<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/NCT03229408</url>
  </required_header>
  <id_info>
    <org_study_id>2017-0476</org_study_id>
    <secondary_id>R01DK107605-01</secondary_id>
    <nct_id>NCT03229408</nct_id>
  </id_info>
  <brief_title>Treating Inflammation in Polycystic Ovary Syndrome to Ameliorate Ovarian Dysfunction</brief_title>
  <acronym>TIN-PCOS-AOD</acronym>
  <official_title>Treating Inflammation in Polycystic Ovary Syndrome to Ameliorate Ovarian Dysfunction</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Illinois at Chicago</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Illinois at Chicago</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, ovulatory dysfunction&#xD;
      and polycystic ovaries. Insulin resistance (IR) is a common feature of PCOS, and the&#xD;
      resultant hyperinsulinemia is theorized to promote hyperandrogenism in the disorder. However,&#xD;
      30-50% of women with PCOS who are lean do not have insulin resistance. Women with PCOS also&#xD;
      exhibit chronic low-grade inflammation. In PCOS, glucose ingestion activates nuclear factor&#xD;
      ĸB (NFĸB), the cardinal signal of inflammation culminating in upregulation of the&#xD;
      inflammation pathway within mononuclear cells (MNC). This phenomenon is independent of excess&#xD;
      adiposity and is highly correlated with circulating androgens. In addition, in vitro exposure&#xD;
      to proinflammatory stimuli is capable of directly stimulating ovarian theca cell androgen&#xD;
      production. Nonacetylated salicylates suppress NFĸB activation and are well tolerated in&#xD;
      humans.&#xD;
&#xD;
      The proposed research is a randomized double-blind placebo-controlled study of 90 women with&#xD;
      PCOS. Forty-five subjects with PCOS (15 lean without IR), 15 lean with IR and 15 obese)&#xD;
      receiving salsalate, a nonacetylated salicylate, at an oral dose of 3-4 gm daily for 12 weeks&#xD;
      will be compared with 45 age- and body-composition-matched control women with PCOS receiving&#xD;
      placebo. The overarching hypothesis is that inflammation contributes to ovarian dysfunction,&#xD;
      independent of excess adiposity or IR.&#xD;
&#xD;
      The specific aims are, I: To examine the effect of salsalate administration on the ovarian&#xD;
      capacity to secrete androgen and on insulin sensitivity in PCOS. II: To examine the effect of&#xD;
      salsalate administration on the inflammatory response of mononuclear cells induced by lipid&#xD;
      ingestion and glucose infusion in PCOS. The approach involves evaluation of ovarian androgen&#xD;
      secretion in response to human chorionic gonadotropin (HCG) administration and insulin&#xD;
      sensitivity during the euglycemic phase of a two-step pancreatic clamp along with ovulation&#xD;
      monitoring before and after salsalate administration. The inflammatory response of MNC to&#xD;
      lipid ingestion and the hyperglycemic phase of the two-step clamp will also be evaluated&#xD;
      during treatment by measuring reactive oxygen species, the mRNA and protein content of&#xD;
      inflammation markers, NFĸB activation and cytokine release in culture.&#xD;
&#xD;
      The investigators expect that women with PCOS receiving salsalate will exhibit decreased&#xD;
      ovarian androgen secretion and reduced inflammation regardless of adiposity or IR status.&#xD;
      These results will be significant if they show a causal contribution of inflammation to&#xD;
      ovarian dysfunction in PCOS, thus improving our understanding of the pathogenesis of PCOS,&#xD;
      opening previously unexplored therapeutic avenues that are not necessarily dependent on&#xD;
      improving IR, and guiding the design of future studies aimed at determining what&#xD;
      interventions will optimally attenuate inflammation in PCOS to reduce medical disease and&#xD;
      enhance fertility.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PCOS is characterized by hyperandrogenism, ovarian dysfunction and polycystic ovarian&#xD;
      morphology. Obesity and IR are common features of PCOS. Under the current model of&#xD;
      pathophysiology of PCOS, the compensatory hyperinsulinemia of IR is the primary driver of&#xD;
      hyperandrogenism. This concept was born from the cross-sectional observation that insulin is&#xD;
      positively correlated with androgens in obese women with PCOS, and is supported by reports of&#xD;
      increased androgen production from theca cells obtained from obese women with PCOS following&#xD;
