<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/NCT01686828</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00002641</org_study_id>
    <nct_id>NCT01686828</nct_id>
  </id_info>
  <brief_title>T-IR- Study to Understand the Effects of Testosterone and Estrogen on the Body's Response to the Hormone Insulin</brief_title>
  <acronym>T-IR</acronym>
  <official_title>Androgen-mediated Pathways in the Regulation of Insulin Sensitivity in Men</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Washington</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to understand the effects of testosterone and estrogen&#xD;
      on the body's response to the hormone insulin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators will examine the effects of testosterone on insulin sensitivity and body&#xD;
      composition in men. This study may lend greater insight into the increased risk of diabetes&#xD;
      evident in men with low circulating levels of testosterone. Three drugs will be used in this&#xD;
      study: acyline, given by injection; testosterone (T) gel that is applied to the skin; and&#xD;
      letrozole, which is an oral drug that blocks the conversion of androgens (male hormones) to&#xD;
      estrogens (female hormones). Acyline inhibits the production of luteinizing hormone (LH) and&#xD;
      follicle stimulating hormone (FSH). When acyline stops the production of these hormones, it&#xD;
      blocks the signal from the brain that stimulates the testicles to make testosterone. Adding&#xD;
      testosterone to acyline will restore physiologic levels of testosterone in some study&#xD;
      participants. One group of men will receive T gel with letrozole, an aromatase inhibitor;&#xD;
      these men will have normal levels of testosterone but low levels of estrogen in the blood.&#xD;
      This design will enable determination of the respective metabolic effects of testosterone and&#xD;
      estrogen.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 2013</start_date>
  <completion_date type="Actual">December 2017</completion_date>
  <primary_completion_date type="Actual">May 2015</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, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Insulin Sensitivity Quantified by Matsuda Index</measure>
    <time_frame>4 weeks</time_frame>
    <description>Whole body insulin sensitivity as quantified by Matsuda Index at the end of the treatment period, calculated by the following equation: 10,000/square root of(FPG*FI)*(FPG+PG30*2+PG60*2+PG90*2+PG120)/8*(FPI+PI30*2+PI60*2+PI90*2+PI)/8). FPG=fasting plasma glucose level; FPI=fasting plasma insulin level; PG30,60,90, and 120=plasma glucose levels sampled at 30,60,90, and 120 minutes after oral glucose load; PI30,60,90, and 120=plasma insulin levels sampled at 30,60,90, and 120 minutes after the oral glucose load</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in Body Composition</measure>
    <time_frame>4 weeks</time_frame>
    <description>Fat mass and lean mass were measured by dual energy X-ray absorptiometry (DEXA) at baseline and at the end of the 4 week treatment period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Adipose Tissue Gene Expression</measure>
    <time_frame>4 weeks</time_frame>
    <description>We examined whether differences in lipoprotein lipase expression would be evident across study treatment groups. RNA was isolated from whole adipose tissue gene expression, and complementary DNA (cDNA) was synthesized from 1.5 ug of RNA per sample. Gene expression was measured by polymerase chain reaction (PCR) using predesigned TaqMan® Gene Expression Assays. Standard curves were included on each plate, so Ct values were converted to copy numbers of the target gene. Expression values were normalized to the geometric mean of the housekeeping genes phosphoglycerate kinase and 18s.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">53</enrollment>
  <condition>Insulin Resistance</condition>
  <condition>Type 2 Diabetes Mellitus</condition>
  <condition>Obesity</condition>
  <condition>Androgen Deficiency</condition>
  <condition>Metabolic Disease</condition>
  <arm_group>
    <arm_group_label>Acyline &amp; placebo gel &amp; placebo pill</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acyline (300mcg/kg) + placebo transdermal gel + placebo pill daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Acyline &amp; Testosterone 1.25g &amp; placebo pill</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acyline (300mcg/kg) + Testosterone gel (1.25g) daily + placebo pill daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Acyline &amp; Testosterone 5g &amp; placebo pill</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acyline (300mcg/kg) + Testosterone gel (5g) daily + placebo pill daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Acyline &amp; Testosterone &amp; Letrozole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acyline (300mcg/kg) + Testosterone gel (5g) daily + letrozole (5mg) daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acyline</intervention_name>
