<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/NCT02991950</url>
  </required_header>
  <id_info>
    <org_study_id>876</org_study_id>
    <nct_id>NCT02991950</nct_id>
  </id_info>
  <brief_title>Weight Adjusted Low Molecular Weight Heparin in Recurrent Implantation Failure: a Randomized Open Labeled Trial</brief_title>
  <official_title>Weight Adjusted Low Molecular Weight Heparin in Recurrent Implantation Failure: a Randomized Open Labeled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Istituto Clinico Humanitas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Istituto Clinico Humanitas</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prospective randomized study of patients with infertility candidates to Assisted&#xD;
      ReproductiveTechniques (ART), screened for all inclusion and exclusion criteria, submitted to&#xD;
      ART cycle with or without low molecular weight heparin (LMWH) administration. Aims of the&#xD;
      study are to evaluate, primarily, pregnancy rate/embryo transfer, secondarily take home&#xD;
      babies/embryo transfer, implantation rate, and the role of thrombophilic factors&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an interventional, stratified, randomized, open blind study. It will conducted on&#xD;
      outpatients selected on the basis of inclusion and exclusion criteria.&#xD;
&#xD;
      Patients will be randomised according to a computer generated list of randomization to&#xD;
      receive or not LMWH at prophylactic daily dosage (100 IU/kg).&#xD;
&#xD;
      For a correct selection and analysis some parameters have to be checked before randomization&#xD;
      (see randomization check list at the end). The women in LMWH arm will treated starting the&#xD;
      day before the beginning of stimulation phase of the cycle of ART until the result of the&#xD;
      procedure is confirmed in terms of pregnancy yes or no, and if the pregnancy will be&#xD;
      confirmed until the delivery or the end of pregnancy. Women in the control arm are&#xD;
      administered routine hormonal support without LMWH.&#xD;
&#xD;
      Data will be collected on smoking habits, BMI, the number of retrieved oocytes, transferred&#xD;
      embryos and implantation rate, ART outcome and parameters used for randomization on the basis&#xD;
      of inclusion and exclusion criteria.&#xD;
&#xD;
      During the study blood will be collected for analysis at the randomization, the moment in&#xD;
      wich patient will be assigned to one of the two arms, at the transfer and at the day of check&#xD;
      for betaHCG and in in case of pregnancy all women will be checked at 12, 24, 36 week for&#xD;
      testing of functional parameters of coagulation (protein C, protein S, AT, ddimer,&#xD;
      fibrinogen, PT, aPTT, FVII, FVIII, FIX, and vonWillebrand factor antigen), blood cells count&#xD;
      and of lipids (cholesterol and triglycerides).&#xD;
&#xD;
      The samples, identified with a sequential identification number, will be collected, processed&#xD;
      and storage at -20/-80°C in the promoter center and will be destroyed after the analyses.&#xD;
&#xD;
      Study treatment Women in LMWH arm are administered with prophylactic weight adjusted dose of&#xD;
      LMWH, starting the day before the beginning of stimulation phase of the cycle until the&#xD;
      result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy&#xD;
      until the delivery or the end of pregnancy. Women in the LMWH arm will be tested for blood&#xD;
      cell count twice in the first 10 days of therapy.&#xD;
&#xD;
      Initial dose and schedule Parnaparin will be administered at the dose of 100 IU/kg/day from&#xD;
      the day before the beginning of stimulation phase of the cycle until the result of the&#xD;
      procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until&#xD;
      delivery or the end of the pregnancy.&#xD;
&#xD;
      None of patients can receive concomitant acetylsalicylic acid (ASA) or steroids therapy&#xD;
      Treatment duration&#xD;
&#xD;
      Women in LMWH arm are administered with prophylactic weight adjusted dose of parnaparin,&#xD;
      starting the day before the beginning of stimulation phase of the cycle until the result of&#xD;
      the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until the&#xD;
      delivery or the end of the pregnancy.&#xD;
&#xD;
      Whatever the disease status, the treatment will always be discontinued in case of patient&#xD;
      refusal excessive toxicity precluding further therapy, according to the responsible&#xD;
      physicianother complications, according to the responsible physician&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Difficulty with patient enrollment&#xD;
  </why_stopped>
  <start_date>July 2011</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">March 2015</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>pregnancy rate/embryo transfer</measure>
    <time_frame>12-14 days</time_frame>
    <description>the investigators measured the pregnancy rate/embryo transfer using betaHcg dosage 12 days after embryo transfer</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>take home babies/embryo transfer</measure>
    <time_frame>38-40 weeks after embryo transfer</time_frame>
