<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03803228</url>
  </required_header>
  <id_info>
    <org_study_id>BISTIM</org_study_id>
    <nct_id>NCT03803228</nct_id>
  </id_info>
  <brief_title>Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Hospitalier Intercommunal Creteil</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Laboratoires Genévrier</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>IBSA Institut Biochimique SA</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Centre Hospitalier Intercommunal Creteil</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      During ovarian stimulation, all the follicles grow under the action of FSH, only the selected&#xD;
      follicles and with the faster growth are taken. However during this stimulation, other&#xD;
      smaller follicles are also recruited and sensitized, which may increase the selection of&#xD;
      follicles available on the follicular wave following. In patients with weak reserve this&#xD;
      potentiation has a great interest, and the sequence of 2 stimulations on the same cycle could&#xD;
      make it possible to obtain a larger number of oocytes and embryos, thus giving a better&#xD;
      chance of delivery than on 2 distinct cycles of stimulation. However, this is preliminary&#xD;
      data that needs to be confirmed with a randomized controlled trial. In this population of&#xD;
      poor prognosis, the use of FSH-associated LH activity may optimize the ovarian response to&#xD;
      stimulation, particularly the combination containing placental HCG (Fertistartkit®) that&#xD;
      obtaining a slightly higher number of oocytes than highly purified HMG (Menopur®).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ovarian stimulation is an essential prerequisite for any in vitro fertilization attempt (IVF)&#xD;
      to optimize the chances of delivery per cycle. These depend in the first place on the age of&#xD;
      the patients and secondly on the number of oocytes collected. There is a strong correlation&#xD;
      between these two factors, the ovarian reserve diminishing with age. In older patients or&#xD;
      patients with decreased reserve, however, the number of oocytes collected remains a&#xD;
      prognostic factor for the chances of delivery.&#xD;
&#xD;
      At the present time, there is no validated intervention that would bring a significant&#xD;
      interest on the number of oocytes obtained in the group of bad responder patients. However,&#xD;
      it is a very heterogeneous population whose definition has been proposed only recently, the&#xD;
      Bologna criteria and questioned by a new proposal from the Poseidon group. The latter is more&#xD;
      focused on the prognosis of success, differentiating patients with a diminished reserve&#xD;
      (count of antral follicles CFA &lt;5 and / or AMH &lt;1.2 ng / ml) from those with an &quot;unexpected&quot;&#xD;
      bad response. As the profiles are better defined, it is easier to determine the impact of a&#xD;
      strategy in a specific group.&#xD;
&#xD;
      Recent clarifications on the ovarian cycle and folliculogenesis have shown that several waves&#xD;
      of follicular development coexist on the same cycle and that it is perfectly possible to&#xD;
      obtain a follicular development with a luteal phase equivalent oocyte quality, compared to&#xD;
      conventional stimulations performed in the follicular phase. The main constraint of luteal&#xD;
      phase stimulation is the lack of possibility of fresh transfer due to non-synchronization&#xD;
      with the endometrium. This constraint is today secondary given the evolution of conservation&#xD;
      techniques with the development of embryonic and oocyte vitrification.&#xD;
&#xD;
      On the other hand, there is a differential dependence of FSH follicles, their sensitivity&#xD;
      depending on the number of FSH receptors and their duration of exposure to FSH. During&#xD;
      ovarian stimulation, all the follicles grow under the action of FSH, only the selected&#xD;
      follicles and with the faster growth are taken. However during this stimulation, other&#xD;
      smaller follicles are also recruited and sensitized, which may increase the selection of&#xD;
      follicles available on the follicular wave following. In patients with weak reserve this&#xD;
      potentiation has a great interest, and the sequence of 2 stimulations on the same cycle could&#xD;
      make it possible to obtain a larger number of oocytes and embryos, thus giving a better&#xD;
      chance of delivery than on 2 distinct cycles of stimulation. However, this is preliminary&#xD;
      data that needs to be confirmed with a randomized controlled trial. In this population of&#xD;
