<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/NCT03792984</url>
  </required_header>
  <id_info>
    <org_study_id>Ph-CT-2685</org_study_id>
    <nct_id>NCT03792984</nct_id>
  </id_info>
  <brief_title>The Effect of Calcium and Vitamin D Supplements on Metabolic and Hormonal Disturbances in Polycystic Ovary Syndrome Patients</brief_title>
  <official_title>The Effect of Calcium and Vitamin D Supplements as an Adjuvant Therapy to Metformin on Metabolic and Hormonal Disturbances in Polycystic Ovary Syndrome Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Damascus University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Damascus University</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>
      The aim of this study is to investigate the safety and metabolic-hormonal efficiency of&#xD;
      supplementation vitamin D deficient/insufficient PCOS women with (calcium +vitamin D +&#xD;
      metformin) for 8 weeks compared to (placebo+ metformin).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among females of&#xD;
      reproductive age. The main manifestations of this syndrome are ovulatory dysfunction,&#xD;
      hyperandrogenism, and polycystic ovarian morphology. Noticeably, PCOS is associated with&#xD;
      several metabolic disturbances such as insulin resistance, compensatory hyperinsulinemia,&#xD;
      dyslipidemia and central obesity, which increase the risk for long-term complications like&#xD;
      type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Moreover, previous&#xD;
      data demonstrated that, compared to normo-ovulatory women, PCOS patients might exhibit a&#xD;
      dysregulation in the IGF system represented as an elevation in the serum levels of free&#xD;
      Insulin-like growth factor-1 (IGF-1) and a reduction in the serum levels of Insulin-like&#xD;
      growth factor binding protein-1 (IGFBP-1). However, the exact aetiology of PCOS remains&#xD;
      unclear and current treatments are only moderately effective at controlling PCOS symptoms and&#xD;
      preventing its complications. Growing evidence suggests a role of vitamin D in female&#xD;
      reproductive diseases as the expression of Vitamin D Receptors (VDR) was identified in many&#xD;
      organs throughout the female reproductive tract. On the top of that, vitamin D regulates over&#xD;
      300 genes, including genes that are important for glucose and lipid metabolism. Moreover,&#xD;
      vitamin D deficiency is a common condition among women with PCOS, and several studies&#xD;
      indicated an association between low levels of serum 25-hydroxyvitamin D (25-OH-Vitamin D)&#xD;
      and manifestations of PCOS including insulin resistance, hyperandrogenism, and infertility.&#xD;
      Further, a recent in-vitro study showed that vitamin D regulated steroidogenesis and IGFBP-1&#xD;
      production in cultured human ovarian cells, and many reports have suggested an interrelation&#xD;
      between IGF-1 and vitamin D.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2016</start_date>
  <completion_date type="Actual">December 30, 2017</completion_date>
  <primary_completion_date type="Actual">October 1, 2017</primary_completion_date>
  <phase>Phase 3</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>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in quantitative insulin sensitivity check index (QUICKI).</measure>
    <time_frame>baseline, 8 weeks weeks.</time_frame>
    <description>Assessment of QUICKI index at baseline and after 8 weeks of intervention.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Raynaud's index.</measure>
    <time_frame>baseline, 8 weeks weeks.</time_frame>
    <description>Assessment of Raynaud's index at baseline and after 8 weeks of intervention.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in McAuley Index.</measure>
    <time_frame>baseline, 8 weeks weeks.</time_frame>
    <description>Assessment of McAuley Index at baseline and after 8 weeks of intervention.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in glucose concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of glucose at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in insulin concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of insulin at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in homeostasis model assessment of insulin resistance index (HOMA-IR).</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of HOMA-IR index at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in homeostasis model assessment of β-cell function index (HOMA-B).</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of HOMA-B index at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in menstrual cycle abnormalities.</measure>
    <time_frame>up to 8 weeks.</time_frame>
