The Effect of Vitamin D Supplementation Among Overweight Jordanian Women With Polycystic Ovary Syndrome (PCOS)

Study Overview
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Brief Summary
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This is a prospective double-blind, randomized, parallel-group, placebo-controlled trial designed to examine the effect of supplementation with 50,000 IU vitamin D3 for 3 months on Polycystic Ovary Syndrome (PCOS) prognosis, serum 25-Hydroxy Vitamin D (25(OH)D) level, serum chromium level, insulin resistance, and Body Mass Index (BMI), in 60 overweight Jordanian female patients diagnosed with PCOS and with hypovitaminosis D.

Detailed Description
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This study is designed to assess the safety and efficacy of 50,000 IU vitamin D supplementation once weekly for 3 months on improvement in PCOS prognosis and improvement in serum 25(OH)D levels in 60 overweight Jordanian females (defined as having a BMI 25-30kg/m2), diagnosed with PCOS (based on Rotterdam criteria), and with hypovitaminosis D (defined as a serum 25(OH)D level < 20 ng/mL), compared with placebo. Evaluation of the safety and efficacy of the dosing regimen will be conducted over 6 study visits during which clinical and biochemical signs of PCOS as well as serum 25(OH)D level, serum chromium level, insulin resistance, and BMI will be evaluated. The measurements will be collected as follows : day (-7) during screening , Day (0) base line measurements , Day (30) , Day(60), Day (90), day (104).

Official Title
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The Effect of Vitamin D Supplementation on Chromium Serum Levels and Insulin Resistance Among Overweight Jordanian Women With Polycystic Ovary Syndrome in Irbid

Conditions
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Polycystic Ovary Syndrome, Hypovitaminosis D

Intervention / Treatment
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* Drug: 50,000 IU vitamin D3
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female gender. Aged between 18 and 49 years old. Ethnic group (Caucasian, Middle-eastern). Overweight (BMI 25-30 kg^m2). Diagnosed with Polycystic ovary syndrome according to Rotterdam criteria (Rotterdam SHRE-ASRM Sponsored Polycystic ovary syndrome consensus workshop group, 2004). Diagnosed with hypovitaminosis D (serum 25(OH)D level < 20 ng/mL). Inadequate dietary intake of vitamin D (<600 IU/day or <15μg/day). Physical examination being assessed and accepted by the attending physician. Systolic blood pressure within the normal range (90-140 mmHg). Diastolic blood pressure within the normal range (60-90 mmHg). Heart rate within the normal range (60-100 BPM). Oral body temperature within the normal range (35.9 - 37.6 Cᵒ). Normal complete blood count , Liver Function enzymes test , Aspartate Transaminase (AST) , Alanine Transaminase (ALT) and Kidney function tests , Blood Urea Nitrogen (BUN) and Serum Creatinine (SrCr). Participant is willing and able to give informed consent for participation in the study. Able and willing to comply with all study requirements. Exclusion Criteria: Female participants who are pregnant, lactating or planning pregnancy during the course of the study. Ethnic group: non Caucasian. Females aged <18 or >49 years old. Underweight, normal body weight ,Body Mass Index (BMI) < 25 kg^m2 Obese or morbidly obese (BMI > 30 kg/m2) Diagnosis with type 1 or type 2 diabetes mellitus, hypothyroidism, hyperthyroidism, liver disease, renal dysfunction, cardiovascular diseases, androgen-secreting tumor, Cushing syndrome, congenital adrenal hyperplasia, hyperprolactinemia, and/or virilism. Known history or presence of food allergies or intolerance (e.g dairy products or gluten-containing foods), or any known condition that could interfere with the absorption, distribution, metabolism, or excretion of drugs. History of drug or alcohol abuse, smoking of 10 cigarettes or more (or equivalent) per day. Participants who took medications known to affect metabolic parameters, such as metformin and corticosteroid drugs, vitamin D and calcium. Adequate dietary intake of vitamin D (600 IU/day or 15μg/day or more). Participation in another clinical or bioequivalence study within 90 days prior to the start of this study period. Participants with abnormal Electrocardiogram (ECG). Participants with any abnormal laboratory results excluding [ 25(OH)D, Creatinine (Cr), Calcium (Ca), phosphorus (PO4), C-reactive protein(CRP) , triglyceride , High Density Lipoprotien Cholesterol (HDL-C), Low Density Lipoprotien Cholesterol (LDL-C), total cholesterol (TC)/HDL-C ratio, fasting insulin , fasting blood glucose, oral glucose tolerance test, impaired glucose tolerance, Progesterone, total testosterone, sex hormone binding globulin, parathyroid hormone and free androgen index].