      insulin exposure in vitro4 and increases in circulating androgens in women with PCOS&#xD;
      following insulin infusion in vivo. However, these in vitro - in vivo responses were elicited&#xD;
      with supraphysiological insulin concentrations. Physiological insulin infusion on the other&#xD;
      hand does not augment androgen levels in PCOS. The current model also does not explain the&#xD;
      cause of hyperandrogenism and ovarian dysfunction in the 30-50% of women with PCOS who are&#xD;
      lean and lack IR. Thus, some other factor contributes to these abnormalities in PCOS.&#xD;
&#xD;
      The investigators have shown that ingestion of glucose and saturated fat elicits an&#xD;
      inflammatory response from circulating MNC in lean women with PCOS who lack excess abdominal&#xD;
      adiposity. The hallmark of this response is increased activation of NFĸB, the cardinal signal&#xD;
      of inflammation. These findings illustrate the separate and discrete role of MNC in&#xD;
      manifesting inflammation in PCOS and that MNC are an excellent model to assess systemic&#xD;
      inflammation in PCOS.&#xD;
&#xD;
      The investigators have also shown that in PCOS, there is a link between molecular markers of&#xD;
      inflammation from MNC and circulating androgens. Chronic suppression of ovarian androgen&#xD;
      production does not ameliorate inflammation in lean women with PCOS. However, in vitro&#xD;
      exposure of ovarian theca cells to proinflammatory stimuli upregulates CYP17, the androgen&#xD;
      producing enzyme and increases testosterone.&#xD;
&#xD;
      Salsalate is an inexpensive, safe, well-tolerated, well-understood anti-inflammatory agent&#xD;
      that inhibits NFĸB activation when used at higher doses. The salsalate dose required to&#xD;
      achieve a salicylate level in the upper therapeutic range is dependent on body mass. This is&#xD;
      achieved in lean individuals using 3.0 gm/day as the maximum dose recommended in the&#xD;
      salsalate package insert. Individuals across the obese range (30-40 kg/m2) require &gt;3.0&#xD;
      gm/day to achieve the same objective. Salsalate and other salicylates have also been shown to&#xD;
      decrease IR. However, the ability of salsalate to decrease IR would not be necessary if the&#xD;
      beneficial anti-inflammatory effect of salsalate to reduce hyperandrogenism is on the&#xD;
      ovaries. In fact, we have shown that in lean insulin-sensitive women with PCOS, salsalate&#xD;
      reduces HCG-stimulated ovarian androgen secretion by 44% and normalizes basal testosterone&#xD;
      levels. Studies performed by the investigators in MNC also confirm the ability of salsalate&#xD;
      to suppress NFĸB activation. Together these observations validate the use of these&#xD;
      measurements as endpoints to assess the effects of salsalate to probe the pathophysiology of&#xD;
      PCOS.&#xD;
&#xD;
      Salsalate raises circulating insulin due to its ability to decreased insulin clearance from&#xD;
      the liver which confounds the assessment of insulin sensitivity from post-treatment&#xD;
      hyperinsulinemic-euglycemic clamp studies. Performance of a novel minimal model-based&#xD;
      analysis from an insulin-modified frequently-sampled intravenous glucose tolerance test&#xD;
      (FS-IVGTT) is able to address this confounding factor. With this approach, hepatic and&#xD;
      extrahepatic insulin clearance can be estimated before and after salsalate treatment to&#xD;
      obtain measures of insulin sensitivity that take into account the salsalate-induced&#xD;
      alteration in insulin clearance.&#xD;
&#xD;
      In this context, the rationale for the proposed study revolves around the concept that in&#xD;
      PCOS, inflammation contributes to ovarian dysfunction independent of excess adiposity or IR,&#xD;
      and may also improve insulin sensitivity when IR is present. The investigators will undertake&#xD;
      a 12-week randomized, double-blind, placebo-controlled trial to test the link between&#xD;
      inflammation and ovarian androgen secretion in PCOS unrelated to IR. If this study of&#xD;
      pathophysiology demonstrates beneficial effects, this will pave the way for developing novel&#xD;
      therapies for ovarian dysfunction in PCOS.&#xD;
&#xD;
      The main objective of this proposal is to evaluate the ability of salsalate to reduce ovarian&#xD;
      androgen secretion, induce ovulation and decrease lipid-stimulated inflammation independent&#xD;
