<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/NCT01662466</url>
  </required_header>
  <id_info>
    <org_study_id>072312-01</org_study_id>
    <secondary_id>CHR-DHEA-testosterone-2012</secondary_id>
    <nct_id>NCT01662466</nct_id>
  </id_info>
  <brief_title>Effect of Testosterone Treatment on Embryo Quality</brief_title>
  <official_title>A Randomized Double Blind Control Trial of Transdermal Testosterone Supplementation vs Placebo on Follicular Development and Atresia, Oocyte and Embryo Quality Among Women With Diminished Ovarian Reserve Undergoing in Vitro Fertilization</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Center for Human Reproduction</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Foundation for Reproductive Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Center for Human Reproduction</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the effect of treatment with trans-dermal&#xD;
      testosterone cream compared to placebo on measures of ovarian reserve, oocyte and embryo&#xD;
      quality, and pregnancy rates among women with evidence of diminished ovarian reserve that&#xD;
      have persistently low serum testosterone and free testosterone after completing six previous&#xD;
      weeks of DHEA supplementation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      At CHR the investigators have been using DHEA supplementation to improve ovarian response to&#xD;
      ovulation induction for in vitro fertilization for about five years (Barad, Brill et al.&#xD;
      2007; Barad, Weghofer et al .2009; Gleicher, Ryan et al. 2009; Gleicher, Weghofer et al.&#xD;
      2010; Gleicher and Barad 2011). Our views on the effect of androgens on the follicular&#xD;
      environment have recently been reviewed (Gleicher, Weghofer et al. 2011). A recent analysis&#xD;
      of androgen metabolites of DHEA in our patients suggested that women who successfully respond&#xD;
      to DHEA supplementation with increased egg production and clinical pregnancy had testosterone&#xD;
      above the normal median values for reproductive age women. There also appears to be a cohort&#xD;
      of women who did not respond to DHEA and who had very low serum testosterone. The&#xD;
      investigators decided to investigate if supplementing those women with testosterone to the&#xD;
      normal female range would improve ovarian function and possibly increase pregnancy rates.&#xD;
&#xD;
      Recruitment &amp; Experimental Plan&#xD;
&#xD;
        -  A baseline blood draw following completion of 6 weeks of DHEA supplementation will&#xD;
           determine eligibility for the study. The baseline blood determinations are part of the&#xD;
           standard pre cycle screening at CHR for all patients.&#xD;
&#xD;
        -  After signing informed consent subjects will be randomly assigned to either active&#xD;
           testosterone cream treatment or placebo.&#xD;
&#xD;
        -  Active treatment will consist of a testosterone delivery system that will deliver&#xD;
           transdermal testosterone cream(0.5 mg per gram of cream.) The cream and placebo cream&#xD;
           will be compounded by Metro Drugs (New York, NY) and dispensed in calibrated pump that&#xD;
           will deliver one gram of cream per stroke. Transdermal absorption is about 10% so 2&#xD;
           grams (1.0 mg) per day applied to the skin will deliver about 100 ug per day. In&#xD;
           preliminary analysis we have determined that a 2 gram dose of this preparation will&#xD;
           raise total testosterone to our target range of between 50 and 100 ng/dL.&#xD;
&#xD;
        -  The dose of testosterone cream will be 2 grams of cream per day applied to the left&#xD;
           inner forearm. The study medication will continue to be applied for 6 weeks.&#xD;
&#xD;
        -  All patients with evidence of diminished ovarian reserve in our practice are treated&#xD;
           with DHEA. Thus, patients in this study will be receiving DHEA + testosterone or DHEA +&#xD;
           Placebo. Patients who achieve a level of serum testosterone in the desired range using&#xD;
           DHEA alone will not be eligible for this study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>July 1, 2012</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">June 1, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical and Ongoing Pregnancy</measure>
    <time_frame>8 weeks post treatment initiation</time_frame>
    <description>Clinical pregnancy is defined as the presence of a viable gestational sac visible in the uterus 4 weeks after embryo transfer. Clinical ongoing pregnancy is defined as intrauterine pregnancy with evidence of an active fetal heart at 6 weeks after embryo transfer.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Measures of Atresia</measure>
    <time_frame>8 weeks after intervention initiation</time_frame>
    <description>Follicular fluid will be collected separately for the first 5 follicles aspirated that are at least 18mm diameter for each patient.&#xD;
Granulosa cell counts will be performed on each follicle fluid. Granulosa cell counts of &lt;10,000 per follicle will be considered atretic.&#xD;
Aliquots of follicular fluid will be analyzed for Testosterone, androstenedoine and estradiol using standard immuno assay. Healthy follicles should be capable of metabolizing testosterone to estradiol and should have a higher concentration estradiol (in nmol/ml) compared to testosterone</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oocytes number</measure>
    <time_frame>8 weeks after initiation of intervention</time_frame>
    <description>The number of oocytes retrieved at oocyte retrieval for in-vitro fertilization will be compared between the treatment group and placebo.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">180</enrollment>
  <condition>Primary Ovarian Insufficiency</condition>
  <condition>Female Infertility Due to Diminished Ovarian Reserve</condition>
  <arm_group>
    <arm_group_label>DHEA+Testosterone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>These patients will be administered the testosterone cream along with standard DHEA supplements</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DHEA+Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>These patients will receive the placebo cream along with her DHEA supplements. In other words, no testosterone will be administered.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Testosterone cream (0.5mg per gram)</intervention_name>