      poor prognosis, the use of FSH-associated LH activity may optimize the ovarian response to&#xD;
      stimulation, particularly the combination containing placental HCG (Fertistartkit®) that&#xD;
      obtaining a slightly higher number of oocytes than highly purified HMG (Menopur®).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 3, 2018</start_date>
  <completion_date type="Actual">November 24, 2021</completion_date>
  <primary_completion_date type="Actual">March 3, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>cumulative number of oocytes on 2 punctures</measure>
    <time_frame>up to 60 days</time_frame>
    <description>cumulative number of oocytes on 2 punctures</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>cumulative number of follicles&gt; 14mm</measure>
    <time_frame>up to 60 days</time_frame>
    <description>cumulative number of follicles&gt; 14mm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>cumulative number of oocytes in metaphase II</measure>
    <time_frame>up to 60 days</time_frame>
    <description>cumulative number of oocytes in metaphase II</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>cumulative number of embryos obtained</measure>
    <time_frame>1 month</time_frame>
    <description>cumulative number of embryos obtained</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of embryos transferred</measure>
    <time_frame>up to 60 days</time_frame>
    <description>number of embryos transferred</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of frozen embryos</measure>
    <time_frame>1.5 month</time_frame>
    <description>number of frozen embryos</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>dose of FSH</measure>
    <time_frame>up to 60 days</time_frame>
    <description>cumulative total dose of FSH</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the number of stimulation days</measure>
    <time_frame>up to 20 days</time_frame>
    <description>the number of stimulation days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>estradiol level</measure>
    <time_frame>up to 20 days</time_frame>
    <description>estradiol level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LH level</measure>
    <time_frame>up to 20 days</time_frame>
    <description>LH level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>progesterone level</measure>
    <time_frame>up to 20 days</time_frame>
    <description>progesterone level</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>transfer rate</measure>
    <time_frame>3 months</time_frame>
    <description>cancellation or no transfer rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>rates of early pregnancy</measure>
    <time_frame>up to 9 months</time_frame>
    <description>cumulative rates of early pregnancy (HCG&gt; 100) and ultrasound (6-7SA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of beginner pregnancy</measure>
    <time_frame>up to 9 months</time_frame>
    <description>number of beginner pregnancy in each groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>cumulative cost</measure>
    <time_frame>up to 9 months</time_frame>
    <description>cumulative cost of 2 attempts including frozen embryo transfers (treatments, consultations, MPA laboratory and monitoring exams)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Side effects</measure>
    <time_frame>up to 9 months</time_frame>
    <description>reported side effects</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">88</enrollment>
  <condition>Fertility Disorders</condition>
  <arm_group>
    <arm_group_label>DUOSTIM</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>(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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Conventional stimuli</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>(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.&#xD;
(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</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>DUOSTIM</intervention_name>
    <description>2 consecutive stimulations by Fertistartkit® on the same cycle</description>
    <arm_group_label>DUOSTIM</arm_group_label>
    <other_name>Same monthly cycle</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Conventional stimuli</intervention_name>
    <description>2 stimulations by Fertistartkit® performed on 2 different cycles</description>
    <arm_group_label>Conventional stimuli</arm_group_label>
    <other_name>Two different menstrual cycles</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Women from 20 to 41 years old&#xD;
&#xD;
          -  CFA &lt;5 and / or AMH &lt;1, 2 ng / ml&#xD;
&#xD;
          -  19 ≤ BMI ≤ 32&#xD;
&#xD;
          -  Supports IVF or ICSI&#xD;
&#xD;
          -  If antecedent IVF / ICSI, number of oocytes collected &lt;4&#xD;
&#xD;
