<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/NCT04407754</url>
  </required_header>
  <id_info>
    <org_study_id>12103</org_study_id>
    <nct_id>NCT04407754</nct_id>
  </id_info>
  <brief_title>Myo-Inositol for Infertility in PCOS</brief_title>
  <official_title>Myo-Inositol as an Adjuvant to Letrozole for Infertility in PolyCystic Ovary Syndrome (MALI-PCOS): a Randomized Pilot Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Oklahoma</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Oklahoma</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This will be a prospective, double-blind randomized clinical trial of letrozole and placebo&#xD;
      versus letrozole and inositols for up to 5 treatment cycles of ovulation induction or until&#xD;
      pregnancy is achieved. All participants and members of the research team will be blinded to&#xD;
      the treatment arms. Placebo and inositol supplement will be packaged to appear the same,&#xD;
      tested, and packaged by a commercial supply company. The inositols will be a 40:1 blend of&#xD;
      myo-inositol and D-chiro inositol.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      At the screening visit, blood pressure and heart rate will be measured, weight and height&#xD;
      obtained and body mass index calculated (kg/m2). If not already completed at their new&#xD;
      patient visit, transvaginal ultrasound will be performed to assess uterine anatomy and obtain&#xD;
      antral follicle count, TSH, prolactin, and testosterone will be drawn, and serum samples will&#xD;
      be obtained and analyzed for metabolic parameters (fasting lipids, insulin, and complete&#xD;
      metabolic panel). One additional tube of blood will be drawn to store for potential future&#xD;
      analysis. Once enrolled, randomization will occur and subjects will start either inositols or&#xD;
      placebo. 84 women will be stratified by BMI and randomized 1:1 into two treatment arms, A)&#xD;
      &quot;Control Arm&quot; = twice daily placebo powder and B) &quot;Inositol Arm&quot; = twice daily myo-inositol&#xD;
      (2,000mg) plus d-chiro-inositol (50mg) supplement powder.&#xD;
&#xD;
      Treatment with either placebo or inositol will begin upon randomization. Participants will&#xD;
      complete a validated quality of life in PCOS questionnaire (PCOSQ) at this visit and again&#xD;
      upon study completion (11). Treatment with letrozole will begin after the baseline visit,&#xD;
      which will occur after spontaneous menses or withdrawal bleeding induced by progestin&#xD;
      administration. Because of this timing, participants will undergo pretreatment with inositol&#xD;
      or placebo for a variable amount of time up to 6 weeks, with an anticipated average of 2-3&#xD;
      weeks. Metabolic parameters will be repeated after approximately 6 (7-9) and approximately 12&#xD;
      (11-13) weeks of inositol or placebo, at whichever study visit is most proximal in time to&#xD;
      this goal timeframe. Both groups will receive letrozole 5mg every day for 5 days on days 3-7&#xD;
      of their menstrual cycle and instructed on timing intercourse with anticipated ovulation&#xD;
      dates. Blood will be drawn for a serum progesterone each cycle between cycle days 20-22 to&#xD;
      confirm ovulation, and repeated 1 week later if the initial progesterone level is below the&#xD;
      threshold to confirm ovulation. Once ovulation is confirmed, they patient will expect a&#xD;
      period 7-10 days later. They will call with cycle day 1 of bleeding if it occurs to start&#xD;
      their next cycle of treatment, up to 5 cycles. If no bleeding occurs within the expected&#xD;
      timeframe, they will check a home pregnancy test and call with results. Patients will&#xD;
      complete medication side effect questionnaires at the first blood draw for progesterone of&#xD;
      each cycle. This will be reviewed same-day and in person with the research nurse coordinator.&#xD;
      Each patient will complete up to 5 cycles. Dose of letrozole will be increased in subsequent&#xD;
      cycles for non-response or late ovulatory response (ovulation later than the progesterone&#xD;
      blood draw) up to 10mg of letrozole a day. For patients with a second progesterone level&#xD;
      below the threshold to confirm ovulation (day 21 and day 28), the higher dose of letrozole&#xD;
      will be initiated following the receipt of the second low progesterone result. For patients&#xD;
      who do not ovulate on the maximum dose of letrozole, their study participation will be&#xD;
      considered complete.&#xD;
&#xD;
