xml: <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/NCT06015594</url>
    </required_header>
    <id_info>
      <org_study_id>PG/2020/12426</org_study_id>
      <nct_id>NCT06015594</nct_id>
    </id_info>
    <brief_title>Metformin Treatment in Adolescent Patients With PCOS: A Long-term, Winning Metabolic Choice.</brief_title>
    <official_title>Metformin Treatment in Adolescent Patients With PCOS: A Long-term, Winning Metabolic Choice. Results From a Single Center 5-years Retrospective Clinical Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Cagliari</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University of Cagliari</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        This study aimed to understand whether metformin therapy can improve insulin resistance in&#xD;
        adolescent PCOS patients, both during treatment and after discontinuation, and to evaluate&#xD;
        its action on the hormonal and metabolic pathways.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Data were retrospectively retrieved from a database of clinical data collected in the&#xD;
        Outpatient Pediatric and Adolescent Gynecology Clinic of the University Hospital &quot;Duilio&#xD;
        Casula,&quot; Monserrato, Cagliari (Division of Gynecology and Obstetrics, Department of Surgical&#xD;
        Sciences, University of Cagliari, Italy), between 2015 and 2019. PCOS diagnosis was adapted&#xD;
        for age following the 2019 update from Witchel SF and Carmina's recommendation.&#xD;
  &#xD;
        The population consisted of 168 PCOS patients aged 12 to 17. Clinical examination, medical&#xD;
        history, blood sampling, and pelvic ultrasound (US) were performed. The number of&#xD;
        post-menarche years and the body mass index (BMI) were collected.&#xD;
  &#xD;
        The patients were subjected to physical examination to evaluate hirsutism, according to the&#xD;
        criteria of the Ferriman and Gallwey score, as well as acne, using the Cremoncini&#xD;
        classification.&#xD;
  &#xD;
        Each participant received detailed advice on improving their lifestyle, such as physical&#xD;
        activity and nutrition. Investigators gave indications of the various food and their weighted&#xD;
        intake and a balanced composition of macronutrients (carbohydrates 55%, lipids 25%, protein&#xD;
        20%; fiber ≥25 g/day), as recommended by the Reference intake levels of nutrients and energy&#xD;
        for the Italian population (LARN) guidelines. Vegetables, fruit, cereals, fish, and pulses,&#xD;
        typical of the Mediterranean style, were included in the diet.&#xD;
  &#xD;
        Investigators recommended ≥150 minutes per week of moderate or ≥75 minutes of&#xD;
        vigorous-intensity exercise for weight gain prevention, minimizing sedentary time, and&#xD;
        including strength training exercises for two days per week, as reported from the 2018 PCOS&#xD;
        guideline.&#xD;
  &#xD;
        Laboratory evaluations were performed during the menstrual cycle's first follicular phase&#xD;
        (days 3-7) and after a fast of 10-12 hours. Menstrual bleeding was induced by administering&#xD;
        medroxyprogesterone acetate (10 mg/day for five days) in amenorrhoeic patients.&#xD;
  &#xD;
        Follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17-β estradiol (E2), total&#xD;
        testosterone (TT), delta-4-androstenedione (A), 17-hydroxyprogesterone (17-OH-P) and sex&#xD;
        hormone binding globulin (SHBG) were tested. In addition, total cholesterol, HDL, LDL, and&#xD;
        triglycerides were measured with these blood tests.&#xD;
  &#xD;
        The following day, the patients underwent a 75 g oral glucose tolerance test (OGTT). The OGTT&#xD;
        was performed at 9 am after fasting overnight. Blood samples were collected basally and 60,&#xD;
        90, 120, and 180 min after ingesting 75 g of glucose in 150 ml of water. Insulin and glucose&#xD;
        were assayed in all samples. Serum E2, FSH, LH, and TT were measured by chemiluminescence&#xD;
        immunoassay Immulite (Siemens Products Corporation, Los Angeles, CA). Enzymatic methods were&#xD;
        used for glucose, cholesterol, and triglycerides determination. Radioimmunoassay (RIA) was&#xD;
        used to measure serum A, insulin and 17-OHP (Diagnostic System Laboratories, Inc. [DSL],&#xD;
        Webster, TX). Insulin and glucose values were expressed as the area under the curve (AUC).&#xD;
        The AUC was calculated using the trapezoidal rule method and reported as mIU/ml times 180 min&#xD;
        for insulin.&#xD;
  &#xD;
        A normal glycemic response to OGTT was defined according to the criteria of the National&#xD;
        Diabetes Data Group (1979).&#xD;
  &#xD;
        As previously described, a normal insulinemic response to OGTT was defined by a threshold AUC&#xD;
        value of 16,900 mIU / ml / 180 min.&#xD;
  &#xD;
        Insulin sensitivity evaluation was estimated using the homeostatic model assessment index&#xD;
        (HOMA), which was calculated as follows: HOMA = [fasting insulin (mU/ml) * fasting glucose&#xD;
        (mmol/l)/22, 5].&#xD;
  &#xD;
        The same operator acquired ovarian morphology and ovarian volume for all patients. Ultrasound&#xD;
        was performed by a transabdominal probe in a whole bladder or transvaginally. A Voluson E6&#xD;
        ultrasound system equipped with a 2-8 MHz RAB4-8-D convex transducer (GE Medical Systems,&#xD;
        Austria) was used for the investigation. The ultrasound examination was performed on the same&#xD;
        day the blood samples were taken. Ovarian volume was calculated using the formula for a&#xD;
        modified prolate ellipsoid (longitudinal x transverse x anterior-posterior * 0.5233). The&#xD;
        mean volume values of both ovaries were included in the statistical analysis.&#xD;
  &#xD;
        Participants were categorized into two groups: the study group, consisting of patients who&#xD;
        received metformin therapy, and the control group, which did not receive metformin during the&#xD;
        study period.&#xD;
  &#xD;
        The metformin dose was determined based on the study by Fulghesu et al. Both the study and&#xD;