    <description>Live birth was defined as delivery of one or more live infants after 23 gestational weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>implantation rate</measure>
    <time_frame>3 weeks</time_frame>
    <description>ultrasound was performed to evaluate implantation rate calculated as as number of gestational sacs divided by number of transferred embryos multiplied by 100</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>role of thrombophilia in interfering with pregnancy rate/take home baby/implantation rate</measure>
    <time_frame>12-14 days and 38-40 weeks and 3 weeks</time_frame>
    <description>All enrolled patients were previously screened for the presence or not of thrombophilic defects: protein C or protein S or AT deficiency, FV G1691A and FIIG20210A mutations, C677T MTHFR polymorphism,hyperhomocysteinemia, antiphospholipid antibodies. The investigators excluded from the enrollment patients with severe thrombophilia: protein C, protein S, AT deficiency or homozygous FV Leiden and FIIG20210A mutations or double heterozygosity for FV Leiden and FIIG20120 mutations because in this patients the international guide lines suggest and recommend the use of antithrombotic prophylaxis</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">271</enrollment>
  <condition>Infertility</condition>
  <condition>Low Molecular Weight Heparin</condition>
  <arm_group>
    <arm_group_label>parnaparin sodium</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Women in LMWH arm are administered with routine ovulation induction protocol and prophylactic dose of parnaparin sodium (LMWH), starting the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until the delivery or the end of pregnancy. Women in the LMWH arm will be tested for blood cell count twice in the first 10 days of therapy.&#xD;
Parnaparin will be administered at the dose of 100 IU/kg/day from the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until delivery or the end of the pregnancy.&#xD;
Used dosages Parnaparin 0.4 4250 UI Parnaparin 0.6 6400 UI</description>
  </arm_group>
  <arm_group>
    <arm_group_label>no treatment</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Women in the control arm are administered with routine ovulation induction protocol, without the addition of parnaparin sodium.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Parnaparin Sodium</intervention_name>
    <description>Parnaparin sodium ( Fluxum 4250 anti-Xa IU /0.4 mL or Fluxum 6400 anti-Xa IU /0.6mL; Alfa Wassermann S.p.A.) was administered at a dose of 100 IU/kg/day from the day before the beginning of the stimulation phase of the cycle until the result of the procedure was confirmed by pregnancy and, in the case of evolutive pregnancy, until delivery or the end of pregnancy</description>
    <arm_group_label>parnaparin sodium</arm_group_label>
    <other_name>Fluxum</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Women ≥18 years and ≤40 years, candidated to a fresh IVF/ICSI cycle with routine&#xD;
             ovulation induction protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        v-vCouples candidated to a frozen IVF/ICSI cycle with routine ovulation induction protocol&#xD;
&#xD;
          -  Testicular or frozen sperm (TESE procedure not allowed)&#xD;
&#xD;
          -  Presence of hormonal disorders not compensated with specific therapy or history of&#xD;
             immunological disease (autoimmune thyroiditis, connectivitis, RA, SLE, etc )&#xD;
&#xD;
          -  Presence of antiphospholipides autoantibodies or other severe thrombophilia (AT, PS,&#xD;
             PC deficiency or homozygous FV Leiden or FIIG20210A, or double eterozygous FV Leiden&#xD;
             and FIIG20210A)&#xD;
&#xD;
          -  Presence of abnormal platelets count and congenital or acquired coagulopathy ASA or&#xD;
             steroid therapy administration&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>corrado lodigiani, MD,PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Thrombosis Center</affiliation>
  </overall_official>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>November 29, 2016</study_first_submitted>
  <study_first_submitted_qc>December 13, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 14, 2016</study_first_posted>
  <last_update_submitted>December 13, 2016</last_update_submitted>
  <last_update_submitted_qc>December 13, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 14, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Body Weight</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Parnaparin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT02991950
org study id: 876
nct id: NCT02991950
lead sponsor: 
has dmc: Yes
Prospective randomized study of patients with infertility candidates to Assisted
      ReproductiveTechniques (ART), screened for all inclusion and exclusion criteria, submitted to
      ART cycle with or without low molecular weight heparin (LMWH) administration. Aims of the
      study are to evaluate, primarily, pregnancy rate/embryo transfer, secondarily take home
      babies/embryo transfer, implantation rate, and the role of thrombophilic factors
This is an interventional, stratified, randomized, open blind study. It will conducted on
      outpatients selected on the basis of inclusion and exclusion criteria.

