<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/NCT03759301</url>
  </required_header>
  <id_info>
    <org_study_id>NRC 0214</org_study_id>
    <nct_id>NCT03759301</nct_id>
  </id_info>
  <brief_title>Efficacy of Growth Hormone Supplementation With Gonadotrophins in IVF/ICSI for Poor Responders</brief_title>
  <official_title>Efficacy of Growth Hormone Supplementation With Gonadotrophins in IVF/ICSI for Poor Responders; a Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ClinAmygate</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Research Centre, Egypt</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>ClinAmygate</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>
      The objective of this study is to assess the effectiveness of adjuvant growth hormone&#xD;
      injection during controlled ovarian stimulation, in poor responder women undergoing&#xD;
      intracytoplasmic sperm injection (ICSI) procedures.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Infertility is defined as the failure to achieve a clinical pregnancy after 12 months or more&#xD;
      of regular unprotected sexual intercourse (and there is no other reason, such as&#xD;
      breastfeeding or postpartum amenorrhoea). Primary infertility is infertility in a couple who&#xD;
      have never had a child. Secondary infertility is a failure to conceive following a previous&#xD;
      pregnancy.&#xD;
&#xD;
      Subfertility, usually defined as the absence of conception after one year of regular&#xD;
      intercourse, subfertility is a common problem affecting as many as one in six couples.&#xD;
&#xD;
      According to the European Society of Human Reproduction and Embryology (ESHRE)&#xD;
      recommendations, couples with an estimated live birth rate of 40% or higher per year are&#xD;
      encouraged to continue aiming for a spontaneous pregnancy .&#xD;
&#xD;
      Treatment methods for infertility may be grouped as medical, complementary and alternative&#xD;
      treatments. Some methods may be used in concert with other methods. Drugs may be used for&#xD;
      both women and men.&#xD;
&#xD;
      If conservative medical treatments fail to achieve a full term pregnancy, the physician may&#xD;
      suggest the patient undergo assisted reproductive fertilization (ART). Methods for ART&#xD;
      include artificial insemination (IUI), gamete intrafallopian transfer (GIFT), zygot&#xD;
      intrafallopian transfer (ZIFT) or ICSI.&#xD;
&#xD;
      Intracytoplasmic sperm injection (ICSI) is an in vitro fertilization procedure in which a&#xD;
      single sperm is injected directly into an oocyte. During the past decade, ICSI has been&#xD;
      applied increasingly around the world to alleviate problems of severe male infertility&#xD;
      because too few motile and morphologically normal sperm were present in the ejaculate of the&#xD;
      male partner.&#xD;
&#xD;
      Although there have been several improvements in techniques of ART during the last three&#xD;
      decades clinical pregnancy and live-birth rates remain at approximately 30-40%.&#xD;
&#xD;
      Increasing these rates is desirable for couples undergoing ART, as treatment failure is a&#xD;
      source of psychological distress, and the most common cause of drop-out before achieving&#xD;
      pregnancy.The most common interventions to improve ART outcome are the use of maximized&#xD;
      controlled ovarian stimulation (COS), transference of multiple embryos into the uterus and&#xD;
      cryopreservation of surplus oocytes/embryos. However, the first two of these interventions&#xD;
      might increase the risk of ovarian hyperstimulation syndrome and multiple pregnancy.&#xD;
&#xD;
      In-vitro fertilization (IVF) protocols are constantly under review in an attempt to decrease&#xD;
      hormone (gonadotrophin) requirement, improve follicular recruitment, whilst primarily to&#xD;
      increase live birth rates.&#xD;
&#xD;
      Implantation failure is thought to result from impairment of embryo development and/or from&#xD;
      abnormal uterine receptivity.&#xD;
&#xD;
      Some protocols have considered the role of growth hormone in IVF. Growth hormone is a&#xD;
      biological peptide hormone, synthesized, stored and secreted by somatotroph cells located in&#xD;
      the anterior pituitary gland. Growth hormone can be synthetically produced using recombinant&#xD;
      DNA technology and is licensed to be used in the human population. There is currently no&#xD;
      consensus as to the route, dose or timing of growth hormone administration in IVF protocols.&#xD;
&#xD;
      Poor Ovarian Response (POR) is defined by the Bologna criteria, with an incidence between 9&#xD;
      and 24% of all cycles of IVF, usually it indicates a reduction in follicular response,&#xD;
      resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to&#xD;
      define the poor response in IVF, at least two of the following three features must be&#xD;
      present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and&#xD;
      (iii) an abnormal ovarian reserve test (ORT). Two episodes of POR after maximal stimulation&#xD;
      are sufficient to define a patient as poor responder in the absence of advanced maternal age&#xD;
      or abnormal ORT. By definition, the term POR refers to the ovarian response, and therefore,&#xD;
      one stimulated cycle is considered essential for the diagnosis of POR. However, patients of&#xD;
      advanced age with an abnormal ORT may be classified as poor responders since both advanced&#xD;
      age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of&#xD;
      ovarian stimulation cycle outcome. In this case, the patients should be more properly defined&#xD;
      as 'expected poor responder'. If this definition of POR is uniformly adapted as the 'minimal'&#xD;
      criteria needed to select patients for future clinical trials, more homogeneous populations&#xD;
      will be tested for any new protocols. Finally, by reducing bias caused by spurious POR&#xD;
      definitions, it will be possible to compare results and to draw reliable conclusions.&#xD;
&#xD;
      How the intervention might work? The administration of growth hormone may potentiate the&#xD;
      effect of exogenous gonadotrophins. Growth hormone is reported to modulate the action of&#xD;
      follicular stimulating hormone on granulosa cells by up-regulating the local synthesis of&#xD;
      insulin-like growth factor-I (IGF-1). This interest has been stimulated by animal studies&#xD;
      which suggest that growth hormone may increase the intra-ovarian production of the IGF-1.&#xD;
      IGF-1 displays growth hormone dependence both in-vivo and in-vitro The interaction between&#xD;
      growth hormone and IGF-1 is of significance since IGF-1 has been shown to play an important&#xD;
      part in ovarian function in both animal and human models. The addition of IGF-1 to&#xD;
      gonadotrophins in granulosa cell cultures increased gonadotrophin action on the ovary by&#xD;