      of body composition and IR in women with PCOS; and to also improve insulin sensitivity in IR&#xD;
      women with PCOS. Effects of salsalate will be assessed based on the following aims:&#xD;
&#xD;
      Specific Aim 1. To examine the effects of salsalate administration on the ovarian capacity to&#xD;
      secrete androgens, menstrual function, and insulin sensitivity in PCOS.&#xD;
&#xD;
      The hypothesis for this aim is that salsalate treatment will decrease HCG-stimulated ovarian&#xD;
      androgen secretion and induce ovulation in women with PCOS regardless of body composition or&#xD;
      IR status; and may also improve insulin sensitivity in IR women with PCOS. The investigators&#xD;
      will test this hypothesis in a randomized double-blind placebo-controlled study. The ovarian&#xD;
      androgen response to HCG administration will be evaluated in women with PCOS (15 lean with&#xD;
      IR, 15 lean without IR and 15 obese) before and after administration of a therapeutic&#xD;
      salsalate dose for ~12 weeks compared with women with PCOS receiving placebo for ~12 weeks&#xD;
      (15 lean with IR, 15 lean without IR and 15 obese). Ovulation monitoring and assessment of&#xD;
      insulin sensitivity during FS-IVGTT will be performed before and after salsalate or placebo&#xD;
      administration. It is anticipated that salsalate will reduce HCG-stimulated ovarian androgen&#xD;
      secretion, induce ovulation regardless of body composition or IR status when compared with&#xD;
      placebo. It is also anticipated that salsalate will increase insulin sensitivity in IR women&#xD;
      with PCOS compared with placebo.&#xD;
&#xD;
      Specific Aim 2. To examine the effect of salsalate administration on the inflammatory&#xD;
      response of mononuclear cells induced by lipid ingestion in PCOS.&#xD;
&#xD;
      The hypothesis for this aim is that salsalate administration will down-regulate inflammatory&#xD;
      signal transduction and cytokine production within MNC following lipid ingestion in women&#xD;
      with PCOS regardless of body composition or IR status. The investigators will test this&#xD;
      hypothesis using the study design described in Aim 1. The inflammatory response of MNC to a&#xD;
      cream challenge test will be evaluated in women with PCOS before and after salsalate&#xD;
      treatment. It is anticipated that lipid-induced inflammation will decrease with salsalate use&#xD;
      regardless of body composition or IR status when compared with placebo.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 5, 2018</start_date>
  <completion_date type="Anticipated">July 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2024</primary_completion_date>
  <phase>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>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Aim 1: Area under the curve (AUC) for circulating testosterone from serial measurements during HCG stimulation test</measure>
    <time_frame>Change from pre-treatment baseline after 12 weeks of salsalate administration</time_frame>
    <description>Serum ovarian androgen measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Aim 2: Maximum lipid-stimulated mononuclear cell nuclear factor ĸB activation during cream challenge test</measure>
    <time_frame>Change from pre-treatment baseline after 12 weeks of salsalate administration</time_frame>
    <description>Transcription factor that is the cardinal signal of inflammation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Aim1: Fractional glucose disappearance / insulin concentration unit during insulin-modified frequently-sampled intravenous tolerance test adjusted for hepatic and peripheral insulin clearance</measure>
    <time_frame>Change from pre-treatment baseline after 12 weeks of salsalate administration</time_frame>
    <description>Peripheral insulin sensitivity measurement</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Anticipated">90</enrollment>
  <condition>Polycystic Ovary Syndrome</condition>
  <arm_group>
    <arm_group_label>Salsalate-Treated Lean PCOS without IR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>n=15</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo-Treated Lean PCOS without IR</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>n=15</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Salsalate-Treated Lean PCOS with IR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>n=15</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo-Treated Lean PCOS with IR</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>n=15</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Salsalate-Treated Obese PCOS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>n=15</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo-Treated Obese PCOS</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>n=15</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Salsalate</intervention_name>