        control group underwent the same combined oral contraceptive pills (COCs), containing&#xD;
        drospirenone 3 mg/ethinyl estradiol 20 μg (3 mg DRSP/20 μg EE-24/4).&#xD;
  &#xD;
        Follow-up was performed every 3-6 months in the first year, then after 12 months by OGTT and&#xD;
        clinical evaluation.&#xD;
  &#xD;
        After about 24 months of treatment, the patients returned to the hospital and repeated&#xD;
        clinical and laboratory examinations. Finally, the patients repeated the same blood tests and&#xD;
        overall assessment at least 24 months after discontinuing metformin therapy. Baseline data&#xD;
        are expressed as b-AUC, b-HOMA, and b-BMI. End-of-therapy evaluation data are described as&#xD;
        e-AUC, e-HOMA, and e-BMI.&#xD;
  &#xD;
        Evaluation data after the end of therapy are reported as ae-AUC, ae-HOMA, and ae-BMI.&#xD;
  &#xD;
        Patient data were collected anonymously on an Excel® database (Office 365). Statistical&#xD;
        analysis was performed using the IBM SPSS Statistics statistical software, version 26 (IBM&#xD;
        SPSS Statistics, Chicago, IL, USA). Measurement data corresponding to the normal distribution&#xD;
        were expressed by mean ± SD, and the t-test was used for the paired samples (Student's&#xD;
        t-test). In addition, the count data were expressed as n (%), and the beta coefficient of&#xD;
        linear regression with a 95% confidence interval (95% CI) was reported for each analysis. In&#xD;
        all calculations, a p-value &lt; 0.05 was considered significant.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Completed</overall_status>
    <start_date type="Actual">January 1, 2015</start_date>
    <completion_date type="Actual">May 1, 2022</completion_date>
    <primary_completion_date type="Actual">August 1, 2019</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Single (Participant)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Insulin resistance change in eighty hyperinsulinemic patients after metformin therapy and its discontinuation</measure>
      <time_frame>about 3 years</time_frame>
      <description>To verify metformin treatment's immediate and long-term efficacy in hyperinsulinemic adolescent patients with PCOS and the evolution of metabolic status after treatment discontinuation.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Androgen levels change in eighty hyperinsulinemic patients after metformin therapy and its discontinuation</measure>
      <time_frame>about 3 years</time_frame>
      <description>To compare changes in androgen plasmatic levels such as total testosterone (TT) and delta-4-androstenedione (A) between the hyperinsulinemic adolescent patients with PCOS and the control group who have not received the metformin treatment by immediate and secondary assessment at the end of treatment of androgen plasmatic levels.</description>
    </primary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Actual">168</enrollment>
    <condition>Polycystic Ovary Syndrome</condition>
    <arm_group>
      <arm_group_label>Metformin group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Treated with metformin</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control group</arm_group_label>
      <arm_group_type>No Intervention</arm_group_type>
      <description>not treated</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Metformin</intervention_name>
      <description>Patients treated with metformin</description>
      <arm_group_label>Metformin group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria: Pcos Adolescents&#xD;
  &#xD;
          -&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          Other type of hyperandrogenism&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <minimum_age>10 Years</minimum_age>
      <maximum_age>19 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 3, 2023</study_first_submitted>
    <study_first_submitted_qc>August 22, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 29, 2023</study_first_posted>
    <last_update_submitted>August 22, 2023</last_update_submitted>
    <last_update_submitted_qc>August 22, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 29, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of Cagliari</investigator_affiliation>
      <investigator_full_name>Stefano Di Michele</investigator_full_name>
      <investigator_title>Principal investigator (Medical doctor)</investigator_title>
    </responsible_party>
    <keyword>insulin resistance</keyword>
    <keyword>metformin</keyword>
    <keyword>adolescents</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Polycystic Ovary Syndrome</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Metformin</mesh_term>
    </intervention_browse>
    <provided_document_section>
      <provided_document>
        <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
        <document_has_protocol>Yes</document_has_protocol>
        <document_has_icf>Yes</document_has_icf>
        <document_has_sap>Yes</document_has_sap>
        <document_date>July 1, 2015</document_date>
        <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT06015594/Prot_SAP_ICF_000.pdf</document_url>
      </provided_document>
    </provided_document_section>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06015594
  org study id: PG/2020/12426
  nct id: NCT06015594
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  This study aimed to understand whether metformin therapy can improve insulin resistance in
        adolescent PCOS patients, both during treatment and after discontinuation, and to evaluate
        its action on the hormonal and metabolic pathways.
  Data were retrospectively retrieved from a database of clinical data collected in the
        Outpatient Pediatric and Adolescent Gynecology Clinic of the University Hospital "Duilio
        Casula," Monserrato, Cagliari (Division of Gynecology and Obstetrics, Department of Surgical
        Sciences, University of Cagliari, Italy), between 2015 and 2019. PCOS diagnosis was adapted
        for age following the 2019 update from Witchel SF and Carmina's recommendation.
  