      several mechanisms including augmentation of aromatase activity, 17 beta-oestradiol and&#xD;
      progesterone production and luteinising hormone receptor formation. IGF-1 has also been found&#xD;
      to stimulate follicular development, oestrogen production and oocyte maturation.&#xD;
&#xD;
      Improving the outcomes of ICSI by the use of growth hormone adjuvant therapy is important&#xD;
      particularly in those women who are considered poor responders. The aim of this study is to&#xD;
      establish the role of growth hormone in ICSI.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 20, 2018</start_date>
  <completion_date type="Actual">June 5, 2019</completion_date>
  <primary_completion_date type="Actual">May 5, 2019</primary_completion_date>
  <phase>Phase 4</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>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>clinical pregnancy rate</measure>
    <time_frame>3 weeks</time_frame>
    <description>The main outcome is clinical pregnancy per allocated woman, defined as the presence of at least one fetus with heart beat.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>E2 levels</measure>
    <time_frame>Day 1 of COS, the same day of Human Chorionic Gonadotropin (HCG) injection</time_frame>
    <description>Human Chorionic Gonadotropin (HCG) is given to induce triggering of ovulation then ovum pick up is scheduled 36 hour after the injection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of oocytes collected</measure>
    <time_frame>Day 6 of COS</time_frame>
    <description>Transvaginal ultrasound will be done starting from day 6 of COS for assessment of follicular development and assessment of endometrial thickness, serial E2 measurement will be scheduled to start on day 6 of COS repeating every other day</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metaphase I (MI) and Metaphase II (MII) oocyte number</measure>
    <time_frame>Day 6 of COS</time_frame>
    <description>Transvaginal ultrasound will be done starting from day 6 of COS for assessment of follicular development and assessment of endometrial thickness, serial E2 measurement will be scheduled to start on day 6 of COS repeating every other day</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Pronucleus</measure>
    <time_frame>Day 6 of COS</time_frame>
    <description>Transvaginal ultrasound will be done starting from day 6 of COS for assessment of follicular development and assessment of endometrial thickness, serial E2 measurement will be scheduled to start on day 6 of COS repeating every other day</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Multiple pregnancy</measure>
    <time_frame>6 weeks from last period</time_frame>
    <description>Multiple pregnancy</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">156</enrollment>
  <condition>Infertility, Female</condition>
  <arm_group>
    <arm_group_label>Growth Hormones Somatropin Recombinant</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Growth hormone (Somatropin) 4 IU/day subcutaneous from the 2nd day of the cycle and stopped 1 day before ovum pickup for the treatment group which consists of 70 women.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo saline solution</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Control group consisting of 70 women who will receive subcutaneous placebo injection in the same dosing as the treatment group</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Growth Hormones Somatropin Recombinant</intervention_name>
    <description>Growth Hormones Somatropin Recombinant 4 IU/day subcutaneous from the 2nd day of the cycle and stopped 1 day before ovum pickup</description>
    <arm_group_label>Growth Hormones Somatropin Recombinant</arm_group_label>
    <other_name>Cetrorelix</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo saline solution</intervention_name>
    <description>same volume as growth hormone ampule used</description>
    <arm_group_label>Placebo saline solution</arm_group_label>
    <other_name>Cetrorelix</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age: 25 to 38 years old.&#xD;
&#xD;
          -  IVF previous poor responders: at least two failed cycles with &lt; five oocytes or&#xD;
             abnormal ORT e.g. antimullerian hormone &lt; 1&#xD;
&#xD;
          -  Patients with unexplained infertility.&#xD;
&#xD;
          -  Normal follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin and&#xD;
             ovarian ultrasound.&#xD;
&#xD;
          -  Normal pelvic ultrasound including 3D ultrasound of the uterus with no detected&#xD;
             hydrosalpinx.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Refusal to participate in the study&#xD;
&#xD;
          -  Patients with known medical disease (e.g. severe hypertension or hepatic disease).&#xD;
&#xD;
          -  Altered karyotype in one or both partners.&#xD;
&#xD;
          -  History of chronic, autoimmune or metabolic diseases&#xD;
&#xD;
          -  Presence of endocrinopathies.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>38 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mohamed M Shafeek, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Al-Azhar University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Al Azhar University Hospitals (Kasr Al-Aini)</name>
      <address>
        <city>Cairo</city>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>November 22, 2018</study_first_submitted>
  <study_first_submitted_qc>November 28, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 29, 2018</study_first_posted>
  <last_update_submitted>June 21, 2019</last_update_submitted>
  <last_update_submitted_qc>June 21, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 24, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>ClinAmygate</investigator_affiliation>
    <investigator_full_name>Emad Roushdy</investigator_full_name>
    <investigator_title>Director</investigator_title>
  </responsible_party>
  <keyword>Growth Hormone</keyword>
  <keyword>IVF/ICSI</keyword>
  <keyword>Poor Responders</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Infertility, Female</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cetrorelix</mesh_term>
    <mesh_term>Hormones</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03759301
org study id: NRC 0214
nct id: NCT03759301
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The objective of this study is to assess the effectiveness of adjuvant growth hormone
      injection during controlled ovarian stimulation, in poor responder women undergoing
      intracytoplasmic sperm injection (ICSI) procedures.
Infertility is defined as the failure to achieve a clinical pregnancy after 12 months or more
      of regular unprotected sexual intercourse (and there is no other reason, such as
      breastfeeding or postpartum amenorrhoea). Primary infertility is infertility in a couple who
      have never had a child. Secondary infertility is a failure to conceive following a previous
      pregnancy.