    <description>300 mcg/mL administered subcutaneously (at Day 0, Week 2)</description>
    <arm_group_label>Acyline &amp; Testosterone &amp; Letrozole</arm_group_label>
    <arm_group_label>Acyline &amp; Testosterone 1.25g &amp; placebo pill</arm_group_label>
    <arm_group_label>Acyline &amp; Testosterone 5g &amp; placebo pill</arm_group_label>
    <arm_group_label>Acyline &amp; placebo gel &amp; placebo pill</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Testosterone 1.62% gel</intervention_name>
    <description>Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks</description>
    <arm_group_label>Acyline &amp; Testosterone &amp; Letrozole</arm_group_label>
    <arm_group_label>Acyline &amp; Testosterone 1.25g &amp; placebo pill</arm_group_label>
    <arm_group_label>Acyline &amp; Testosterone 5g &amp; placebo pill</arm_group_label>
    <other_name>Androgel</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Letrozole</intervention_name>
    <description>Letrozole oral aromatase inhibitor 5mg daily for 4 weeks</description>
    <arm_group_label>Acyline &amp; Testosterone &amp; Letrozole</arm_group_label>
    <other_name>Femara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo gel (for Testosterone 1.62% gel)</intervention_name>
    <description>placebo gel manufactured to mimic Testosterone 1.62% gel</description>
    <arm_group_label>Acyline &amp; placebo gel &amp; placebo pill</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo pill (for Letrozole)</intervention_name>
    <description>Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
    <arm_group_label>Acyline &amp; Testosterone 1.25g &amp; placebo pill</arm_group_label>
    <arm_group_label>Acyline &amp; Testosterone 5g &amp; placebo pill</arm_group_label>
    <arm_group_label>Acyline &amp; placebo gel &amp; placebo pill</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Prostate-specific antigen (PSA) ≤ 3 ng/mL&#xD;
&#xD;
          -  Age 25-55 years&#xD;
&#xD;
          -  Ability to understand the study, study procedures and provide informed consent&#xD;
&#xD;
          -  Serum total T &gt; 300 ng/dL&#xD;
&#xD;
          -  Normal reproductive history and exam&#xD;
&#xD;
          -  International Prostate Symptom Score (IPSS) &lt; 11&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A history of prostate cancer including suspicious digital rectal exam (DRE) or history&#xD;
             of highgrade prostatic intraepithelial neoplasia (PIN) on prostate biopsy&#xD;
&#xD;
          -  Invasive therapy for benign prostatic hyperplasia (BPH) in the past&#xD;
&#xD;
          -  History of acute urinary retention in the previous 3 months&#xD;
&#xD;
          -  Current or recent past use of androgenic or anti-androgenic drugs, steroids or drugs&#xD;
             which interfere with steroid metabolism (within the last 3 months)&#xD;
&#xD;
          -  Current use of statins or glucocorticoids&#xD;
&#xD;
          -  Severe systemic illness (renal, liver, cardiac, lung disease, cancer, diabetes&#xD;
             mellitus) or skin disease&#xD;
&#xD;
          -  A history of or current breast cancer&#xD;
&#xD;
          -  Known, untreated obstructive sleep apnea&#xD;
&#xD;
          -  Hematocrit &gt; 50 or &lt; 34&#xD;
&#xD;
          -  Hypersensitivity to any of the drugs used in the study&#xD;
&#xD;
          -  History of a bleeding disorder or anticoagulation&#xD;
&#xD;
          -  Participation in any other drug study within past 90 days&#xD;
&#xD;
          -  History of drug or alcohol abuse within the last 12 months&#xD;
&#xD;
          -  Weight &gt; 280 lbs. or BMI ≥ 33&#xD;
&#xD;
          -  Desire for fertility in the next 6 months or current pregnant partner&#xD;
&#xD;
          -  Sperm concentration &lt;14 million/ml&#xD;
&#xD;
          -  Significant, uncontrolled hypertension (BP &gt;160/100 mmHg); subjects with&#xD;
             well-controlled BP on medical therapy will be eligible to participate&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>William J Bremner, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Stephanie T Page, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Katya Rubinow, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Washington</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://depts.washington.edu/popctr/</url>
    <description>Dedicated to basic and clinical research focused primarily on the male reproductive system.</description>
  </link>