          -  Attack rank (puncture with transfer) &lt;3&#xD;
&#xD;
          -  Affiliation to the general social security scheme and benefiting from 100% infertility&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Confirmed ovarian insufficiency (amenorrhea)&#xD;
&#xD;
          -  FSH&gt; 20 IU / l or CFA &lt;1&#xD;
&#xD;
          -  Puncture rank&gt; 3&#xD;
&#xD;
          -  Azoospermia or cryptozoospermia&#xD;
&#xD;
          -  Against indication to ovarian stimulation&#xD;
&#xD;
          -  Presence of a cyst of indeterminate etiology, ovarian, uterine or mammary carcinoma,&#xD;
             hypothalamic or pituitary tumors&#xD;
&#xD;
          -  Hypersensitivity to any of the medicines in the protocol&#xD;
&#xD;
          -  Moderate or severe pathology of renal or hepatic function&#xD;
&#xD;
          -  Evolutionary thromboembolic accidents&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>41 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nathalie MASSIN, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CHI Créteil</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Polyclinique Jean Villar</name>
      <address>
        <city>Bruges</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHI Creteil</name>
      <address>
        <city>Créteil</city>
        <zip>94000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cabinet Médical Carré Saint Giniez</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Polyclinique Saint Roch</name>
      <address>
        <city>Montpellier</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>August 8, 2018</study_first_submitted>
  <study_first_submitted_qc>January 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>December 5, 2022</last_update_submitted>
  <last_update_submitted_qc>December 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03803228
org study id: BISTIM
nct id: NCT03803228
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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®).
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®).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: cumulative number of oocytes on 2 punctures
time frame: up to 60 days
description: cumulative number of oocytes on 2 punctures
measure: cumulative number of follicles> 14mm
time frame: up to 60 days
description: cumulative number of follicles> 14mm
measure: cumulative number of oocytes in metaphase II
time frame: up to 60 days
description: cumulative number of oocytes in metaphase II
measure: cumulative number of embryos obtained
time frame: 1 month
description: cumulative number of embryos obtained
measure: number of embryos transferred
time frame: up to 60 days
description: number of embryos transferred
measure: number of frozen embryos
time frame: 1.5 month
description: number of frozen embryos
measure: dose of FSH
time frame: up to 60 days
description: cumulative total dose of FSH
measure: the number of stimulation days
time frame: up to 20 days
description: the number of stimulation days
measure: estradiol level
time frame: up to 20 days
description: estradiol level
measure: LH level
time frame: up to 20 days
description: LH level
measure: progesterone level
time frame: up to 20 days
description: progesterone level
measure: transfer rate
time frame: 3 months
description: cancellation or no transfer rate
measure: rates of early pregnancy
time frame: up to 9 months
description: cumulative rates of early pregnancy (HCG> 100) and ultrasound (6-7SA)
measure: number of beginner pregnancy
time frame: up to 9 months
description: number of beginner pregnancy in each groups
measure: cumulative cost
time frame: up to 9 months
description: cumulative cost of 2 attempts including frozen embryo transfers (treatments, consultations, MPA laboratory and monitoring exams)
measure: Side effects
time frame: up to 9 months
description: reported side effects
arm group label: DUOSTIM
arm group type: Experimental
description: (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.
arm group label: Conventional stimuli
arm group type: Active Comparator
description: (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
intervention type: Drug
intervention name: DUOSTIM
description: 2 consecutive stimulations by Fertistartkit® on the same cycle
arm group label: DUOSTIM
other name: Same monthly cycle
intervention type: Drug
intervention name: Conventional stimuli
description: 2 stimulations by Fertistartkit® performed on 2 different cycles
arm group label: Conventional stimuli
other name: Two different menstrual cycles
criteria: 
gender: Female
minimum age: 20 Years
maximum age: 41 Years
healthy volunteers: No
last name: Nathalie MASSIN, MD
role: Principal Investigator
affiliation: CHI Créteil
facility: 
facility: 
facility: 
facility: 
country: France
responsible party type: Sponsor