    <description>Assessment of menstrual cycles regularity (having normal menstrual cycle 21-35 days) was done at baseline and during the study period using a calendar by recording the time of the onset of the menstrual periods and the duration of menses.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in hirsutism score</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of modified Ferriman-Gallwey score for hirsutism at baseline and after 8 weeks of intervention. (The score represents the hair growth in a male pattern on a woman shown in four different degrees of severity ( 0= no hair growth; 1= light hair growth; 2= moderate hair growth; 4= severe hair growth) in 9 different body parts; namely the upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, upper arms and thighs. The score is the sum of each region sub-score. Thus, it ranges between 0 and 36, where a score ≥ 6 was considered as a cut off Hirsutism).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in free testosterone concentration</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum free testosterone concentration at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum concentration of follicle-stimulating hormone (FSH)</measure>
    <time_frame>baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status.</time_frame>
    <description>Assessment of serum concentration of FSH during the early follicular phase of menses at baseline and after 8 weeks of intervention if menstrual cycle regularity was reached during treatment period, or at baseline and the next spontaneous menstrual cycle after finishing the treatment if menstrual cycle regularity was not reached during treatment period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum concentration of luteinizing hormone (LH) .</measure>
    <time_frame>baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status.</time_frame>
    <description>Assessment of serum concentration of LH during the early follicular phase of menses at baseline and after 8 weeks of intervention if menstrual cycle regularity was reached during treatment period, or at baseline and the next spontaneous menstrual cycle after finishing the treatment if menstrual cycle regularity was not reached during treatment period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum concentration of Insulin-like growth factor-1 (IGF-1).</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of IGF-1 at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum concentration of Insulin-like growth factor binding protein-1 (IGFBP-1).</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of IGFBP-1 at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in IGF-1 to IGFBP-1 ratio.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of IGF-1 to IGFBP-1 ratio at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lipid profile.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG) and non-HDL cholesterol (non-HDL) at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum concentration of C-reactive protein (CRP)</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of CRP at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Body mass index (BMI).</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of weight and height in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention. Weight and height will be combined to report BMI in kg/m^2.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in waist circumference.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of waist circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Hip circumference.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of Hip circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in waist to hip ratio.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of waist to hip ratio in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in calcium concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of calcium at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in 25-OH-vitamin D concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of 25-OH-vitamin D at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in phosphorus concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of phosphorus at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in alanine transaminase (ALT) concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of ALT at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in aspartate transaminase (AST) concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of AST at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in urea concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of urea at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in creatinine concentration.</measure>
    <time_frame>baseline, 8 weeks.</time_frame>
    <description>Assessment of serum concentration of creatinine at baseline and after 8 weeks of intervention.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Polycystic Ovary Syndrome</condition>
  <condition>Vitamin D Deficiency/Insufficiency</condition>
  <arm_group>
    <arm_group_label>Metformin + Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Calcium carbonate + Vitamin D3 + Metformin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Vitamin D3</intervention_name>
    <description>Vitamin D3 (Cholecalciferol) (6000 IU/daily). PO for 8 weeks.</description>
    <arm_group_label>Calcium carbonate + Vitamin D3 + Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Calcium Carbonate</intervention_name>
    <description>Calcium carbonate (1000 mg/daily). PO for 8 weeks.</description>