      Data to be collected will include: demographic information and medical history [age,&#xD;
      race/ethnicity, body mass index (BMI), antral follicle count, length of infertility, prior&#xD;
      infertility treatment (yes or no), obstetrical history, medical history, surgical history,&#xD;
      current medication and allergy lists], partner information [age, race/ethnicity, BMI, general&#xD;
      medical health assessment, prior paternity history], transvaginal ultrasound results, and&#xD;
      serum studies [TSH, prolactin, progesterone, hCG levels, androgen levels (total and free&#xD;
      testosterone, SHBG), and metabolic factors (fasting lipid panel, fasting glucose, fasting&#xD;
      insulin, glucose:insulin ratio, HOMA-IR index)]. Questionnaires to be completed include:&#xD;
      PCOSQ validated questionnaire for PCOS-related quality of life, and a side effect&#xD;
      questionnaire about known side effects of letrozole and inositols. In addition to the&#xD;
      baseline transvaginal ultrasound, additional ultrasounds may be performed as indicated&#xD;
      clinically (including for establishing clinical pregnancy). Pertinent demographic and&#xD;
      clinical information on patients who are participating in the study will be entered into a&#xD;
      study database REDCap secure software.&#xD;
&#xD;
      Using the reported clinical pregnancy rate for infertile PCOS patients treated with letrozole&#xD;
      of 31.3% (12) as the control group proportion (0.31) with a goal of 10% effect size (and&#xD;
      therefore treatment group proportion 0.41), an alpha of 0.05, and power of 0.8, our sample&#xD;
      size is estimated (for a full clinical trial) at ~361 in each arm. In considering the&#xD;
      previously observed drop-out rate of ~20% in a similar patient population (3), we estimate&#xD;
      that for a full clinical trial, we would need 452 participants randomized in each arm. Based&#xD;
      on previously published literature regarding estimation of pilot randomized trial sample&#xD;
      sizes, we will target 9% of this sample size for our pilot study to suggest or identify a&#xD;
      significant difference (13). In conclusion, our planned study size will be 42 participants in&#xD;
      each study arm.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 19, 2020</start_date>
  <completion_date type="Anticipated">September 2023</completion_date>
  <primary_completion_date type="Anticipated">September 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical pregnancy</measure>
    <time_frame>Through study completion, an average of 6 months</time_frame>
    <description>Clinical pregnancy will be defined as documentation of a viable intrauterine pregnancy as noted by visualization of fetal heart motion on ultrasonography.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">168</enrollment>
  <condition>Polycystic Ovary Syndrome</condition>
  <arm_group>
    <arm_group_label>Control Arm</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This group will receive placebo powder twice daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Inositol Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This group will receive myo-inositol (2,000mg) plus d-chiro-inositol (50mg) supplement powder twice daily.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Inositol supplement</intervention_name>
    <description>Inositol supplements given to inositol arm</description>
    <arm_group_label>Inositol Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo supplement</intervention_name>
    <description>Placebo supplement given to placebo arm</description>
    <arm_group_label>Control Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female patient age 18-36&#xD;
&#xD;
          -  Desire for pregnancy&#xD;
&#xD;
          -  Diagnosis of oligo- or anovulation secondary to polycystic ovary syndrome -All&#xD;
             subjects must have ovulatory dysfunction and at least one of the remaining two&#xD;
             criteria:hyperandrogenism or polycystic ovarian morphology on ultrasound&#xD;
&#xD;
          -  At least one patent fallopian tube&#xD;
&#xD;
          -  Normal uterine cavity&#xD;
&#xD;
          -  Male partner with sperm concentration of at least 14 million/mL in at least one&#xD;
             ejaculate.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cause of anovulation other than PCOS such as uncontrolled thyroid dysfunction or&#xD;
             hyperprolactinemia&#xD;
&#xD;
          -  Presence of another major infertility factor&#xD;
&#xD;
          -  Diabetes&#xD;
&#xD;
          -  Contraindication to pregnancy&#xD;
&#xD;