        The population consisted of 168 PCOS patients aged 12 to 17. Clinical examination, medical
        history, blood sampling, and pelvic ultrasound (US) were performed. The number of
        post-menarche years and the body mass index (BMI) were collected.
  
        The patients were subjected to physical examination to evaluate hirsutism, according to the
        criteria of the Ferriman and Gallwey score, as well as acne, using the Cremoncini
        classification.
  
        Each participant received detailed advice on improving their lifestyle, such as physical
        activity and nutrition. Investigators gave indications of the various food and their weighted
        intake and a balanced composition of macronutrients (carbohydrates 55%, lipids 25%, protein
        20%; fiber ≥25 g/day), as recommended by the Reference intake levels of nutrients and energy
        for the Italian population (LARN) guidelines. Vegetables, fruit, cereals, fish, and pulses,
        typical of the Mediterranean style, were included in the diet.
  
        Investigators recommended ≥150 minutes per week of moderate or ≥75 minutes of
        vigorous-intensity exercise for weight gain prevention, minimizing sedentary time, and
        including strength training exercises for two days per week, as reported from the 2018 PCOS
        guideline.
  
        Laboratory evaluations were performed during the menstrual cycle's first follicular phase
        (days 3-7) and after a fast of 10-12 hours. Menstrual bleeding was induced by administering
        medroxyprogesterone acetate (10 mg/day for five days) in amenorrhoeic patients.
  
        Follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17-β estradiol (E2), total
        testosterone (TT), delta-4-androstenedione (A), 17-hydroxyprogesterone (17-OH-P) and sex
        hormone binding globulin (SHBG) were tested. In addition, total cholesterol, HDL, LDL, and
        triglycerides were measured with these blood tests.
  
        The following day, the patients underwent a 75 g oral glucose tolerance test (OGTT). The OGTT
        was performed at 9 am after fasting overnight. Blood samples were collected basally and 60,
        90, 120, and 180 min after ingesting 75 g of glucose in 150 ml of water. Insulin and glucose
        were assayed in all samples. Serum E2, FSH, LH, and TT were measured by chemiluminescence
        immunoassay Immulite (Siemens Products Corporation, Los Angeles, CA). Enzymatic methods were
        used for glucose, cholesterol, and triglycerides determination. Radioimmunoassay (RIA) was
        used to measure serum A, insulin and 17-OHP (Diagnostic System Laboratories, Inc. [DSL],
        Webster, TX). Insulin and glucose values were expressed as the area under the curve (AUC).
        The AUC was calculated using the trapezoidal rule method and reported as mIU/ml times 180 min
        for insulin.
  