    <arm_group_label>Calcium carbonate + Vitamin D3 + Metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Metformin (1500 mg/daily; the metformin dose was increased stepwise, starting with 500 mg once daily for the 1st week, 500 mg twice daily in the 2nd week, followed by 500 mg 3 times daily from the 3rd week onward). PO for 8 weeks.</description>
    <arm_group_label>Calcium carbonate + Vitamin D3 + Metformin</arm_group_label>
    <arm_group_label>Metformin + Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>PO for 8 weeks.</description>
    <arm_group_label>Metformin + Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  PCOS women aged 18-30 years diagnosed according to the Rotterdam criteria.&#xD;
&#xD;
          -  Vitamin D deficiency or insufficiency according to the Endocrine Society Clinical&#xD;
             Practice Guideline.&#xD;
&#xD;
          -  Normal liver function.&#xD;
&#xD;
          -  Normal kidney function.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant, postpartum or breastfeeding women.&#xD;
&#xD;
          -  Females aged &lt;18 or &gt;30 years old.&#xD;
&#xD;
          -  Patients who were diagnosed with androgen-secreting tumours, Cushing's syndrome,&#xD;
             congenital adrenal hyperplasia, hyperprolactinemia, hypercalcemia, malabsorption&#xD;
             disorders, diabetes mellitus, thyroid disorders, liver disease, renal disease,&#xD;
             epilepsy, cardiovascular disease.&#xD;
&#xD;
          -  History of kidney stones.&#xD;
&#xD;
          -  Usage of any hormonal therapy, corticosteroids (other than topical corticosteroids&#xD;
             forms), insulin sensitizers, hypolipidemic agents, anti-obesity medications, vitamin D&#xD;
             or calcium supplements, anti-epileptic drugs, or any other drugs known to affect&#xD;
             endocrine parameters, carbohydrate metabolism, or calciotropic hormone concentrations&#xD;
             during the last 3 months.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sally Kadoura, B Pharm, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Abdul Hakim Nattouf, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Professor at Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marwan Alhalabi, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Professor at Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syria.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Damascus University of Obstetrics and Gynecology Hospital</name>
      <address>
        <city>Damascus</city>
        <country>Syrian Arab Republic</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Orient Hospital</name>
      <address>
        <city>Damascus</city>
        <country>Syrian Arab Republic</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Syrian Arab Republic</country>
  </location_countries>
  <reference>
    <citation>Ameri P, Giusti A, Boschetti M, Murialdo G, Minuto F, Ferone D. Interactions between vitamin D and IGF-I: from physiology to clinical practice. Clin Endocrinol (Oxf). 2013 Oct;79(4):457-63. doi: 10.1111/cen.12268. Epub 2013 Aug 9.</citation>
    <PMID>23789983</PMID>
  </reference>
  <reference>
    <citation>Hahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S, Kimmig R, Mann K, Janssen OE. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006 Nov;114(10):577-83. doi: 10.1055/s-2006-948308.</citation>
    <PMID>17177140</PMID>
  </reference>
  <reference>
    <citation>Irani M, Merhi Z. Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril. 2014 Aug;102(2):460-468.e3. doi: 10.1016/j.fertnstert.2014.04.046. Epub 2014 Jun 3.</citation>
    <PMID>24933120</PMID>
  </reference>
  <reference>
    <citation>Krul-Poel YH, Snackey C, Louwers Y, Lips P, Lambalk CB, Laven JS, Simsek S. The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: a systematic review. Eur J Endocrinol. 2013 Oct 23;169(6):853-65. doi: 10.1530/EJE-13-0617. Print 2013 Dec.</citation>
    <PMID>24044903</PMID>
  </reference>
  <reference>
    <citation>Li HW, Brereton RE, Anderson RA, Wallace AM, Ho CK. Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome. Metabolism. 2011 Oct;60(10):1475-81. doi: 10.1016/j.metabol.2011.03.002. Epub 2011 May 6.</citation>
    <PMID>21550088</PMID>
  </reference>
  <reference>
    <citation>Ott J, Wattar L, Kurz C, Seemann R, Huber JC, Mayerhofer K, Vytiska-Binstorfer E. Parameters for calcium metabolism in women with polycystic ovary syndrome who undergo clomiphene citrate stimulation: a prospective cohort study. Eur J Endocrinol. 2012 May;166(5):897-902. doi: 10.1530/EJE-11-1070. Epub 2012 Feb 13.</citation>
    <PMID>22330149</PMID>
  </reference>
  <reference>
    <citation>Pal L, Zhang H, Williams J, Santoro NF, Diamond MP, Schlaff WD, Coutifaris C, Carson SA, Steinkampf MP, Carr BR, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Myers E, Legro RS; Reproductive Medicine Network. Vitamin D Status Relates to Reproductive Outcome in Women With Polycystic Ovary Syndrome: Secondary Analysis of a Multicenter Randomized Controlled Trial. J Clin Endocrinol Metab. 2016 Aug;101(8):3027-35. doi: 10.1210/jc.2015-4352. Epub 2016 May 17.</citation>
    <PMID>27186859</PMID>
  </reference>