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    <citation>Belgorosky A, Guercio G, Pepe C, Saraco N, Rivarola MA. Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res. 2009;72(6):321-30. doi: 10.1159/000249159. Epub 2009 Oct 21.</citation>
    <PMID>19844120</PMID>
  </reference>
  <reference>
    <citation>Campbell KL, Makar KW, Kratz M, Foster-Schubert KE, McTiernan A, Ulrich CM. A pilot study of sampling subcutaneous adipose tissue to examine biomarkers of cancer risk. Cancer Prev Res (Phila). 2009 Jan;2(1):37-42. doi: 10.1158/1940-6207.CAPR-08-0073.</citation>
    <PMID>19139016</PMID>
  </reference>
  <reference>
    <citation>Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E15-26. doi: 10.1152/ajpendo.00645.2007. Epub 2007 Oct 23.</citation>
    <PMID>17957034</PMID>
  </reference>
  <reference>
    <citation>Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219-46. doi: 10.1146/annurev-physiol-021909-135846.</citation>
    <PMID>20148674</PMID>
  </reference>
  <verification_date>April 2018</verification_date>
  <study_first_submitted>September 12, 2012</study_first_submitted>
  <study_first_submitted_qc>September 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2012</study_first_posted>
  <results_first_submitted>February 16, 2017</results_first_submitted>
  <results_first_submitted_qc>May 15, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">June 14, 2017</results_first_posted>
  <last_update_submitted>April 5, 2018</last_update_submitted>
  <last_update_submitted_qc>April 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 8, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Washington</investigator_affiliation>
    <investigator_full_name>Katya Rubinow</investigator_full_name>
    <investigator_title>Assistant Professor, Division of Metabolism, Endocrinology and Nutrition</investigator_title>
  </responsible_party>
  <keyword>insulin</keyword>
  <keyword>androgens</keyword>
  <keyword>insulin resistance</keyword>
  <keyword>testosterone</keyword>
  <keyword>estradiol</keyword>
  <keyword>obesity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Metabolic Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Letrozole</mesh_term>
    <mesh_term>Methyltestosterone</mesh_term>
    <mesh_term>Acyline</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>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment period: 06/01/13-11/30/2014 Location: University/Medical Center Flyers, newspaper ads, online postings</recruitment_details>
      <pre_assignment_details>116 subjects were screened, 63 subjects didn't meet study inclusion/exclusion criteria or they withdrew consent prior to group assignment, and 3 subjects withdrew prior to the baseline visit.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Acyline &amp; Placebo Gel &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + placebo transdermal gel + placebo aromatase inhibitor daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Placebo gel (for Testosterone 1.62% gel): placebo gel manufactured to mimic Testosterone 1.62% gel&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="P2">
          <title>Acyline &amp; Testosterone Gel 1.25g/d &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone 1.62% gel (1.25g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="P3">
          <title>Acyline &amp; Testosterone Gel 5g/d &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg every 2 weeks, by injections) + Testosterone 1.62% gel (5g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="P4">
          <title>Acyline &amp; Testosterone Gel &amp; Letrozole</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone transdermal 1.62% gel (5g) daily + letrozole (5mg) aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Letrozole: Letrozole oral aromatase inhibitor 5mg daily for 4 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="14"/>
                <participants group_id="P3" count="13"/>
                <participants group_id="P4" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="13"/>
                <participants group_id="P3" count="12"/>
                <participants group_id="P4" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>New Job</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Weight Loss</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Acyline &amp; Placebo Gel &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + placebo transdermal gel + placebo aromatase inhibitor daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Placebo gel (for Testosterone 1.62% gel): placebo gel manufactured to mimic Testosterone 1.62% gel&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="B2">
          <title>Acyline &amp; Testosterone Gel 1.25g/d &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone 1.62% gel (1.25g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="B3">