      Subfertility, usually defined as the absence of conception after one year of regular
      intercourse, subfertility is a common problem affecting as many as one in six couples.

      According to the European Society of Human Reproduction and Embryology (ESHRE)
      recommendations, couples with an estimated live birth rate of 40% or higher per year are
      encouraged to continue aiming for a spontaneous pregnancy .

      Treatment methods for infertility may be grouped as medical, complementary and alternative
      treatments. Some methods may be used in concert with other methods. Drugs may be used for
      both women and men.

      If conservative medical treatments fail to achieve a full term pregnancy, the physician may
      suggest the patient undergo assisted reproductive fertilization (ART). Methods for ART
      include artificial insemination (IUI), gamete intrafallopian transfer (GIFT), zygot
      intrafallopian transfer (ZIFT) or ICSI.

      Intracytoplasmic sperm injection (ICSI) is an in vitro fertilization procedure in which a
      single sperm is injected directly into an oocyte. During the past decade, ICSI has been
      applied increasingly around the world to alleviate problems of severe male infertility
      because too few motile and morphologically normal sperm were present in the ejaculate of the
      male partner.

      Although there have been several improvements in techniques of ART during the last three
      decades clinical pregnancy and live-birth rates remain at approximately 30-40%.

      Increasing these rates is desirable for couples undergoing ART, as treatment failure is a
      source of psychological distress, and the most common cause of drop-out before achieving
      pregnancy.The most common interventions to improve ART outcome are the use of maximized
      controlled ovarian stimulation (COS), transference of multiple embryos into the uterus and
      cryopreservation of surplus oocytes/embryos. However, the first two of these interventions
      might increase the risk of ovarian hyperstimulation syndrome and multiple pregnancy.

      In-vitro fertilization (IVF) protocols are constantly under review in an attempt to decrease
      hormone (gonadotrophin) requirement, improve follicular recruitment, whilst primarily to
      increase live birth rates.

      Implantation failure is thought to result from impairment of embryo development and/or from
      abnormal uterine receptivity.

      Some protocols have considered the role of growth hormone in IVF. Growth hormone is a
      biological peptide hormone, synthesized, stored and secreted by somatotroph cells located in
      the anterior pituitary gland. Growth hormone can be synthetically produced using recombinant
      DNA technology and is licensed to be used in the human population. There is currently no
      consensus as to the route, dose or timing of growth hormone administration in IVF protocols.