          -  Myo-inositol use &lt; 3 months prior to study enrollment&#xD;
&#xD;
          -  Concomitant metformin use. Previous use is allowed with last use at least 6 weeks&#xD;
             prior to randomization.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>36 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Heather Burks, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>OUHSC</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Christy Zornes, MHR</last_name>
    <phone>4052718001</phone>
    <phone_ext>48137</phone_ext>
    <email>christy-zornes@ouhsc.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kyra Woods, BA</last_name>
    <phone>4052718001</phone>
    <phone_ext>45750</phone_ext>
    <email>kyra-woods@ouhsc.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>OUHSC Reproductive Medicine Clinic</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Heather Burks, MD</last_name>
      <phone>405-271-1616</phone>
      <email>Heather-Burks@ouhsc.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>May 21, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>June 12, 2023</last_update_submitted>
  <last_update_submitted_qc>June 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Polycystic Ovary Syndrome</mesh_term>
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inositol</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04407754
org study id: 12103
nct id: NCT04407754
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
This will be a prospective, double-blind randomized clinical trial of letrozole and placebo
      versus letrozole and inositols for up to 5 treatment cycles of ovulation induction or until
      pregnancy is achieved. All participants and members of the research team will be blinded to
      the treatment arms. Placebo and inositol supplement will be packaged to appear the same,
      tested, and packaged by a commercial supply company. The inositols will be a 40:1 blend of
      myo-inositol and D-chiro inositol.
At the screening visit, blood pressure and heart rate will be measured, weight and height
      obtained and body mass index calculated (kg/m2). If not already completed at their new
      patient visit, transvaginal ultrasound will be performed to assess uterine anatomy and obtain
      antral follicle count, TSH, prolactin, and testosterone will be drawn, and serum samples will
      be obtained and analyzed for metabolic parameters (fasting lipids, insulin, and complete
      metabolic panel). One additional tube of blood will be drawn to store for potential future
      analysis. Once enrolled, randomization will occur and subjects will start either inositols or
      placebo. 84 women will be stratified by BMI and randomized 1:1 into two treatment arms, A)
      "Control Arm" = twice daily placebo powder and B) "Inositol Arm" = twice daily myo-inositol
      (2,000mg) plus d-chiro-inositol (50mg) supplement powder.

      Treatment with either placebo or inositol will begin upon randomization. Participants will
      complete a validated quality of life in PCOS questionnaire (PCOSQ) at this visit and again
      upon study completion (11). Treatment with letrozole will begin after the baseline visit,
      which will occur after spontaneous menses or withdrawal bleeding induced by progestin
      administration. Because of this timing, participants will undergo pretreatment with inositol
      or placebo for a variable amount of time up to 6 weeks, with an anticipated average of 2-3
      weeks. Metabolic parameters will be repeated after approximately 6 (7-9) and approximately 12
      (11-13) weeks of inositol or placebo, at whichever study visit is most proximal in time to
      this goal timeframe. Both groups will receive letrozole 5mg every day for 5 days on days 3-7
      of their menstrual cycle and instructed on timing intercourse with anticipated ovulation
      dates. Blood will be drawn for a serum progesterone each cycle between cycle days 20-22 to
      confirm ovulation, and repeated 1 week later if the initial progesterone level is below the
      threshold to confirm ovulation. Once ovulation is confirmed, they patient will expect a
      period 7-10 days later. They will call with cycle day 1 of bleeding if it occurs to start
      their next cycle of treatment, up to 5 cycles. If no bleeding occurs within the expected
      timeframe, they will check a home pregnancy test and call with results. Patients will
      complete medication side effect questionnaires at the first blood draw for progesterone of
      each cycle. This will be reviewed same-day and in person with the research nurse coordinator.