          <title>Acyline &amp; Testosterone Gel 5g/d &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg every 2 weeks, by injections) + Testosterone 1.62% gel (5g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="B4">
          <title>Acyline &amp; Testosterone Gel &amp; Letrozole</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone transdermal 1.62% gel (5g) daily + letrozole (5mg) aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Letrozole: Letrozole oral aromatase inhibitor 5mg daily for 4 weeks</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="13"/>
            <count group_id="B2" value="14"/>
            <count group_id="B3" value="13"/>
            <count group_id="B4" value="13"/>
            <count group_id="B5" value="53"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="37" lower_limit="27" upper_limit="51"/>
                    <measurement group_id="B2" value="35" lower_limit="27" upper_limit="45"/>
                    <measurement group_id="B3" value="42" lower_limit="31" upper_limit="51"/>
                    <measurement group_id="B4" value="34" lower_limit="28" upper_limit="45"/>
                    <measurement group_id="B5" value="36" lower_limit="29" upper_limit="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="13"/>
                    <measurement group_id="B5" value="53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="13"/>
                    <measurement group_id="B5" value="44"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="11"/>
                    <measurement group_id="B5" value="37"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="13"/>
                    <measurement group_id="B5" value="53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index (BMI)</title>
          <units>kg/m2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26" spread="4"/>
                    <measurement group_id="B2" value="26" spread="4"/>
                    <measurement group_id="B3" value="25" spread="2"/>
                    <measurement group_id="B4" value="25" spread="4"/>
                    <measurement group_id="B5" value="25" spread="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="82" spread="14"/>
                    <measurement group_id="B2" value="81" spread="15"/>
                    <measurement group_id="B3" value="78" spread="8"/>
                    <measurement group_id="B4" value="82" spread="11"/>
                    <measurement group_id="B5" value="81" spread="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Fasting Glucose</title>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="97" spread="6"/>
                    <measurement group_id="B2" value="97" spread="13"/>
                    <measurement group_id="B3" value="101" spread="7"/>
                    <measurement group_id="B4" value="98" spread="9"/>
                    <measurement group_id="B5" value="98" spread="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Percentage Body Fat</title>
          <units>%total body mass</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28" spread="7"/>
                    <measurement group_id="B2" value="23" spread="6"/>
                    <measurement group_id="B3" value="24" spread="4"/>
                    <measurement group_id="B4" value="23" spread="7"/>
                    <measurement group_id="B5" value="24" spread="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Percentage Lean Mass</title>
          <units>%total body mass</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68" spread="7"/>
                    <measurement group_id="B2" value="73" spread="5"/>
                    <measurement group_id="B3" value="72" spread="4"/>
                    <measurement group_id="B4" value="73" spread="7"/>
                    <measurement group_id="B5" value="72" spread="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Insulin Sensitivity Quantified by Matsuda Index</title>
        <description>Whole body insulin sensitivity as quantified by Matsuda Index at the end of the treatment period, calculated by the following equation: 10,000/square root of(FPG*FI)*(FPG+PG30*2+PG60*2+PG90*2+PG120)/8*(FPI+PI30*2+PI60*2+PI90*2+PI)/8). FPG=fasting plasma glucose level; FPI=fasting plasma insulin level; PG30,60,90, and 120=plasma glucose levels sampled at 30,60,90, and 120 minutes after oral glucose load; PI30,60,90, and 120=plasma insulin levels sampled at 30,60,90, and 120 minutes after the oral glucose load</description>
        <time_frame>4 weeks</time_frame>
        <population>Of the 53 subjects who attended the baseline study visit, 2 withdrew from the study and 1 was discontinued due to a protocol violation. 50 subjects completed the week 10 study visit. Of these, 5 subjects were excluded from the final analyses; 1 was found to have undiagnosed diabetes, and 4 subjects were excluded due to study drug non-adherence.</population>