    <description>Lean PCOS Arms: Salsalate 1.5 gm PO bid; Obese PCOS Arm: Salsalate 2.0 gm PO bid</description>
    <arm_group_label>Salsalate-Treated Lean PCOS with IR</arm_group_label>
    <arm_group_label>Salsalate-Treated Lean PCOS without IR</arm_group_label>
    <arm_group_label>Salsalate-Treated Obese PCOS</arm_group_label>
    <other_name>Disalcid®</other_name>
    <other_name>Salsitab®</other_name>
    <other_name>Amigesic®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Appears identical to experimental drug</description>
    <arm_group_label>Placebo-Treated Lean PCOS with IR</arm_group_label>
    <arm_group_label>Placebo-Treated Lean PCOS without IR</arm_group_label>
    <arm_group_label>Placebo-Treated Obese PCOS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of PCOS based on the presence of hyperandrogenism (skin manifestations of&#xD;
             androgen excess such as hirsutism, acne or temporal balding - or -elevation of at&#xD;
             least one serum androgen [i.e. total testosterone, free testosterone, androstenedione&#xD;
             or dehydroepiandrosterone-sulphate] using predetermined local laboratory cutoffs),&#xD;
             oligo/amenorrhea and evidence of withdrawal bleeding after progestin administration.&#xD;
&#xD;
          -  18-40 years of age.&#xD;
&#xD;
          -  Good health as evidenced by medical history, physical examination and gynecologic&#xD;
             examination within 30 days prior to starting the study.&#xD;
&#xD;
          -  Willingness to provide informed consent according to the guidelines of the University&#xD;
             of Illinois at Chicago (UIC) Institutional Review Board (IRB).&#xD;
&#xD;
          -  Willingness to use double-barrier contraception such as condoms and topical spermicide&#xD;
             (foam, cream or gel), condom and diaphragm, diaphragm and topical spermicide or sponge&#xD;
             with topical spermicide if sexually active. Use of a non-hormonal intrauterine device&#xD;
             (IUD), or permanent sterilization of the subject or her partner (i.e. tubal ligation&#xD;
             or vasectomy) is also acceptable in all instances.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Hyperprolactinemia.&#xD;
&#xD;
          -  Uncontrolled thyroid disease.&#xD;
&#xD;
          -  Evidence of Cushing's syndrome, nonclassic congenital adrenal hyperplasia or a hormone&#xD;
             producing tumor based on physical findings and serum androgen levels on initial&#xD;
             screening.&#xD;
&#xD;
          -  Known or suspected pregnancy.&#xD;
&#xD;
          -  Regular vigorous physical activity during previous 6 months.&#xD;
&#xD;
          -  Use of any medications known to affect carbohydrate or sex hormone metabolism such as&#xD;
             oral contraceptives, progestins, glucocorticoids or insulin sensitizing agents within&#xD;
             30 days of beginning the study.&#xD;
&#xD;
          -  Acute or chronic inflammatory illnesses (e.g. upper respiratory infection, asthma,&#xD;
             rheumatoid arthritis or systemic lupus erythematosus).&#xD;
&#xD;
          -  Type 1 or type 2 diabetes mellitus defined as having a fasting glucose &gt;126 mg/dl&#xD;
             and/or a 2-hour postprandial glucose &gt;200 mg/dl.&#xD;
&#xD;
          -  Regular smoking defined as more than 2 cigarettes a month, or any smoking within 30&#xD;
             days of beginning the study.&#xD;
&#xD;
          -  History of any illness exacerbated by salicylate use (e.g. peptic ulcer hepatic or&#xD;
             renal disease, anemia, thrombosis, coagulopathy, congestive heart failure,&#xD;
             hypertension or gout).&#xD;
&#xD;
          -  Allergy to salicylate or dairy products.&#xD;
&#xD;
          -  Medication use interacting with salicylates such as anti-platelet drugs (e.g.&#xD;
             cilostazol, clopidogrel), anticoagulants (e.g. enoxaparin, heparin, warfarin),&#xD;
             corticosteroids (e.g., prednisone), certain diabetes drugs (e.g. sulfonylureas such as&#xD;
             glyburide), certain anti-seizure drugs (e.g. phenytoin, valproic acid), cidofovir,&#xD;
             cyclosporine, drugs for gout (e.g. probenecid, sulfinpyrazone), anti-hypertensives&#xD;