        A normal glycemic response to OGTT was defined according to the criteria of the National
        Diabetes Data Group (1979).
  
        As previously described, a normal insulinemic response to OGTT was defined by a threshold AUC
        value of 16,900 mIU / ml / 180 min.
  
        Insulin sensitivity evaluation was estimated using the homeostatic model assessment index
        (HOMA), which was calculated as follows: HOMA = [fasting insulin (mU/ml) * fasting glucose
        (mmol/l)/22, 5].
  
        The same operator acquired ovarian morphology and ovarian volume for all patients. Ultrasound
        was performed by a transabdominal probe in a whole bladder or transvaginally. A Voluson E6
        ultrasound system equipped with a 2-8 MHz RAB4-8-D convex transducer (GE Medical Systems,
        Austria) was used for the investigation. The ultrasound examination was performed on the same
        day the blood samples were taken. Ovarian volume was calculated using the formula for a
        modified prolate ellipsoid (longitudinal x transverse x anterior-posterior * 0.5233). The
        mean volume values of both ovaries were included in the statistical analysis.
  
        Participants were categorized into two groups: the study group, consisting of patients who
        received metformin therapy, and the control group, which did not receive metformin during the
        study period.
  
        The metformin dose was determined based on the study by Fulghesu et al. Both the study and
        control group underwent the same combined oral contraceptive pills (COCs), containing
        drospirenone 3 mg/ethinyl estradiol 20 μg (3 mg DRSP/20 μg EE-24/4).
  
        Follow-up was performed every 3-6 months in the first year, then after 12 months by OGTT and
        clinical evaluation.
  
        After about 24 months of treatment, the patients returned to the hospital and repeated
        clinical and laboratory examinations. Finally, the patients repeated the same blood tests and
        overall assessment at least 24 months after discontinuing metformin therapy. Baseline data
        are expressed as b-AUC, b-HOMA, and b-BMI. End-of-therapy evaluation data are described as
        e-AUC, e-HOMA, and e-BMI.
  
        Evaluation data after the end of therapy are reported as ae-AUC, ae-HOMA, and ae-BMI.
  
        Patient data were collected anonymously on an Excel® database (Office 365). Statistical
        analysis was performed using the IBM SPSS Statistics statistical software, version 26 (IBM
        SPSS Statistics, Chicago, IL, USA). Measurement data corresponding to the normal distribution
        were expressed by mean ± SD, and the t-test was used for the paired samples (Student's
        t-test). In addition, the count data were expressed as n (%), and the beta coefficient of
        linear regression with a 95% confidence interval (95% CI) was reported for each analysis. In
        all calculations, a p-value < 0.05 was considered significant.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Single (Participant)
  measure: Insulin resistance change in eighty hyperinsulinemic patients after metformin therapy and its discontinuation
  time frame: about 3 years
  description: To verify metformin treatment's immediate and long-term efficacy in hyperinsulinemic adolescent patients with PCOS and the evolution of metabolic status after treatment discontinuation.
  measure: Androgen levels change in eighty hyperinsulinemic patients after metformin therapy and its discontinuation
  time frame: about 3 years
  description: To compare changes in androgen plasmatic levels such as total testosterone (TT) and delta-4-androstenedione (A) between the hyperinsulinemic adolescent patients with PCOS and the control group who have not received the metformin treatment by immediate and secondary assessment at the end of treatment of androgen plasmatic levels.
  arm group label: Metformin group
  arm group type: Experimental
  description: Treated with metformin
  arm group label: Control group
  arm group type: No Intervention
  description: not treated
  intervention type: Drug
  intervention name: Metformin
  description: Patients treated with metformin
  arm group label: Metformin group
  criteria: 
  gender: Female
  minimum age: 10 Years
  maximum age: 19 Years
  healthy volunteers: Accepts Healthy Volunteers
  responsible party type: Principal Investigator
  investigator affiliation: University of Cagliari
  investigator full name: Stefano Di Michele
  investigator title: Principal investigator (Medical doctor)
  mesh term: Polycystic Ovary Syndrome
  mesh term: Metformin
  provided document: 