  <reference>
    <citation>Parikh G, Varadinova M, Suwandhi P, Araki T, Rosenwaks Z, Poretsky L, Seto-Young D. Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells. Horm Metab Res. 2010 Sep;42(10):754-7. doi: 10.1055/s-0030-1262837. Epub 2010 Aug 13.</citation>
    <PMID>20711952</PMID>
  </reference>
  <reference>
    <citation>Thierry van Dessel HJ, Lee PD, Faessen G, Fauser BC, Giudice LC. Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome. J Clin Endocrinol Metab. 1999 Sep;84(9):3030-5. doi: 10.1210/jcem.84.9.5941.</citation>
    <PMID>10487660</PMID>
  </reference>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>January 3, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 4, 2019</study_first_posted>
  <last_update_submitted>June 4, 2019</last_update_submitted>
  <last_update_submitted_qc>June 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Polycystic Ovary Syndrome</keyword>
  <keyword>Calcium</keyword>
  <keyword>Vitamin D</keyword>
  <keyword>Metformin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Polycystic Ovary Syndrome</mesh_term>
    <mesh_term>Vitamin D Deficiency</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Cholecalciferol</mesh_term>
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Calcium Carbonate</mesh_term>
    <mesh_term>Calcium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03792984
org study id: Ph-CT-2685
nct id: NCT03792984
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The aim of this study is to investigate the safety and metabolic-hormonal efficiency of
      supplementation vitamin D deficient/insufficient PCOS women with (calcium +vitamin D +
      metformin) for 8 weeks compared to (placebo+ metformin).
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among females of
      reproductive age. The main manifestations of this syndrome are ovulatory dysfunction,
      hyperandrogenism, and polycystic ovarian morphology. Noticeably, PCOS is associated with
      several metabolic disturbances such as insulin resistance, compensatory hyperinsulinemia,
      dyslipidemia and central obesity, which increase the risk for long-term complications like
      type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Moreover, previous
      data demonstrated that, compared to normo-ovulatory women, PCOS patients might exhibit a
      dysregulation in the IGF system represented as an elevation in the serum levels of free
      Insulin-like growth factor-1 (IGF-1) and a reduction in the serum levels of Insulin-like
      growth factor binding protein-1 (IGFBP-1). However, the exact aetiology of PCOS remains
      unclear and current treatments are only moderately effective at controlling PCOS symptoms and
      preventing its complications. Growing evidence suggests a role of vitamin D in female
      reproductive diseases as the expression of Vitamin D Receptors (VDR) was identified in many
      organs throughout the female reproductive tract. On the top of that, vitamin D regulates over
      300 genes, including genes that are important for glucose and lipid metabolism. Moreover,
      vitamin D deficiency is a common condition among women with PCOS, and several studies
      indicated an association between low levels of serum 25-hydroxyvitamin D (25-OH-Vitamin D)
      and manifestations of PCOS including insulin resistance, hyperandrogenism, and infertility.
      Further, a recent in-vitro study showed that vitamin D regulated steroidogenesis and IGFBP-1
      production in cultured human ovarian cells, and many reports have suggested an interrelation
      between IGF-1 and vitamin D.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Change in quantitative insulin sensitivity check index (QUICKI).
time frame: baseline, 8 weeks weeks.
description: Assessment of QUICKI index at baseline and after 8 weeks of intervention.
measure: Change in Raynaud's index.
time frame: baseline, 8 weeks weeks.
description: Assessment of Raynaud's index at baseline and after 8 weeks of intervention.
measure: Change in McAuley Index.
time frame: baseline, 8 weeks weeks.
description: Assessment of McAuley Index at baseline and after 8 weeks of intervention.
measure: Change in glucose concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of glucose at baseline and after 8 weeks of intervention.
measure: Change in insulin concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of insulin at baseline and after 8 weeks of intervention.
measure: Change in homeostasis model assessment of insulin resistance index (HOMA-IR).
time frame: baseline, 8 weeks.
description: Assessment of HOMA-IR index at baseline and after 8 weeks of intervention.
measure: Change in homeostasis model assessment of β-cell function index (HOMA-B).
time frame: baseline, 8 weeks.
description: Assessment of HOMA-B index at baseline and after 8 weeks of intervention.
measure: Change in menstrual cycle abnormalities.
time frame: up to 8 weeks.
description: Assessment of menstrual cycles regularity (having normal menstrual cycle 21-35 days) was done at baseline and during the study period using a calendar by recording the time of the onset of the menstrual periods and the duration of menses.