        <group_list>
          <group group_id="O1">
            <title>Acyline &amp; Placebo Gel &amp; Placebo Pill</title>
            <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + placebo transdermal gel + placebo aromatase inhibitor daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Placebo gel (for Testosterone 1.62% gel): placebo gel manufactured to mimic Testosterone 1.62% gel&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
          </group>
          <group group_id="O2">
            <title>Acyline &amp; Testosterone Gel 1.25g/d &amp; Placebo Pill</title>
            <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone 1.62% gel (1.25g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
          </group>
          <group group_id="O3">
            <title>Acyline &amp; Testosterone Gel 5g/d &amp; Placebo Pill</title>
            <description>Acyline (300mcg/kg every 2 weeks, by injections) + Testosterone 1.62% gel (5g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
          </group>
          <group group_id="O4">
            <title>Acyline &amp; Testosterone Gel &amp; Letrozole</title>
            <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone transdermal 1.62% gel (5g) daily + letrozole (5mg) aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Letrozole: Letrozole oral aromatase inhibitor 5mg daily for 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Insulin Sensitivity Quantified by Matsuda Index</title>
          <description>Whole body insulin sensitivity as quantified by Matsuda Index at the end of the treatment period, calculated by the following equation: 10,000/square root of(FPG*FI)*(FPG+PG30*2+PG60*2+PG90*2+PG120)/8*(FPI+PI30*2+PI60*2+PI90*2+PI)/8). FPG=fasting plasma glucose level; FPI=fasting plasma insulin level; PG30,60,90, and 120=plasma glucose levels sampled at 30,60,90, and 120 minutes after oral glucose load; PI30,60,90, and 120=plasma insulin levels sampled at 30,60,90, and 120 minutes after the oral glucose load</description>
          <population>Of the 53 subjects who attended the baseline study visit, 2 withdrew from the study and 1 was discontinued due to a protocol violation. 50 subjects completed the week 10 study visit. Of these, 5 subjects were excluded from the final analyses; 1 was found to have undiagnosed diabetes, and 4 subjects were excluded due to study drug non-adherence.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="11"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.0" lower_limit="3.9" upper_limit="6.3"/>
                    <measurement group_id="O2" value="9.4" lower_limit="4.5" upper_limit="14.0"/>
                    <measurement group_id="O3" value="7.2" lower_limit="4.6" upper_limit="15.0"/>
                    <measurement group_id="O4" value="7.3" lower_limit="5.9" upper_limit="10.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.164</p_value>
            <p_value_desc>The a prior threshold for statistical significance was p&lt;0.05.</p_value_desc>
            <method>RM-ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Body Composition</title>
        <description>Fat mass and lean mass were measured by dual energy X-ray absorptiometry (DEXA) at baseline and at the end of the 4 week treatment period</description>
        <time_frame>4 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Acyline &amp; Placebo Gel &amp; Placebo Pill</title>
            <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + placebo transdermal gel + placebo aromatase inhibitor daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Placebo gel (for Testosterone 1.62% gel): placebo gel manufactured to mimic Testosterone 1.62% gel&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
          </group>
          <group group_id="O2">
            <title>Acyline &amp; Testosterone Gel 1.25g/d &amp; Placebo Pill</title>
            <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone 1.62% gel (1.25g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
          </group>
          <group group_id="O3">
            <title>Acyline &amp; Testosterone Gel 5g/d &amp; Placebo Pill</title>
            <description>Acyline (300mcg/kg every 2 weeks, by injections) + Testosterone 1.62% gel (5g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
          </group>
          <group group_id="O4">
            <title>Acyline &amp; Testosterone Gel &amp; Letrozole</title>
            <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone transdermal 1.62% gel (5g) daily + letrozole (5mg) aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Letrozole: Letrozole oral aromatase inhibitor 5mg daily for 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Body Composition</title>