             (e.g. angiotensin converting enzyme inhibitors such as captopril, angiotensin II&#xD;
             receptor antagonists such as losartan, and beta blockers such as metoprolol), drugs&#xD;
             that affect the acidity of urine (e.g. ammonium chloride, acetazolamide), lithium,&#xD;
             methotrexate, oral bisphosphonates (e.g. alendronate), pemetrexed, selective serotonin&#xD;
             reuptake inhibitor antidepressants (e.g. fluoxetine, sertraline), tenofovir, and&#xD;
             diuretics (furosemide, hydrochlorothiazide, spironolactone).&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Polycystic ovary syndrome is a female endocrine disorder.</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Frank González, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Illinois at Chicago</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Frank González, M.D.</last_name>
    <phone>(312) 413-1984</phone>
    <email>frgz12@uic.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ana Jay, R.N.</last_name>
    <phone>(312) 996-6675</phone>
    <email>analeono@uic.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Frank González</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Frank González, M.D.</last_name>
      <phone>312-413-1984</phone>
      <phone_ext>3124131984</phone_ext>
      <email>frgz12@uic.edu</email>
    </contact>
    <contact_backup>
      <last_name>Frank González, M.D.</last_name>
      <phone>3124131984</phone>
      <phone_ext>3124131984</phone_ext>
      <email>frgz12@uic.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://chicago.medicine.uic.edu/departments/academic-departments/obstetrics-and-gynecology/laboratory-for-reproductive-endocrine-and-inflammation-research/</url>
    <description>Principal Investigator's research laboratory and research program description</description>
  </link>
  <link>
    <url>https://www.ncbi.nlm.nih.gov/myncbi/browse/collection/41157534/?sort=date&amp;direction=descending</url>
    <description>Principal Investigator's National Center for Biotechnology Information MyBibliography</description>
  </link>
  <link>
    <url>https://www.doximity.com/pub/frank-gonzalez-md</url>
    <description>Principal Investigator's career profile</description>
  </link>
  <reference>
    <citation>Gonzalez F, Mather KJ, Considine RV, Abdelhadi OA, Acton AJ. Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome. Am J Physiol Endocrinol Metab. 2020 Oct 1;319(4):E744-E752. doi: 10.1152/ajpendo.00228.2020. Epub 2020 Aug 24.</citation>
    <PMID>32830548</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 15, 2017</study_first_submitted>
  <study_first_submitted_qc>July 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 25, 2017</study_first_posted>
  <last_update_submitted>May 28, 2023</last_update_submitted>
  <last_update_submitted_qc>May 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Illinois at Chicago</investigator_affiliation>
    <investigator_full_name>Frank Gonzalez</investigator_full_name>
    <investigator_title>Director, Laboratory for Reproductive Endocrine and Inflammation Research</investigator_title>
  </responsible_party>
  <keyword>Inflammation</keyword>
  <keyword>Hyperandrogenism</keyword>
  <keyword>Anovulation</keyword>
  <keyword>Insulin Resistance</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Polycystic Ovary Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Salicylsalicylic acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03229408
org study id: 2017-0476
secondary id: R01DK107605-01
nct id: NCT03229408
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, ovulatory dysfunction
      and polycystic ovaries. Insulin resistance (IR) is a common feature of PCOS, and the
      resultant hyperinsulinemia is theorized to promote hyperandrogenism in the disorder. However,
      30-50% of women with PCOS who are lean do not have insulin resistance. Women with PCOS also
      exhibit chronic low-grade inflammation. In PCOS, glucose ingestion activates nuclear factor
      ĸB (NFĸB), the cardinal signal of inflammation culminating in upregulation of the
      inflammation pathway within mononuclear cells (MNC). This phenomenon is independent of excess
      adiposity and is highly correlated with circulating androgens. In addition, in vitro exposure
      to proinflammatory stimuli is capable of directly stimulating ovarian theca cell androgen
      production. Nonacetylated salicylates suppress NFĸB activation and are well tolerated in
      humans.