    <description>Testosterone cream 2 gms per day applied transdermally to the left wrist to deliver 1.mg daily dose with estimated absorption of 100 ug per day testosterone</description>
    <arm_group_label>DHEA+Testosterone</arm_group_label>
    <other_name>Testosterone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>DHEA</intervention_name>
    <description>DHEA 25mg tid</description>
    <arm_group_label>DHEA+Placebo</arm_group_label>
    <arm_group_label>DHEA+Testosterone</arm_group_label>
    <other_name>Dehydroepiandrosterone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Carrier cream without added testosterone in the identical type of pump</description>
    <arm_group_label>DHEA+Placebo</arm_group_label>
    <other_name>Carrier cream without added testosterone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Women with 38 to 44 years old planning to undergo ovulation induction for IVF who are&#xD;
             willing to sign an informed consent.&#xD;
&#xD;
          -  BMI &gt; 18 and &lt;= 30 kg/m^2&#xD;
&#xD;
          -  FSH &gt; 10 mIU/mL&#xD;
&#xD;
          -  AMH =&lt; 1.05 ng/mL&#xD;
&#xD;
          -  Using DHEA for treatment of DOR/POA.&#xD;
&#xD;
          -  Baseline Total Testosterone less than 30 ng per deciliter (1.0 nmol per liter) or&#xD;
             serum free testosterone concentrations of less than 3.5 pg per milliliter (12.1 pmol&#xD;
             per liter), which are below the median values for normal premenopausal women&#xD;
             (Endocrine Sciences, Calabasas Hills, Calif.).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of hormone dependent neoplasm&#xD;
&#xD;
          -  History of severe acne or hirsutism.&#xD;
&#xD;
          -  Hyperlipidemia.&#xD;
&#xD;
          -  Pre existing cardiac, renal or hepatic disease&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>38 Years</minimum_age>
    <maximum_age>44 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Norbert Gleicher, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Center for Human Reproduction</affiliation>
  </overall_official>
  <overall_official>
    <last_name>David H Barad, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Human Reproduction</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jolanta Tapper, MD MS</last_name>
    <phone>212 994-4400</phone>
    <phone_ext>4406</phone_ext>
    <email>jtapper@theCHR.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Center For Human Reproduction</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10021</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jolanta Tapper</last_name>
      <phone>212-994-4400</phone>
      <email>jtapper@theCHR.com</email>
    </contact>
    <investigator>
      <last_name>David H Barad, MD MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Norbert Gleicher, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Vitaly Kushnir, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Aritro Sen, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Department of Medicine; Division of Endocrinology and Metabolism, University of Rochester School of Medicine and Dentistry</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.centerforhumanreprod.com/</url>
    <description>Center For Human Reproduction Website</description>
  </link>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>August 2, 2012</study_first_submitted>
  <study_first_submitted_qc>August 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 10, 2012</study_first_posted>
  <last_update_submitted>November 9, 2020</last_update_submitted>
  <last_update_submitted_qc>November 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 12, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>testosterone</keyword>
  <keyword>DHEA</keyword>
  <keyword>IVF</keyword>
  <keyword>egg quality</keyword>
  <keyword>pregnancy rates</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>
    <mesh_term>Primary Ovarian Insufficiency</mesh_term>
    <mesh_term>Menopause, Premature</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methyltestosterone</mesh_term>
    <mesh_term>Testosterone</mesh_term>
    <mesh_term>Testosterone undecanoate</mesh_term>
    <mesh_term>Testosterone enanthate</mesh_term>
    <mesh_term>Testosterone 17 beta-cypionate</mesh_term>
    <mesh_term>Dehydroepiandrosterone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>We do not plan to share IPD</ipd_description>
  </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/NCT01662466
org study id: 072312-01
secondary id: CHR-DHEA-testosterone-2012
nct id: NCT01662466
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is to determine the effect of treatment with trans-dermal
      testosterone cream compared to placebo on measures of ovarian reserve, oocyte and embryo
      quality, and pregnancy rates among women with evidence of diminished ovarian reserve that
      have persistently low serum testosterone and free testosterone after completing six previous
      weeks of DHEA supplementation.
At CHR the investigators have been using DHEA supplementation to improve ovarian response to
      ovulation induction for in vitro fertilization for about five years (Barad, Brill et al.
      2007; Barad, Weghofer et al .2009; Gleicher, Ryan et al. 2009; Gleicher, Weghofer et al.
      2010; Gleicher and Barad 2011). Our views on the effect of androgens on the follicular
      environment have recently been reviewed (Gleicher, Weghofer et al. 2011). A recent analysis
      of androgen metabolites of DHEA in our patients suggested that women who successfully respond
      to DHEA supplementation with increased egg production and clinical pregnancy had testosterone
      above the normal median values for reproductive age women. There also appears to be a cohort
      of women who did not respond to DHEA and who had very low serum testosterone. The
      investigators decided to investigate if supplementing those women with testosterone to the
      normal female range would improve ovarian function and possibly increase pregnancy rates.