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: vitamin D3 (Biodal 50,000 IU)<br>50,000 IU Vitamin D3 tablet given orally once weekly for 3 months | Drug: 50,000 IU vitamin D3<br>* Film-coated tablet Biodal 50,000 IU containing cholecalciferol 50,000 IU<br>* Other names: cholecalciferol 50,000 IU;|
| Placebo Comparator: placebo<br>Placebo tablet given orally once weekly for 3 months | Drug: Placebo<br>* Placebo film-coated tablet of Biodal 50,000 IU<br>* Other names: Biodal 50,000IU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ultrasound Examination of Number of Follicles and Ovarian Volume | Evaluation of the efficacy of the dosing regimen as per the approved Summery of Product Characteristics (SmPC) (50,000 IU vitamin D3 once weekly for 3 months) on improvement in PCOS prognosis clinically using ultrasound examination. In this measure the reported results were the finding of the ultrasound examination after the course of the treatment /intervention as per the study protocol and reporting the numbers of patients with normal ovaries, One normal ovary and the other is polycystic or both ovaries are poly-cystic. An improvement in PCOS prognosis clinically by ultrasound examination is defined by: decreasing the number of follicles to < 12 follicles measuring 2-9 mm in diameter decreasing ovarian volume to < 10 cm3 | 3 months | 
| Menstrual Regularity | Evaluation of the efficacy of the dosing regimen as per the approved SmPC (50,000 IU vitamin D3 once weekly for 3 months) on improvement in PCOS prognosis by assessment of menstrual regularity An improvement in PCOS prognosis by assessment of menstrual regularity is measured through improving progesterone level > 4 ng/mL. One of the clinical signs of improving PCOS prognosis is menstrual cycle regularity. In this measure ,the reported results consist of the number of volunteers/patients in each arm either with regular menstrual cycle or irregular menstrual cycle after completing the course of the treatment/ intervention as per the study protocol. The results will be statistically analyzed using paired student t-test and 95% confidence interval (CI) for the difference of the means within and between the two groups will be calculated. | 3 months | 
| Hirsutism Score | The scale ranges between 0 and 36, where A score of 8 or higher was considered as androgen excess (Ferriman and Gallwey, 1961).Evaluation of the Efficacy of the dose (50,000IU) and the dose regimen as per the approved SmPC on PCOS prognosis by evaluating Hirsutism Score.Hirsutism score was assessed using self-administrated Ferriman-Gallwey scoring system (Ferriman and Gallwey, 1961). Each participant answered the hirsutism test with the help of a trained nurse who was working in the same clinic. The score of each body site may range between 0 (no excessive terminal hair growth) to 4 (extensive terminal hair growth). In this measure , the hirsutism score were reported in each are after completing the course of treatment/ intervention as per the study protocol. after which, the means were compared for statistical significance between the two groups / arms. | 3 months | 
| Serum Progesterone Level | The results below show the Serum Progesterone level after treatment in each arm after completing the course of the treatment / intervention as per the study protocol.after which, the means were compared for statistical significance between the two groups / arms. After which, the means were compared for statistical significance between the two groups / arms. The evaluation of the Efficacy of the dose (50,000IU) and the dose regimen as per the approved SmPC on PCOS Prognosis by measuring Change in Serum Progesterone level. One of the clinical signs of improving PCOS prognosis is the change in progesterone level. the results will be statistically analyzed using paired student t-test at 95% confidence interval (CI) for the difference of the means within and between the two groups will be calculated. | 3 months | 
| Total Testosterone Level | Evaluation of the Efficacy of the dose (50,000IU) and the dose regimen as per the approved SmPC on PCOS Prognosis by measuring Change in Total Testosterone level before and after the treatment. In this measure , the Total Testosterone levels in each arm were reported after completing the course of the treatment / intervention as per the study protocol. One of the clinical signs of improving PCOS prognosis is the change in testosterone level. After which, the means were compared for statistical significance between the two groups / arms. the results will be statistically analyzed using paired student t-test at 95% confidence interval (CI) for the difference of the means within and between the two groups will be calculated. | 3 months | 
| Free Androgen Index | Free Androgen Index is calculated as the ratio of total testosterone to sex hormone binding globulin (SHBG). In this measure , the Free Androgen Index in each arm were reported after completing the course of the treatment / intervention as per the study protocol. After which, the means were compared for statistical significance between the two groups / arms. Improvement assessment of PCOS Prognosis by evaluating the change in Free Androgen Index. One of the clinical signs of improving PCOS prognosis is the change in FAI. the results will be statistically analyzed using Wilcoxon (Mann- Whitney) method at 95% confidence interval (CI) for the difference of the means within and between the two groups will be calculated. | 3 months | 