      The proposed research is a randomized double-blind placebo-controlled study of 90 women with
      PCOS. Forty-five subjects with PCOS (15 lean without IR), 15 lean with IR and 15 obese)
      receiving salsalate, a nonacetylated salicylate, at an oral dose of 3-4 gm daily for 12 weeks
      will be compared with 45 age- and body-composition-matched control women with PCOS receiving
      placebo. The overarching hypothesis is that inflammation contributes to ovarian dysfunction,
      independent of excess adiposity or IR.

      The specific aims are, I: To examine the effect of salsalate administration on the ovarian
      capacity to secrete androgen and on insulin sensitivity in PCOS. II: To examine the effect of
      salsalate administration on the inflammatory response of mononuclear cells induced by lipid
      ingestion and glucose infusion in PCOS. The approach involves evaluation of ovarian androgen
      secretion in response to human chorionic gonadotropin (HCG) administration and insulin
      sensitivity during the euglycemic phase of a two-step pancreatic clamp along with ovulation
      monitoring before and after salsalate administration. The inflammatory response of MNC to
      lipid ingestion and the hyperglycemic phase of the two-step clamp will also be evaluated
      during treatment by measuring reactive oxygen species, the mRNA and protein content of
      inflammation markers, NFĸB activation and cytokine release in culture.

      The investigators expect that women with PCOS receiving salsalate will exhibit decreased
      ovarian androgen secretion and reduced inflammation regardless of adiposity or IR status.
      These results will be significant if they show a causal contribution of inflammation to
      ovarian dysfunction in PCOS, thus improving our understanding of the pathogenesis of PCOS,
      opening previously unexplored therapeutic avenues that are not necessarily dependent on
      improving IR, and guiding the design of future studies aimed at determining what
      interventions will optimally attenuate inflammation in PCOS to reduce medical disease and
      enhance fertility.
PCOS is characterized by hyperandrogenism, ovarian dysfunction and polycystic ovarian
      morphology. Obesity and IR are common features of PCOS. Under the current model of
      pathophysiology of PCOS, the compensatory hyperinsulinemia of IR is the primary driver of
      hyperandrogenism. This concept was born from the cross-sectional observation that insulin is
      positively correlated with androgens in obese women with PCOS, and is supported by reports of
      increased androgen production from theca cells obtained from obese women with PCOS following
      insulin exposure in vitro4 and increases in circulating androgens in women with PCOS
      following insulin infusion in vivo. However, these in vitro - in vivo responses were elicited
      with supraphysiological insulin concentrations. Physiological insulin infusion on the other
      hand does not augment androgen levels in PCOS. The current model also does not explain the
      cause of hyperandrogenism and ovarian dysfunction in the 30-50% of women with PCOS who are
      lean and lack IR. Thus, some other factor contributes to these abnormalities in PCOS.

      The investigators have shown that ingestion of glucose and saturated fat elicits an
      inflammatory response from circulating MNC in lean women with PCOS who lack excess abdominal
      adiposity. The hallmark of this response is increased activation of NFĸB, the cardinal signal
      of inflammation. These findings illustrate the separate and discrete role of MNC in
      manifesting inflammation in PCOS and that MNC are an excellent model to assess systemic
      inflammation in PCOS.

      The investigators have also shown that in PCOS, there is a link between molecular markers of
      inflammation from MNC and circulating androgens. Chronic suppression of ovarian androgen
      production does not ameliorate inflammation in lean women with PCOS. However, in vitro
      exposure of ovarian theca cells to proinflammatory stimuli upregulates CYP17, the androgen
      producing enzyme and increases testosterone.

