Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders

• ClinicalTrials.gov Identifier: NCT03803228
• Recruitment Status: Completed
• First Posted: January 14, 2019
• Last Update Posted: December 3, 2021
• Sponsor: Centre Hospitalier Intercommunal Creteil
• Collaborators: Laboratoires Genévrier; IBSA Institut Biochimique SA
• Information provided by (Responsible Party): Centre Hospitalier Intercommunal Creteil

Study Description

Brief Summary:

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®).

Condition or disease	Intervention/treatment	Phase
Fertility Disorders	Drug: DUOSTIM; Drug: Conventional stimuli	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: September 3, 2018
• Actual Primary Completion Date: March 3, 2021
• Actual Study Completion Date: November 24, 2021

Arms and Interventions

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 Name: 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 Name: Two different menstrual cycles

Outcome Measures

Primary Outcome Measures :

1. cumulative number of oocytes on 2 punctures [ Time Frame: up to 60 days ]
   cumulative number of oocytes on 2 punctures

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

France

Polyclinique Jean Villar

Bruges, France

CHI Creteil

Créteil, France, 94000

Cabinet Médical Carré Saint Giniez

Marseille, France

Polyclinique Saint Roch

Montpellier, France

Sponsors and Collaborators

Centre Hospitalier Intercommunal Creteil

Laboratoires Genévrier

IBSA Institut Biochimique SA

Investigators

• Principal Investigator: Nathalie MASSIN, MD; CHI Créteil

More Information

• Responsible Party: Centre Hospitalier Intercommunal Creteil
• ClinicalTrials.gov Identifier: NCT03803228
• Other Study ID Numbers: BISTIM
• First Posted: January 14, 2019
• Last Update Posted: December 3, 2021
• Last Verified: December 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No