measure: Change in hirsutism score
time frame: baseline, 8 weeks.
description: Assessment of modified Ferriman-Gallwey score for hirsutism at baseline and after 8 weeks of intervention. (The score represents the hair growth in a male pattern on a woman shown in four different degrees of severity ( 0= no hair growth; 1= light hair growth; 2= moderate hair growth; 4= severe hair growth) in 9 different body parts; namely the upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, upper arms and thighs. The score is the sum of each region sub-score. Thus, it ranges between 0 and 36, where a score ≥ 6 was considered as a cut off Hirsutism).
measure: Change in free testosterone concentration
time frame: baseline, 8 weeks.
description: Assessment of serum free testosterone concentration at baseline and after 8 weeks of intervention.
measure: Change in serum concentration of follicle-stimulating hormone (FSH)
time frame: baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status.
description: Assessment of serum concentration of FSH during the early follicular phase of menses at baseline and after 8 weeks of intervention if menstrual cycle regularity was reached during treatment period, or at baseline and the next spontaneous menstrual cycle after finishing the treatment if menstrual cycle regularity was not reached during treatment period.
measure: Change in serum concentration of luteinizing hormone (LH) .
time frame: baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status.
description: Assessment of serum concentration of LH during the early follicular phase of menses at baseline and after 8 weeks of intervention if menstrual cycle regularity was reached during treatment period, or at baseline and the next spontaneous menstrual cycle after finishing the treatment if menstrual cycle regularity was not reached during treatment period.
measure: Change in serum concentration of Insulin-like growth factor-1 (IGF-1).
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of IGF-1 at baseline and after 8 weeks of intervention.
measure: Change in serum concentration of Insulin-like growth factor binding protein-1 (IGFBP-1).
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of IGFBP-1 at baseline and after 8 weeks of intervention.
measure: Change in IGF-1 to IGFBP-1 ratio.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of IGF-1 to IGFBP-1 ratio at baseline and after 8 weeks of intervention.
measure: Change in lipid profile.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG) and non-HDL cholesterol (non-HDL) at baseline and after 8 weeks of intervention.
measure: Change in serum concentration of C-reactive protein (CRP)
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of CRP at baseline and after 8 weeks of intervention.
measure: Change in Body mass index (BMI).
time frame: baseline, 8 weeks.
description: Assessment of weight and height in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention. Weight and height will be combined to report BMI in kg/m^2.
measure: Change in waist circumference.
time frame: baseline, 8 weeks.
description: Assessment of waist circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.
measure: Change in Hip circumference.
time frame: baseline, 8 weeks.
description: Assessment of Hip circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.
measure: Change in waist to hip ratio.
time frame: baseline, 8 weeks.
description: Assessment of waist to hip ratio in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.
measure: Change in calcium concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of calcium at baseline and after 8 weeks of intervention.
measure: Change in 25-OH-vitamin D concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of 25-OH-vitamin D at baseline and after 8 weeks of intervention.
measure: Change in phosphorus concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of phosphorus at baseline and after 8 weeks of intervention.
measure: Change in alanine transaminase (ALT) concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of ALT at baseline and after 8 weeks of intervention.
measure: Change in aspartate transaminase (AST) concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of AST at baseline and after 8 weeks of intervention.
measure: Change in urea concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of urea at baseline and after 8 weeks of intervention.
measure: Change in creatinine concentration.
time frame: baseline, 8 weeks.
description: Assessment of serum concentration of creatinine at baseline and after 8 weeks of intervention.
arm group label: Metformin + Placebo
arm group type: Placebo Comparator
arm group label: Calcium carbonate + Vitamin D3 + Metformin
arm group type: Experimental
intervention type: Dietary Supplement
intervention name: Vitamin D3
description: Vitamin D3 (Cholecalciferol) (6000 IU/daily). PO for 8 weeks.
arm group label: Calcium carbonate + Vitamin D3 + Metformin
intervention type: Dietary Supplement
intervention name: Calcium Carbonate
description: Calcium carbonate (1000 mg/daily). PO for 8 weeks.
