Fertility DisordersPhase 3NCT03803228
Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders
A Phase 3 study testing DUOSTIM and Conventional stimuli in people with Fertility Disorders, run by Centre Hospitalier Intercommunal Creteil at 4 sites in France.
Trial 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… Read more about this study
- Who is it for?
- Ages 20 to 41 years, women only
- Conditions the study is for
- Fertility Disorders
- What is being tested?
- DUOSTIM and Conventional stimuli
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 88 participants
- Where
- 4 sitesFrance
- Study dates
- 3 Sep 2018to 24 Nov 2021
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 41 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- Hypersensitivity to any of the medicines in the protocol
- Moderate or severe pathology of renal or hepatic function
- Evolutionary thromboembolic accidents
Trial locations and contacts
4 sites in 1 country.
France4 sites
Polyclinique Jean Villar
Bruges
CHI Creteil
Créteil, 94000
Cabinet Médical Carré Saint Giniez
Marseille
Polyclinique Saint Roch
Montpellier
About this study
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
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®).
Read the 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®).
- Conditions
- Fertility Disorders
- Being tested
- DUOSTIM, Conventional stimuli
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DUOSTIMDrug
Also called Same monthly cycle
2 consecutive stimulations by Fertistartkit® on the same cycle
Conventional stimuliDrug
Also called Two different menstrual cycles
2 stimulations by Fertistartkit® performed on 2 different cycles
| Study group | Role | What they receive |
|---|---|---|
| DUOSTIM | Experimental | (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. Receives: Drug: DUOSTIM |
| Conventional stimuli | Active comparator | (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 Receives: Drug: Conventional stimuli |
What is being measured
The primary outcome is the main question the study is designed to answer.
cumulative number of oocytes on 2 punctures
cumulative number of oocytes on 2 punctures
Measured: up to 60 days
Secondary outcomes (15)
cumulative number of follicles> 14mm
cumulative number of follicles> 14mm
Measured: up to 60 days
cumulative number of oocytes in metaphase II
cumulative number of oocytes in metaphase II
Measured: up to 60 days
cumulative number of embryos obtained
cumulative number of embryos obtained
Measured: 1 month
number of embryos transferred
number of embryos transferred
Measured: up to 60 days
number of frozen embryos
number of frozen embryos
Measured: 1.5 month
dose of FSH
cumulative total dose of FSH
Measured: up to 60 days
the number of stimulation days
the number of stimulation days
Measured: up to 20 days
estradiol level
estradiol level
Measured: up to 20 days
LH level
LH level
Measured: up to 20 days
progesterone level
progesterone level
Measured: up to 20 days
transfer rate
cancellation or no transfer rate
Measured: 3 months
rates of early pregnancy
cumulative rates of early pregnancy (HCG> 100) and ultrasound (6-7SA)
Measured: up to 9 months
number of beginner pregnancy
number of beginner pregnancy in each groups
Measured: up to 9 months
cumulative cost
cumulative cost of 2 attempts including frozen embryo transfers (treatments, consultations, MPA laboratory and monitoring exams)
Measured: up to 9 months
Side effects
reported side effects
Measured: up to 9 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jan 2019
- Study start3 Sep 2018
- Primary completion3 Mar 2021
- Study completion24 Nov 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Fertility DisordersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 88 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre Hospitalier Intercommunal Creteil
- Sponsor type
- University, hospital or other
- Collaborators
- Laboratoires Genévrier, IBSA Institut Biochimique SA
- Responsible party
- Sponsor
- Investigators
- Nathalie MASSIN, MD, Principal investigator, CHI Créteil
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03803228
- Sponsor's protocol ID
- BISTIM
- Status last verified
- Dec 2022
- First submitted
- 8 Aug 2018
- Last updated
- 7 Dec 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Massin N, Abdennebi I, Porcu-Buisson G, Chevalier N, Descat E, Pietin-Vialle C, Goro S, Brussieux M, Pinto M, Pasquier M, Bry-Gauillard H. The BISTIM study: a randomized controlled trial comparing dual ovarian stimulation (duostim) with two conventional ovarian stimulations in poor ovarian responders undergoing IVF. Hum Reprod. 2023 May 2;38(5):927-937. doi: 10.1093/humrep/dead038.
PubMed 36864699
Study at a glance
From the registry record, last updated by the sponsor on 7 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03803228
- Acronym / sponsor ID
- BISTIM
- Conditions
- Fertility Disorders
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 88 participants (actual)
- Lead sponsor
- Centre Hospitalier Intercommunal CreteilUniversity, hospital or other
- Collaborators
- Laboratoires Genévrier, IBSA Institut Biochimique SA
- Study start
- 3 Sep 2018 (actual)
- Primary completion
- 3 Mar 2021 (actual)
- Study completion
- 24 Nov 2021 (actual)
- First posted
- 14 Jan 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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®).
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| DUOSTIM | Experimental | Drug: 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. |
| Conventional stimuli | Active comparator | Drug: 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 |
Who may qualify
- Ages
- 20 to 41 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (9 listed)
- Confirmed ovarian insufficiency (amenorrhea)
- FSH> 20 IU / l or CFA <1
- Puncture rank> 3
- Azoospermia or cryptozoospermia
- Against indication to ovarian stimulation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DUOSTIMAlso: Same monthly cycle2 consecutive stimulations by Fertistartkit® on the same cycle | Drug | DUOSTIM |
| Conventional stimuliAlso: Two different menstrual cycles2 stimulations by Fertistartkit® performed on 2 different cycles | Drug | Conventional stimuli |
Primary outcome
cumulative number of oocytes on 2 punctures
Time frame: up to 60 days
cumulative number of oocytes on 2 punctures
15 secondary outcomes
cumulative number of follicles> 14mm
Time frame: up to 60 days
cumulative number of oocytes in metaphase II
Time frame: up to 60 days
cumulative number of embryos obtained
Time frame: 1 month
number of embryos transferred
Time frame: up to 60 days
number of frozen embryos
Time frame: 1.5 month
dose of FSH
Time frame: up to 60 days
the number of stimulation days
Time frame: up to 20 days
estradiol level
Time frame: up to 20 days
LH level
Time frame: up to 20 days
progesterone level
Time frame: up to 20 days
transfer rate
Time frame: 3 months
rates of early pregnancy
Time frame: up to 9 months
number of beginner pregnancy
Time frame: up to 9 months
cumulative cost
Time frame: up to 9 months
Side effects
Time frame: up to 9 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Dec 2022.
- Derived from this study: PubMed 36864699Massin N, Abdennebi I, Porcu-Buisson G, Chevalier N, Descat E, Pietin-Vialle C, Goro S, Brussieux M, Pinto M, Pasquier M, Bry-Gauillard H. The BISTIM study: a randomized controlled trial comparing dual ovarian stimulation (duostim) with two conventional ovarian stimulations in poor ovarian responders undergoing IVF. Hum Reprod. 2023 May 2;38(5):927-937. doi: 10.1093/humrep/dead038.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nathalie MASSIN, MD principal investigator
CHI Créteil
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing DUOSTIM and Conventional stimuli in people with Fertility Disorders, run by Centre Hospitalier Intercommunal Creteil at 4 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
cumulative number of oocytes on 2 punctures (time frame: up to 60 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03803228, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Dec 2022.