          <description>Fat mass and lean mass were measured by dual energy X-ray absorptiometry (DEXA) at baseline and at the end of the 4 week treatment period</description>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="11"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Change in fat mass</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.1" spread="0.8"/>
                    <measurement group_id="O2" value="0.7" spread="0.5"/>
                    <measurement group_id="O3" value="-0.4" spread="1.0"/>
                    <measurement group_id="O4" value="0.5" spread="0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in lean mass</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.2" spread="1.0"/>
                    <measurement group_id="O2" value="-1.4" spread="1.5"/>
                    <measurement group_id="O3" value="0.0" spread="1.0"/>
                    <measurement group_id="O4" value="-0.3" spread="1.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Time-by-group interaction for fat mass</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.003</p_value>
            <method>RM-ANOVA</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.03</p_value>
            <p_value_desc>Time-by-group interaction for lean mass</p_value_desc>
            <method>RM-ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Adipose Tissue Gene Expression</title>
        <description>We examined whether differences in lipoprotein lipase expression would be evident across study treatment groups. RNA was isolated from whole adipose tissue gene expression, and complementary DNA (cDNA) was synthesized from 1.5 ug of RNA per sample. Gene expression was measured by polymerase chain reaction (PCR) using predesigned TaqMan® Gene Expression Assays. Standard curves were included on each plate, so Ct values were converted to copy numbers of the target gene. Expression values were normalized to the geometric mean of the housekeeping genes phosphoglycerate kinase and 18s.</description>
        <time_frame>4 weeks</time_frame>
        <population>Subjects were included who had adipose tissue samples available from both baseline and week 4 (end-of-treatment) visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Acyline + Placebo Gel + Placebo Pills</title>
            <description>Acyline (300 mg/kg, subcutaneous injection at weeks 0, 2) + placebo gel + oral placebo pills daily. This treatment regimen resulted in medical castration.</description>
          </group>
          <group group_id="O2">
            <title>Acyline + Testosterone Gel (1.25g/d) + Placebo Pills</title>
            <description>Acyline (300 mcg/kg, subcutaneous injection at weeks 0, 2) + testosterone gel administered daily + daily placebo pills. This group was intended to have low-normal levels of serum testosterone and estradiol.</description>
          </group>
          <group group_id="O3">
            <title>Acyline + Testosterone Gel (5g/d) + Placebo Pills</title>
            <description>Acyline (300 mcg/kg, subcutaneous injection at weeks 0, 2) + testosterone gel administered daily + daily placebo pills. This group was intended to have normal, physiologic levels of serum testosterone and estradiol.</description>
          </group>
          <group group_id="O4">
            <title>Acyline + Testosterone Gel (5g/d) + Letrozole</title>
            <description>Acyline (300 mcg/kg, subcutaneous injection at weeks 0, 2) + testosterone gel administered daily + daily letrozole (pills). This group was intended to have normal levels of serum testosterone with selective estrogen deficiency.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Adipose Tissue Gene Expression</title>
          <description>We examined whether differences in lipoprotein lipase expression would be evident across study treatment groups. RNA was isolated from whole adipose tissue gene expression, and complementary DNA (cDNA) was synthesized from 1.5 ug of RNA per sample. Gene expression was measured by polymerase chain reaction (PCR) using predesigned TaqMan® Gene Expression Assays. Standard curves were included on each plate, so Ct values were converted to copy numbers of the target gene. Expression values were normalized to the geometric mean of the housekeeping genes phosphoglycerate kinase and 18s.</description>
          <population>Subjects were included who had adipose tissue samples available from both baseline and week 4 (end-of-treatment) visits.</population>
          <units>gene copy number per ng RNA</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="11"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7493" spread="1293"/>