      Each patient will complete up to 5 cycles. Dose of letrozole will be increased in subsequent
      cycles for non-response or late ovulatory response (ovulation later than the progesterone
      blood draw) up to 10mg of letrozole a day. For patients with a second progesterone level
      below the threshold to confirm ovulation (day 21 and day 28), the higher dose of letrozole
      will be initiated following the receipt of the second low progesterone result. For patients
      who do not ovulate on the maximum dose of letrozole, their study participation will be
      considered complete.

      Data to be collected will include: demographic information and medical history [age,
      race/ethnicity, body mass index (BMI), antral follicle count, length of infertility, prior
      infertility treatment (yes or no), obstetrical history, medical history, surgical history,
      current medication and allergy lists], partner information [age, race/ethnicity, BMI, general
      medical health assessment, prior paternity history], transvaginal ultrasound results, and
      serum studies [TSH, prolactin, progesterone, hCG levels, androgen levels (total and free
      testosterone, SHBG), and metabolic factors (fasting lipid panel, fasting glucose, fasting
      insulin, glucose:insulin ratio, HOMA-IR index)]. Questionnaires to be completed include:
      PCOSQ validated questionnaire for PCOS-related quality of life, and a side effect
      questionnaire about known side effects of letrozole and inositols. In addition to the
      baseline transvaginal ultrasound, additional ultrasounds may be performed as indicated
      clinically (including for establishing clinical pregnancy). Pertinent demographic and
      clinical information on patients who are participating in the study will be entered into a
      study database REDCap secure software.

      Using the reported clinical pregnancy rate for infertile PCOS patients treated with letrozole
      of 31.3% (12) as the control group proportion (0.31) with a goal of 10% effect size (and
      therefore treatment group proportion 0.41), an alpha of 0.05, and power of 0.8, our sample
      size is estimated (for a full clinical trial) at ~361 in each arm. In considering the
      previously observed drop-out rate of ~20% in a similar patient population (3), we estimate
      that for a full clinical trial, we would need 452 participants randomized in each arm. Based
      on previously published literature regarding estimation of pilot randomized trial sample
      sizes, we will target 9% of this sample size for our pilot study to suggest or identify a
      significant difference (13). In conclusion, our planned study size will be 42 participants in
      each study arm.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Supportive Care
masking: Triple (Participant, Care Provider, Investigator)
measure: Clinical pregnancy
time frame: Through study completion, an average of 6 months
description: Clinical pregnancy will be defined as documentation of a viable intrauterine pregnancy as noted by visualization of fetal heart motion on ultrasonography.
arm group label: Control Arm
arm group type: Placebo Comparator
description: This group will receive placebo powder twice daily.
arm group label: Inositol Arm
arm group type: Active Comparator
description: This group will receive myo-inositol (2,000mg) plus d-chiro-inositol (50mg) supplement powder twice daily.
intervention type: Dietary Supplement
intervention name: Inositol supplement
description: Inositol supplements given to inositol arm
arm group label: Inositol Arm
intervention type: Dietary Supplement
intervention name: Placebo supplement
description: Placebo supplement given to placebo arm
arm group label: Control Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: 36 Years
healthy volunteers: No
last name: Heather Burks, MD
role: Principal Investigator
affiliation: OUHSC
last name: Christy Zornes, MHR
phone: 4052718001
phone ext: 48137
email: christy-zornes@ouhsc.edu
last name: Kyra Woods, BA
phone: 4052718001
phone ext: 45750
email: kyra-woods@ouhsc.edu
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Sponsor
mesh term: Polycystic Ovary Syndrome
mesh term: Infertility
mesh term: Syndrome
mesh term: Inositol