 36h associated with the devitrification of stim 1 oocytes, with sperm collection and embryonic vitrification. Transfer of frozen embryos to the subsequent cycle in the natural cycle (without HCG) and until the frozen embryos are exhausted.	Drug: DUOSTIM; 2 consecutive stimulations by Fertistartkit® on the same cycle; Other Names: Same monthly cycle
Active Comparator: Conventional stimuli; (stim 1) flexible antagonist protocol with pre-treatment with estrogen (S1 between J1 and J8 under E2) and stimulation with Fertistartkit® 300 IU / d; triggering by rHCG (Ovitrelle®250μg) and puncture at 36h; fresh embryonic transfer if satisfactory endometrial conditions with luteal phase support by vaginal micronized progesterone Progestan® 600 mg / d; otherwise embryonic freezing and transfer of frozen embryos to the subsequent cycle in the natural cycle until the frozen embryos are exhausted. (stim 2) ditto starting on the next cycle if possible or the next one. Hormonal Controls + Ultrasound During Stimulation: Blocking / S1 - S5 / S6 - S8 / S9 - SHCG / SHCG-1	Drug: Conventional stimuli; 2 stimulations by Fertistartkit® performed on 2 different cycles; Other Names: Two different menstrual cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cumulative number of oocytes on 2 punctures	cumulative number of oocytes on 2 punctures	up to 60 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cumulative number of follicles> 14mm	cumulative number of follicles> 14mm	up to 60 days
cumulative number of oocytes in metaphase II	cumulative number of oocytes in metaphase II	up to 60 days
cumulative number of embryos obtained	cumulative number of embryos obtained	1 month
number of embryos transferred	number of embryos transferred	up to 60 days
number of frozen embryos	number of frozen embryos	1.5 month
dose of FSH	cumulative total dose of FSH	up to 60 days
the number of stimulation days	the number of stimulation days	up to 20 days
estradiol level	estradiol level	up to 20 days
LH level	LH level	up to 20 days
progesterone level	progesterone level	up to 20 days
transfer rate	cancellation or no transfer rate	3 months
rates of early pregnancy	cumulative rates of early pregnancy (HCG> 100) and ultrasound (6-7SA)	up to 9 months
number of beginner pregnancy	number of beginner pregnancy in each groups	up to 9 months
cumulative cost	cumulative cost of 2 attempts including frozen embryo transfers (treatments, consultations, MPA laboratory and monitoring exams)	up to 9 months
Side effects	reported side effects	up to 9 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Intercommunal Creteil
• Collaborators: IBSA Institut Biochimique SA; Laboratoires Genévrier

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2018
• Primary Completion (Actual): March 3, 2021
• Study Completion (Actual): November 24, 2021

Study Registration Dates

• First Submitted: August 8, 2018
• First Submitted That Met QC Criteria: January 11, 2019
• First Posted (Actual): January 14, 2019

Study Record Updates

• Last Update Posted (Estimate): December 7, 2022
• Last Update Submitted That Met QC Criteria: December 5, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: BISTIM

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No