                    <measurement group_id="O2" value="8224" spread="3485"/>
                    <measurement group_id="O3" value="7885" spread="2736"/>
                    <measurement group_id="O4" value="8320" spread="3133"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis was that short-term testosterone deprivation would not affect lipoprotein lipase expression in adipose tissue. Repeated measures ANOVA was used to determine if a time-by-group effect was apparent for lipoprotein lipase expression.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&gt;0.1</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were recorded through study completion, and subjects who experienced adverse events during the study were followed for up to 6 months after study participation ended.</time_frame>
      <desc>There were numerous, mild complications reported for the fat biopsy procedure such as bleeding, bruising, hematomas, tenderness, redness etc which are not listed. A frequency threshold of &gt;15% was used for reported events.</desc>
      <group_list>
        <group group_id="E1">
          <title>Acyline &amp; Placebo Gel &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + placebo transdermal gel + placebo aromatase inhibitor daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Placebo gel (for Testosterone 1.62% gel): placebo gel manufactured to mimic Testosterone 1.62% gel&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="E2">
          <title>Acyline &amp; Testosterone Gel 1.25g/d &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone 1.62% gel (1.25g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="E3">
          <title>Acyline &amp; Testosterone Gel 5g/d &amp; Placebo Pill</title>
          <description>Acyline (300mcg/kg every 2 weeks, by injections) + Testosterone 1.62% gel (5g) daily + placebo aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d</description>
        </group>
        <group group_id="E4">
          <title>Acyline &amp; Testosterone Gel &amp; Letrozole</title>
          <description>Acyline (300mcg/kg at Day 0 &amp; week 2, by injections) + Testosterone transdermal 1.62% gel (5g) daily + letrozole (5mg) aromatase inhibitor pill daily for 4 weeks&#xD;
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)&#xD;
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks&#xD;
Letrozole: Letrozole oral aromatase inhibitor 5mg daily for 4 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac Arrthymia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Elevated PSA level</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Abnormal Liver enzyme (AST &amp; ALT) levels</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="14"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="10" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hot Flashes</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Low libido</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" events="5" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Decreased testes size</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Low Energy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="14"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="13"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Erectile Dysfunction</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Katya Rubinow</name_or_title>
      <organization>University of Washington</organization>
      <phone>206-7543-3470</phone>
      <email>rubinow@uw.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01686828
org study id: STUDY00002641
nct id: NCT01686828
lead sponsor: 
has dmc: Yes
The purpose of this research study is to understand the effects of testosterone and estrogen
      on the body's response to the hormone insulin.
The investigators will examine the effects of testosterone on insulin sensitivity and body
      composition in men. This study may lend greater insight into the increased risk of diabetes
      evident in men with low circulating levels of testosterone. Three drugs will be used in this
      study: acyline, given by injection; testosterone (T) gel that is applied to the skin; and
      letrozole, which is an oral drug that blocks the conversion of androgens (male hormones) to
      estrogens (female hormones). Acyline inhibits the production of luteinizing hormone (LH) and
      follicle stimulating hormone (FSH). When acyline stops the production of these hormones, it
      blocks the signal from the brain that stimulates the testicles to make testosterone. Adding
      testosterone to acyline will restore physiologic levels of testosterone in some study
      participants. One group of men will receive T gel with letrozole, an aromatase inhibitor;
      these men will have normal levels of testosterone but low levels of estrogen in the blood.