arm group label: Calcium carbonate + Vitamin D3 + Metformin
intervention type: Drug
intervention name: Metformin
description: Metformin (1500 mg/daily; the metformin dose was increased stepwise, starting with 500 mg once daily for the 1st week, 500 mg twice daily in the 2nd week, followed by 500 mg 3 times daily from the 3rd week onward). PO for 8 weeks.
arm group label: Calcium carbonate + Vitamin D3 + Metformin
arm group label: Metformin + Placebo
intervention type: Drug
intervention name: Placebo
description: PO for 8 weeks.
arm group label: Metformin + Placebo
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 30 Years
healthy volunteers: No
last name: Sally Kadoura, B Pharm, MD
role: Principal Investigator
affiliation: Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
last name: Abdul Hakim Nattouf, MD, PhD
role: Study Director
affiliation: Professor at Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
last name: Marwan Alhalabi, MD, PhD
role: Study Director
affiliation: Professor at Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syria.
facility: 
facility: 
country: Syrian Arab Republic
citation: Ameri P, Giusti A, Boschetti M, Murialdo G, Minuto F, Ferone D. Interactions between vitamin D and IGF-I: from physiology to clinical practice. Clin Endocrinol (Oxf). 2013 Oct;79(4):457-63. doi: 10.1111/cen.12268. Epub 2013 Aug 9.
PMID: 23789983
citation: Hahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S, Kimmig R, Mann K, Janssen OE. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006 Nov;114(10):577-83. doi: 10.1055/s-2006-948308.
PMID: 17177140
citation: Irani M, Merhi Z. Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril. 2014 Aug;102(2):460-468.e3. doi: 10.1016/j.fertnstert.2014.04.046. Epub 2014 Jun 3.
PMID: 24933120
citation: Krul-Poel YH, Snackey C, Louwers Y, Lips P, Lambalk CB, Laven JS, Simsek S. The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: a systematic review. Eur J Endocrinol. 2013 Oct 23;169(6):853-65. doi: 10.1530/EJE-13-0617. Print 2013 Dec.
PMID: 24044903
citation: Li HW, Brereton RE, Anderson RA, Wallace AM, Ho CK. Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome. Metabolism. 2011 Oct;60(10):1475-81. doi: 10.1016/j.metabol.2011.03.002. Epub 2011 May 6.
PMID: 21550088
citation: Ott J, Wattar L, Kurz C, Seemann R, Huber JC, Mayerhofer K, Vytiska-Binstorfer E. Parameters for calcium metabolism in women with polycystic ovary syndrome who undergo clomiphene citrate stimulation: a prospective cohort study. Eur J Endocrinol. 2012 May;166(5):897-902. doi: 10.1530/EJE-11-1070. Epub 2012 Feb 13.
PMID: 22330149
citation: Pal L, Zhang H, Williams J, Santoro NF, Diamond MP, Schlaff WD, Coutifaris C, Carson SA, Steinkampf MP, Carr BR, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Myers E, Legro RS; Reproductive Medicine Network. Vitamin D Status Relates to Reproductive Outcome in Women With Polycystic Ovary Syndrome: Secondary Analysis of a Multicenter Randomized Controlled Trial. J Clin Endocrinol Metab. 2016 Aug;101(8):3027-35. doi: 10.1210/jc.2015-4352. Epub 2016 May 17.
PMID: 27186859
citation: Parikh G, Varadinova M, Suwandhi P, Araki T, Rosenwaks Z, Poretsky L, Seto-Young D. Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells. Horm Metab Res. 2010 Sep;42(10):754-7. doi: 10.1055/s-0030-1262837. Epub 2010 Aug 13.
PMID: 20711952
citation: Thierry van Dessel HJ, Lee PD, Faessen G, Fauser BC, Giudice LC. Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome. J Clin Endocrinol Metab. 1999 Sep;84(9):3030-5. doi: 10.1210/jcem.84.9.5941.
PMID: 10487660
responsible party type: Sponsor
mesh term: Polycystic Ovary Syndrome
mesh term: Vitamin D Deficiency
mesh term: Syndrome
mesh term: Vitamin D
mesh term: Cholecalciferol
mesh term: Metformin
mesh term: Calcium Carbonate
mesh term: Calcium
sharing ipd: Undecided