      Salsalate is an inexpensive, safe, well-tolerated, well-understood anti-inflammatory agent
      that inhibits NFĸB activation when used at higher doses. The salsalate dose required to
      achieve a salicylate level in the upper therapeutic range is dependent on body mass. This is
      achieved in lean individuals using 3.0 gm/day as the maximum dose recommended in the
      salsalate package insert. Individuals across the obese range (30-40 kg/m2) require >3.0
      gm/day to achieve the same objective. Salsalate and other salicylates have also been shown to
      decrease IR. However, the ability of salsalate to decrease IR would not be necessary if the
      beneficial anti-inflammatory effect of salsalate to reduce hyperandrogenism is on the
      ovaries. In fact, we have shown that in lean insulin-sensitive women with PCOS, salsalate
      reduces HCG-stimulated ovarian androgen secretion by 44% and normalizes basal testosterone
      levels. Studies performed by the investigators in MNC also confirm the ability of salsalate
      to suppress NFĸB activation. Together these observations validate the use of these
      measurements as endpoints to assess the effects of salsalate to probe the pathophysiology of
      PCOS.

      Salsalate raises circulating insulin due to its ability to decreased insulin clearance from
      the liver which confounds the assessment of insulin sensitivity from post-treatment
      hyperinsulinemic-euglycemic clamp studies. Performance of a novel minimal model-based
      analysis from an insulin-modified frequently-sampled intravenous glucose tolerance test
      (FS-IVGTT) is able to address this confounding factor. With this approach, hepatic and
      extrahepatic insulin clearance can be estimated before and after salsalate treatment to
      obtain measures of insulin sensitivity that take into account the salsalate-induced
      alteration in insulin clearance.

      In this context, the rationale for the proposed study revolves around the concept that in
      PCOS, inflammation contributes to ovarian dysfunction independent of excess adiposity or IR,
      and may also improve insulin sensitivity when IR is present. The investigators will undertake
      a 12-week randomized, double-blind, placebo-controlled trial to test the link between
      inflammation and ovarian androgen secretion in PCOS unrelated to IR. If this study of
      pathophysiology demonstrates beneficial effects, this will pave the way for developing novel
      therapies for ovarian dysfunction in PCOS.

      The main objective of this proposal is to evaluate the ability of salsalate to reduce ovarian
      androgen secretion, induce ovulation and decrease lipid-stimulated inflammation independent
      of body composition and IR in women with PCOS; and to also improve insulin sensitivity in IR
      women with PCOS. Effects of salsalate will be assessed based on the following aims:

      Specific Aim 1. To examine the effects of salsalate administration on the ovarian capacity to
      secrete androgens, menstrual function, and insulin sensitivity in PCOS.

      The hypothesis for this aim is that salsalate treatment will decrease HCG-stimulated ovarian
      androgen secretion and induce ovulation in women with PCOS regardless of body composition or
      IR status; and may also improve insulin sensitivity in IR women with PCOS. The investigators
      will test this hypothesis in a randomized double-blind placebo-controlled study. The ovarian
      androgen response to HCG administration will be evaluated in women with PCOS (15 lean with
      IR, 15 lean without IR and 15 obese) before and after administration of a therapeutic
      salsalate dose for ~12 weeks compared with women with PCOS receiving placebo for ~12 weeks
      (15 lean with IR, 15 lean without IR and 15 obese). Ovulation monitoring and assessment of
      insulin sensitivity during FS-IVGTT will be performed before and after salsalate or placebo
      administration. It is anticipated that salsalate will reduce HCG-stimulated ovarian androgen
      secretion, induce ovulation regardless of body composition or IR status when compared with
      placebo. It is also anticipated that salsalate will increase insulin sensitivity in IR women
      with PCOS compared with placebo.

      Specific Aim 2. To examine the effect of salsalate administration on the inflammatory
      response of mononuclear cells induced by lipid ingestion in PCOS.