      Poor Ovarian Response (POR) is defined by the Bologna criteria, with an incidence between 9
      and 24% of all cycles of IVF, usually it indicates a reduction in follicular response,
      resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to
      define the poor response in IVF, at least two of the following three features must be
      present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and
      (iii) an abnormal ovarian reserve test (ORT). Two episodes of POR after maximal stimulation
      are sufficient to define a patient as poor responder in the absence of advanced maternal age
      or abnormal ORT. By definition, the term POR refers to the ovarian response, and therefore,
      one stimulated cycle is considered essential for the diagnosis of POR. However, patients of
      advanced age with an abnormal ORT may be classified as poor responders since both advanced
      age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of
      ovarian stimulation cycle outcome. In this case, the patients should be more properly defined
      as 'expected poor responder'. If this definition of POR is uniformly adapted as the 'minimal'
      criteria needed to select patients for future clinical trials, more homogeneous populations
      will be tested for any new protocols. Finally, by reducing bias caused by spurious POR
      definitions, it will be possible to compare results and to draw reliable conclusions.

      How the intervention might work? The administration of growth hormone may potentiate the
      effect of exogenous gonadotrophins. Growth hormone is reported to modulate the action of
      follicular stimulating hormone on granulosa cells by up-regulating the local synthesis of
      insulin-like growth factor-I (IGF-1). This interest has been stimulated by animal studies
      which suggest that growth hormone may increase the intra-ovarian production of the IGF-1.
      IGF-1 displays growth hormone dependence both in-vivo and in-vitro The interaction between
      growth hormone and IGF-1 is of significance since IGF-1 has been shown to play an important
      part in ovarian function in both animal and human models. The addition of IGF-1 to
      gonadotrophins in granulosa cell cultures increased gonadotrophin action on the ovary by
      several mechanisms including augmentation of aromatase activity, 17 beta-oestradiol and
      progesterone production and luteinising hormone receptor formation. IGF-1 has also been found
      to stimulate follicular development, oestrogen production and oocyte maturation.

      Improving the outcomes of ICSI by the use of growth hormone adjuvant therapy is important
      particularly in those women who are considered poor responders. The aim of this study is to
      establish the role of growth hormone in ICSI.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Outcomes Assessor)
measure: clinical pregnancy rate
time frame: 3 weeks
description: The main outcome is clinical pregnancy per allocated woman, defined as the presence of at least one fetus with heart beat.
measure: E2 levels
time frame: Day 1 of COS, the same day of Human Chorionic Gonadotropin (HCG) injection
description: Human Chorionic Gonadotropin (HCG) is given to induce triggering of ovulation then ovum pick up is scheduled 36 hour after the injection.
measure: Number of oocytes collected
time frame: Day 6 of COS
description: Transvaginal ultrasound will be done starting from day 6 of COS for assessment of follicular development and assessment of endometrial thickness, serial E2 measurement will be scheduled to start on day 6 of COS repeating every other day
measure: Metaphase I (MI) and Metaphase II (MII) oocyte number
time frame: Day 6 of COS
description: Transvaginal ultrasound will be done starting from day 6 of COS for assessment of follicular development and assessment of endometrial thickness, serial E2 measurement will be scheduled to start on day 6 of COS repeating every other day
measure: Number of Pronucleus
time frame: Day 6 of COS
description: Transvaginal ultrasound will be done starting from day 6 of COS for assessment of follicular development and assessment of endometrial thickness, serial E2 measurement will be scheduled to start on day 6 of COS repeating every other day
measure: Multiple pregnancy
time frame: 6 weeks from last period
description: Multiple pregnancy
arm group label: Growth Hormones Somatropin Recombinant
arm group type: Active Comparator
description: Growth hormone (Somatropin) 4 IU/day subcutaneous from the 2nd day of the cycle and stopped 1 day before ovum pickup for the treatment group which consists of 70 women.
arm group label: Placebo saline solution
arm group type: Placebo Comparator
description: Control group consisting of 70 women who will receive subcutaneous placebo injection in the same dosing as the treatment group
intervention type: Drug
intervention name: Growth Hormones Somatropin Recombinant
description: Growth Hormones Somatropin Recombinant 4 IU/day subcutaneous from the 2nd day of the cycle and stopped 1 day before ovum pickup
arm group label: Growth Hormones Somatropin Recombinant
other name: Cetrorelix
intervention type: Drug
intervention name: Placebo saline solution
description: same volume as growth hormone ampule used
arm group label: Placebo saline solution
other name: Cetrorelix
criteria: 
gender: Female
minimum age: 25 Years
maximum age: 38 Years
healthy volunteers: No
last name: Mohamed M Shafeek, MSc
role: Principal Investigator
affiliation: Al-Azhar University
facility: 
country: Egypt
responsible party type: Principal Investigator
investigator affiliation: ClinAmygate
investigator full name: Emad Roushdy
investigator title: Director
mesh term: Infertility
mesh term: Infertility, Female
mesh term: Cetrorelix
mesh term: Hormones
sharing ipd: Undecided