      Recruitment & Experimental Plan

        -  A baseline blood draw following completion of 6 weeks of DHEA supplementation will
           determine eligibility for the study. The baseline blood determinations are part of the
           standard pre cycle screening at CHR for all patients.

        -  After signing informed consent subjects will be randomly assigned to either active
           testosterone cream treatment or placebo.

        -  Active treatment will consist of a testosterone delivery system that will deliver
           transdermal testosterone cream(0.5 mg per gram of cream.) The cream and placebo cream
           will be compounded by Metro Drugs (New York, NY) and dispensed in calibrated pump that
           will deliver one gram of cream per stroke. Transdermal absorption is about 10% so 2
           grams (1.0 mg) per day applied to the skin will deliver about 100 ug per day. In
           preliminary analysis we have determined that a 2 gram dose of this preparation will
           raise total testosterone to our target range of between 50 and 100 ng/dL.

        -  The dose of testosterone cream will be 2 grams of cream per day applied to the left
           inner forearm. The study medication will continue to be applied for 6 weeks.

        -  All patients with evidence of diminished ovarian reserve in our practice are treated
           with DHEA. Thus, patients in this study will be receiving DHEA + testosterone or DHEA +
           Placebo. Patients who achieve a level of serum testosterone in the desired range using
           DHEA alone will not be eligible for this study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Clinical and Ongoing Pregnancy
time frame: 8 weeks post treatment initiation
description: Clinical pregnancy is defined as the presence of a viable gestational sac visible in the uterus 4 weeks after embryo transfer. Clinical ongoing pregnancy is defined as intrauterine pregnancy with evidence of an active fetal heart at 6 weeks after embryo transfer.
measure: Measures of Atresia
time frame: 8 weeks after intervention initiation
description: Follicular fluid will be collected separately for the first 5 follicles aspirated that are at least 18mm diameter for each patient.
Granulosa cell counts will be performed on each follicle fluid. Granulosa cell counts of <10,000 per follicle will be considered atretic.
Aliquots of follicular fluid will be analyzed for Testosterone, androstenedoine and estradiol using standard immuno assay. Healthy follicles should be capable of metabolizing testosterone to estradiol and should have a higher concentration estradiol (in nmol/ml) compared to testosterone
measure: Oocytes number
time frame: 8 weeks after initiation of intervention
description: The number of oocytes retrieved at oocyte retrieval for in-vitro fertilization will be compared between the treatment group and placebo.
arm group label: DHEA+Testosterone
arm group type: Active Comparator
description: These patients will be administered the testosterone cream along with standard DHEA supplements
arm group label: DHEA+Placebo
arm group type: Placebo Comparator
description: These patients will receive the placebo cream along with her DHEA supplements. In other words, no testosterone will be administered.
intervention type: Drug
intervention name: Testosterone cream (0.5mg per gram)
description: Testosterone cream 2 gms per day applied transdermally to the left wrist to deliver 1.mg daily dose with estimated absorption of 100 ug per day testosterone
arm group label: DHEA+Testosterone
other name: Testosterone
intervention type: Dietary Supplement
intervention name: DHEA
description: DHEA 25mg tid
arm group label: DHEA+Placebo
arm group label: DHEA+Testosterone
other name: Dehydroepiandrosterone
intervention type: Drug
intervention name: Placebo
description: Carrier cream without added testosterone in the identical type of pump
arm group label: DHEA+Placebo
other name: Carrier cream without added testosterone
criteria: 
gender: Female
minimum age: 38 Years
maximum age: 44 Years
healthy volunteers: No
last name: Norbert Gleicher, MD
role: Study Chair
affiliation: Center for Human Reproduction
last name: David H Barad, MD, MS
role: Principal Investigator
affiliation: Center for Human Reproduction
last name: Jolanta Tapper, MD MS
phone: 212 994-4400
phone ext: 4406
email: jtapper@theCHR.com
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Active, not recruiting
country: United States
url: http://www.centerforhumanreprod.com/
description: Center For Human Reproduction Website
responsible party type: Sponsor
mesh term: Infertility
mesh term: Infertility, Female
mesh term: Primary Ovarian Insufficiency
mesh term: Menopause, Premature
mesh term: Methyltestosterone
mesh term: Testosterone
mesh term: Testosterone undecanoate
mesh term: Testosterone enanthate
mesh term: Testosterone 17 beta-cypionate
mesh term: Dehydroepiandrosterone
sharing ipd: No
ipd description: We do not plan to share IPD