      Patients will be randomised according to a computer generated list of randomization to
      receive or not LMWH at prophylactic daily dosage (100 IU/kg).

      For a correct selection and analysis some parameters have to be checked before randomization
      (see randomization check list at the end). The women in LMWH arm will treated starting the
      day before the beginning of stimulation phase of the cycle of ART until the result of the
      procedure is confirmed in terms of pregnancy yes or no, and if the pregnancy will be
      confirmed until the delivery or the end of pregnancy. Women in the control arm are
      administered routine hormonal support without LMWH.

      Data will be collected on smoking habits, BMI, the number of retrieved oocytes, transferred
      embryos and implantation rate, ART outcome and parameters used for randomization on the basis
      of inclusion and exclusion criteria.

      During the study blood will be collected for analysis at the randomization, the moment in
      wich patient will be assigned to one of the two arms, at the transfer and at the day of check
      for betaHCG and in in case of pregnancy all women will be checked at 12, 24, 36 week for
      testing of functional parameters of coagulation (protein C, protein S, AT, ddimer,
      fibrinogen, PT, aPTT, FVII, FVIII, FIX, and vonWillebrand factor antigen), blood cells count
      and of lipids (cholesterol and triglycerides).

      The samples, identified with a sequential identification number, will be collected, processed
      and storage at -20/-80°C in the promoter center and will be destroyed after the analyses.

      Study treatment Women in LMWH arm are administered with prophylactic weight adjusted dose of
      LMWH, starting the day before the beginning of stimulation phase of the cycle until the
      result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy
      until the delivery or the end of pregnancy. Women in the LMWH arm will be tested for blood
      cell count twice in the first 10 days of therapy.

      Initial dose and schedule Parnaparin will be administered at the dose of 100 IU/kg/day from
      the day before the beginning of stimulation phase of the cycle until the result of the
      procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until
      delivery or the end of the pregnancy.

      None of patients can receive concomitant acetylsalicylic acid (ASA) or steroids therapy
      Treatment duration

      Women in LMWH arm are administered with prophylactic weight adjusted dose of parnaparin,
      starting the day before the beginning of stimulation phase of the cycle until the result of
      the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until the
      delivery or the end of the pregnancy.

      Whatever the disease status, the treatment will always be discontinued in case of patient
      refusal excessive toxicity precluding further therapy, according to the responsible
      physicianother complications, according to the responsible physician
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: pregnancy rate/embryo transfer
time frame: 12-14 days
description: the investigators measured the pregnancy rate/embryo transfer using betaHcg dosage 12 days after embryo transfer
measure: take home babies/embryo transfer
time frame: 38-40 weeks after embryo transfer
description: Live birth was defined as delivery of one or more live infants after 23 gestational weeks.
measure: implantation rate
time frame: 3 weeks
description: ultrasound was performed to evaluate implantation rate calculated as as number of gestational sacs divided by number of transferred embryos multiplied by 100
measure: role of thrombophilia in interfering with pregnancy rate/take home baby/implantation rate
time frame: 12-14 days and 38-40 weeks and 3 weeks
description: All enrolled patients were previously screened for the presence or not of thrombophilic defects: protein C or protein S or AT deficiency, FV G1691A and FIIG20210A mutations, C677T MTHFR polymorphism,hyperhomocysteinemia, antiphospholipid antibodies. The investigators excluded from the enrollment patients with severe thrombophilia: protein C, protein S, AT deficiency or homozygous FV Leiden and FIIG20210A mutations or double heterozygosity for FV Leiden and FIIG20120 mutations because in this patients the international guide lines suggest and recommend the use of antithrombotic prophylaxis
arm group label: parnaparin sodium
arm group type: Experimental
description: Women in LMWH arm are administered with routine ovulation induction protocol and prophylactic dose of parnaparin sodium (LMWH), starting the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until the delivery or the end of pregnancy. Women in the LMWH arm will be tested for blood cell count twice in the first 10 days of therapy.
Parnaparin will be administered at the dose of 100 IU/kg/day from the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until delivery or the end of the pregnancy.
Used dosages Parnaparin 0.4 4250 UI Parnaparin 0.6 6400 UI
arm group label: no treatment
arm group type: No Intervention
description: Women in the control arm are administered with routine ovulation induction protocol, without the addition of parnaparin sodium.
intervention type: Drug
intervention name: Parnaparin Sodium
description: Parnaparin sodium ( Fluxum 4250 anti-Xa IU /0.4 mL or Fluxum 6400 anti-Xa IU /0.6mL; Alfa Wassermann S.p.A.) was administered at a dose of 100 IU/kg/day from the day before the beginning of the stimulation phase of the cycle until the result of the procedure was confirmed by pregnancy and, in the case of evolutive pregnancy, until delivery or the end of pregnancy
arm group label: parnaparin sodium
other name: Fluxum
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: No
last name: corrado lodigiani, MD,PHD
role: Principal Investigator
affiliation: Thrombosis Center
responsible party type: Sponsor
mesh term: Infertility
mesh term: Body Weight
mesh term: Parnaparin
sharing ipd: No