      The hypothesis for this aim is that salsalate administration will down-regulate inflammatory
      signal transduction and cytokine production within MNC following lipid ingestion in women
      with PCOS regardless of body composition or IR status. The investigators will test this
      hypothesis using the study design described in Aim 1. The inflammatory response of MNC to a
      cream challenge test will be evaluated in women with PCOS before and after salsalate
      treatment. It is anticipated that lipid-induced inflammation will decrease with salsalate use
      regardless of body composition or IR status when compared with placebo.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Aim 1: Area under the curve (AUC) for circulating testosterone from serial measurements during HCG stimulation test
time frame: Change from pre-treatment baseline after 12 weeks of salsalate administration
description: Serum ovarian androgen measurement
measure: Aim 2: Maximum lipid-stimulated mononuclear cell nuclear factor ĸB activation during cream challenge test
time frame: Change from pre-treatment baseline after 12 weeks of salsalate administration
description: Transcription factor that is the cardinal signal of inflammation
measure: Aim1: Fractional glucose disappearance / insulin concentration unit during insulin-modified frequently-sampled intravenous tolerance test adjusted for hepatic and peripheral insulin clearance
time frame: Change from pre-treatment baseline after 12 weeks of salsalate administration
description: Peripheral insulin sensitivity measurement
arm group label: Salsalate-Treated Lean PCOS without IR
arm group type: Experimental
description: n=15
arm group label: Placebo-Treated Lean PCOS without IR
arm group type: Placebo Comparator
description: n=15
arm group label: Salsalate-Treated Lean PCOS with IR
arm group type: Experimental
description: n=15
arm group label: Placebo-Treated Lean PCOS with IR
arm group type: Placebo Comparator
description: n=15
arm group label: Salsalate-Treated Obese PCOS
arm group type: Experimental
description: n=15
arm group label: Placebo-Treated Obese PCOS
arm group type: Placebo Comparator
description: n=15
intervention type: Drug
intervention name: Salsalate
description: Lean PCOS Arms: Salsalate 1.5 gm PO bid; Obese PCOS Arm: Salsalate 2.0 gm PO bid
arm group label: Salsalate-Treated Lean PCOS with IR
arm group label: Salsalate-Treated Lean PCOS without IR
arm group label: Salsalate-Treated Obese PCOS
other name: Disalcid®
other name: Salsitab®
other name: Amigesic®
intervention type: Other
intervention name: Placebo
description: Appears identical to experimental drug
arm group label: Placebo-Treated Lean PCOS with IR
arm group label: Placebo-Treated Lean PCOS without IR
arm group label: Placebo-Treated Obese PCOS
criteria: 
gender: Female
gender based: Yes
gender description: Polycystic ovary syndrome is a female endocrine disorder.
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Frank González, M.D.
role: Principal Investigator
affiliation: University of Illinois at Chicago
last name: Frank González, M.D.
phone: (312) 413-1984
email: frgz12@uic.edu
last name: Ana Jay, R.N.
phone: (312) 996-6675
email: analeono@uic.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
url: https://chicago.medicine.uic.edu/departments/academic-departments/obstetrics-and-gynecology/laboratory-for-reproductive-endocrine-and-inflammation-research/
description: Principal Investigator's research laboratory and research program description
url: https://www.ncbi.nlm.nih.gov/myncbi/browse/collection/41157534/?sort=date&direction=descending
description: Principal Investigator's National Center for Biotechnology Information MyBibliography
url: https://www.doximity.com/pub/frank-gonzalez-md
description: Principal Investigator's career profile
citation: Gonzalez F, Mather KJ, Considine RV, Abdelhadi OA, Acton AJ. Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome. Am J Physiol Endocrinol Metab. 2020 Oct 1;319(4):E744-E752. doi: 10.1152/ajpendo.00228.2020. Epub 2020 Aug 24.
PMID: 32830548
responsible party type: Principal Investigator
investigator affiliation: University of Illinois at Chicago
investigator full name: Frank Gonzalez
investigator title: Director, Laboratory for Reproductive Endocrine and Inflammation Research
mesh term: Polycystic Ovary Syndrome
mesh term: Syndrome
mesh term: Inflammation
mesh term: Salicylsalicylic acid
sharing ipd: No