| Sex Hormone Binding Globulin Concentration | Evaluation of Biodal 50,000 IU on improvement of PCOS Prognosis by comparing the Sex Hormone Binding Globulin concentrations in both groups/arms. One of the clinical signs of improving PCOS prognosis is the change in the Sex Hormone Binding Globulin Concentration. In this measure , the Sex Hormone Binding Globulin Concentration in each arm were reported after completing the course of the treatment / intervention as per the study protocol. After which, the means were compared for statistical significance between the two groups / arms. The results will be statistically analyzed using Wilcoxon (Mann-Whiteny) method at 95% confidence interval (CI) for the difference of the means within and between the two groups will be calculated. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum 25-Hydroxy Vitamin D3 Level | Evaluation of the Efficacy of the dose (50,000IU) and the dose regimen as per the approved SmPC on increase the level of serum 25(OH)D > 20 ng/ml by measuring of the serum 25(OH)D levels on 104 of the study period after 3 months treatment . In this measure , Serum 25-Hydroxy Vitamin D3 leveln in each arm were reported after completing the course of the treatment / intervention as per the study protocol. After which, the means were compared for statistical significance between the two groups / arms. | 3 months | 
| Serum Chromium Concentration | Evaluation of the Efficacy of the dose (50,000IU) and the dose regimen as per the approved SmPC on improving serum chromium level to be > 0.05 and < 0.5 ppm. which will be assessed by measuring serum chromium level before and after supplementation of Vitamin D3. In this measure , Serum chromium Concentration in each arm were reported after completing the course of the treatment / intervention as per the study protocol. After which, the means were compared for statistical significance between the two groups / arms. One of the clinical signs of improving PCOS prognosis is the improvement in serum chromium level . the results will be statistically analyzed using paired student t-test at 95% confidence interval (CI) for the difference of the means within and between the two groups will be calculated. | 3 months | 
| Serum Glucose Concentration in Oral Glucose Tolerance Test 1st hr After Treatment | Evaluation of the Efficacy of the dose (50,000IU) and the dose regimen as per the approved SmPC on reduction of insulin resistance and improving insulin sensitivity measuring Oral Glucose Tolerance Test 1st hr after the treatment and to compare with same at baseline point within the time frame. In this measure , Serum Glucose Concentration in Oral Glucose Tolerance test in each arm were reported after completing the course of the treatment / intervention as per the study protocol (Treatment with either Biodal or Placebo for 3 months). After which, the means were compared for statistical significance between the two groups / arms. One of the clinical signs of improving PCOS prognosis is the improvement in insulin resistance by evaluating the results of Oral Glucose Tolerance Test 1st hr . the results will be statistically analyzed using paired student t-test at 95% confidence interval (CI). | 3 months | 
| Body Mass Index | Evaluation of the Efficacy of the dose (50,000IU) and the dose regimen as per the approved SmPC on reduction of body mass index to be <25-30 kg/m^2. Evaluation of the Effectiveness of the dose (50,000IU) and the dose regimen as per the approved SmPC on reduction in Body Mass Index before and after the treatment. After which, the means were compared for statistical significance between the two groups / arms. In this measure , Body Mass Index in each arm were reported after completing the course of the treatment / intervention as per the study protocol (Treatment with either Biodal or Placebo for 3 months). | 3 months | 
| Serum Parathyroid Hormone Concentration | Evaluation of the Safety of the Dose and the Dose Regimen as Per the SmPC by measuring the change in the level of serum Serum Parathyroid Hormone (PTH) Concentration before and after the treatment and/or reporting any adverse events through the trial period. In this measure , Serum Parathyroid Hormone Concentration in each arm were reported after completing the course of the treatment / intervention as per the study protocol (Treatment with either Biodal or Placebo for 3 months). After which, the means were compared for statistical significance between the two groups / arms. | 3 months | 
| Serum Calcium Concentration | Evaluation of the safety of the dose and the dose regimen as per the SmPC by measuring the change in the level of serum Calcium before and after the treatment and/or reporting it as adverse. event through the trial period. as the increase of Serum calcium concentration above the normal level is considered as adverse event for the intervention dose regimen of this study for the purpose of evaluating the safety. In this measure , Serum Calcium Concentration in each arm were reported after completing the course of the treatment / intervention as per the study protocol (Treatment with either Biodal or Placebo for 3 months). After which, the means were compared for statistical significance between the two groups / arms. | 3 months | 
| Serum Phosphorous Concentration | Evaluation of the safety of the dose and the dose regimen as per the SmPC by measuring the change in the level of serum PO4 Concentration before and after the treatment and/or reporting as adverse event through the trial period.as the increase of Serum phosphoruse concentration above the normal level is considered as adverse event for the intervention dose regimen of this study for the purpose of evaluating the safety. In this measure , Serum Phosphorous Concentration in each arm were reported after completing the course of the treatment / intervention as per the study protocol (Treatment with either Biodal or Placebo for 3 months). After which, the means were compared for statistical significance between the two groups / arms. | 3 months | 
| Serum C-Reactive Protien Concentration | Evaluation of the Efficacy of the Dose (50,000IU) and the Dose Regimen on inflammation by measuring reduction of the serum concentration of C-Reactive Protein before and after the treatment. In this measure , Serum C-Reactive Protien Concentration in each arm were reported after completing the course of the treatment / intervention as per the study protocol (Treatment with either Biodal or Placebo for 3 months). After which, the means were compared for statistical significance between the two groups / arms. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D, deficiency, hypovitaminosis D, Biodal, 25 hydroxy Vitamin D, 25hydroxyvitamin D, 25(OH)D, PCOS, insulin resistance, BMI, chromium levels, vitamin D 3, cholecalciferol, 50,000 IU