      This design will enable determination of the respective metabolic effects of testosterone and
      estrogen.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Insulin Sensitivity Quantified by Matsuda Index
time frame: 4 weeks
description: Whole body insulin sensitivity as quantified by Matsuda Index at the end of the treatment period, calculated by the following equation: 10,000/square root of(FPG*FI)*(FPG+PG30*2+PG60*2+PG90*2+PG120)/8*(FPI+PI30*2+PI60*2+PI90*2+PI)/8). FPG=fasting plasma glucose level; FPI=fasting plasma insulin level; PG30,60,90, and 120=plasma glucose levels sampled at 30,60,90, and 120 minutes after oral glucose load; PI30,60,90, and 120=plasma insulin levels sampled at 30,60,90, and 120 minutes after the oral glucose load
measure: Changes in Body Composition
time frame: 4 weeks
description: Fat mass and lean mass were measured by dual energy X-ray absorptiometry (DEXA) at baseline and at the end of the 4 week treatment period
measure: Changes in Adipose Tissue Gene Expression
time frame: 4 weeks
description: We examined whether differences in lipoprotein lipase expression would be evident across study treatment groups. RNA was isolated from whole adipose tissue gene expression, and complementary DNA (cDNA) was synthesized from 1.5 ug of RNA per sample. Gene expression was measured by polymerase chain reaction (PCR) using predesigned TaqMan® Gene Expression Assays. Standard curves were included on each plate, so Ct values were converted to copy numbers of the target gene. Expression values were normalized to the geometric mean of the housekeeping genes phosphoglycerate kinase and 18s.
arm group label: Acyline & placebo gel & placebo pill
arm group type: Experimental
description: Acyline (300mcg/kg) + placebo transdermal gel + placebo pill daily
arm group label: Acyline & Testosterone 1.25g & placebo pill
arm group type: Experimental
description: Acyline (300mcg/kg) + Testosterone gel (1.25g) daily + placebo pill daily
arm group label: Acyline & Testosterone 5g & placebo pill
arm group type: Experimental
description: Acyline (300mcg/kg) + Testosterone gel (5g) daily + placebo pill daily
arm group label: Acyline & Testosterone & Letrozole
arm group type: Experimental
description: Acyline (300mcg/kg) + Testosterone gel (5g) daily + letrozole (5mg) daily
intervention type: Drug
intervention name: Acyline
description: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)
arm group label: Acyline & Testosterone & Letrozole
arm group label: Acyline & Testosterone 1.25g & placebo pill
arm group label: Acyline & Testosterone 5g & placebo pill
arm group label: Acyline & placebo gel & placebo pill
intervention type: Drug
intervention name: Testosterone 1.62% gel
description: Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks
arm group label: Acyline & Testosterone & Letrozole
arm group label: Acyline & Testosterone 1.25g & placebo pill
arm group label: Acyline & Testosterone 5g & placebo pill
other name: Androgel
intervention type: Drug
intervention name: Letrozole
description: Letrozole oral aromatase inhibitor 5mg daily for 4 weeks
arm group label: Acyline & Testosterone & Letrozole
other name: Femara
intervention type: Drug
intervention name: Placebo gel (for Testosterone 1.62% gel)
description: placebo gel manufactured to mimic Testosterone 1.62% gel
arm group label: Acyline & placebo gel & placebo pill
intervention type: Drug
intervention name: Placebo pill (for Letrozole)
description: Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d
arm group label: Acyline & Testosterone 1.25g & placebo pill
arm group label: Acyline & Testosterone 5g & placebo pill
arm group label: Acyline & placebo gel & placebo pill
criteria: 
gender: Male
minimum age: 25 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: William J Bremner, MD, PhD
role: Study Chair
affiliation: University of Washington
last name: Stephanie T Page, MD, PhD
role: Study Director
affiliation: University of Washington
last name: Katya Rubinow, MD
role: Principal Investigator
affiliation: University of Washington
facility: 
country: United States
url: http://depts.washington.edu/popctr/
description: Dedicated to basic and clinical research focused primarily on the male reproductive system.
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responsible party type: Principal Investigator
investigator affiliation: University of Washington
investigator full name: Katya Rubinow
investigator title: Assistant Professor, Division of Metabolism, Endocrinology and Nutrition
mesh term: Diabetes Mellitus, Type 2
mesh term: Insulin Resistance
mesh term: Metabolic Diseases
mesh term: Letrozole
mesh term: Methyltestosterone
mesh term: Acyline
mesh term: Testosterone
mesh term: Testosterone undecanoate
mesh term: Testosterone enanthate
mesh term: Testosterone 17 beta-cypionate
sharing ipd: Undecided
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 