PCOS Treatment Using DLBS3233, Metformin, and Combination of Both

Study Overview
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Brief Summary
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This is a 3-arm, randomized, double-blind, double-dummy, and controlled clinical study over 6 months of treatment to evaluate the metabolic and clinical efficacy as well as the safety of DLBS3233 alone, metformin and combination of both, in improving metabolic and reproductive parameters.

Detailed Description
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There will be 3 groups of treatment (N = 186), each consist of 62 subjects, as the following: Treatment I : DLBS3233 100 mg once daily Treatment II : Metformin XR 750 mg twice daily Treatment III : DLBS3233 100 mg once daily and Metformin XR 750 mg twice daily. Laboratory examination to evaluate metabolic efficacy parameters will be performed at baseline, Month 3rd, and end of study (Month 6th). Clinical and laboratory examination to evaluate the reproductive efficacy parameters using trans-vaginal USG and biomarkers (such as reproductive hormones) will be performed at baseline to the end of study. Safety examination will be performed at baseline and end of study. Occurrence of adverse event will be observed along the study conduct.

Official Title
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Polycystic Ovary Syndrome Treatment Using DLBS3233, Metformin, and Combination of Both, and Its Relation to Fertility

Conditions
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Polycystic Ovary Syndrome (PCOS), Insulin Resistance

Intervention / Treatment
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* Drug: DLBS3233
* Drug: Metformin XR
* Drug: Placebo metformin
* Drug: Placebo DLBS3233


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent prior to participation in the study. Female subjects in reproductive age (i.e. 18-40 years) willing to conceive. Subject with a diagnosis of polycystic ovary syndrome confirmed by two of the following (Rotterdam Criteria): Hyperandrogenism (defined by elevated free testosterone concentration; or Ferriman-Gallwey Score of ≥ 8). Ovarian dysfunction indicated by menstrual irregularity: oligomenorrhea (cycles of > 35 days), or amenorrhea (no menses in the last of 3 months) after negative screening pregnancy test. Polycystic ovary as shown by ultrasonography (USG). Subject with insulin resistance defined by : HOMA-IR of > 2.00. Subject with body mass index (BMI) of 19-35 inclusive. Able to take oral medication. Exclusion Criteria: Pregnant or lactating women (urinary pregnancy test will be applied at screening). Based on previous or current medical (either laboratory or clinical) examination, subjects known to have any of the following conditions: Cushing's syndrome, late onset of congenital adrenal hyperplasia, androgen-secreting tumors, uncontrolled thyroid disease, hyperprolactinemia. Known to have the following medical condition: Diabetes mellitus, Uncontrolled hypertension Symptomatic cardiovascular diseases: Acute or chronic infections at baseline. Any known malignancies. History of gynecological surgery. Impaired renal function Impaired liver function Medically-assisted weight loss with medications or surgical procedures. Currently having laparoscopic ovarian diathermy (LOD). Currently under treatment with in vitro fertilization (IVF) techniques. Have been regularly taking any of the following medications, within ≤ 3 months prior to screening, such as: Clomiphene citrate Insulin sensitizers, i.e. metformin and thiazolidinediones Aromatase inhibitors, such as: anastrozole, letrozole Glucocorticoids Gonadotropins Gonadotropin-releasing hormone agonists (GnRHa) Oral contraceptive pills (OCPs) Antiandrogens, such as: spironolactone, cyproterone acetate (CPA), and flutamide Any traditional or herbal medicines Participating in other clinical trial within 30 days prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

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 |
| --- | --- |
| Experimental: Treatment I : DLBS3233<br>DLBS3233 100 mg capsule once daily, and Placebo metformin caplet twice daily; orally, for 6 months | Drug: DLBS3233<br> <br> * Other names: Inlacin;Drug: Placebo metformin<br>* Placebo metformin has the same ingredients with Metformin XR caplet, except that it does not contain the active substance (metformin).<br>|
| Active Comparator: Treatment II : Metformin<br>Metformin XR 750 mg caplet twice daily, and Placebo DLBS3233 once daily; orally, for 6 months | Drug: Metformin XR<br> <br> * Other names: Glumin XR;Drug: Placebo DLBS3233<br>* Placebo DLBS3233 has the same ingredients with DLBS3233 capsule, except that it does not contain the active substance (DLBS3233).<br>|
| Experimental: Treatment III : Combination DLBS3233 and Metformin<br>DLBS3233 100 mg capsule once daily, and Metformin XR 750 mg caplet twice daily; orally, for 6 months. | Drug: DLBS3233<br> <br> * Other names: Inlacin;Drug: Metformin XR<br> <br> * Other names: Glumin XR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HOMA-IR reduction | HOMA-IR reduction from baseline to Month 6th (end of study) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lipid profile improvement | Lipid profile improvement (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides level) from baseline to Month 3rd and Month 6th (end of study) | 3 and 6 months | 
| Improvement of glucose tolerance | Improvement of glucose tolerance (reduction of FPG and 2-hour PPPG) from baseline to Month 3rd and Month 6th (end of study) | 3 and 6 months | 
| Change of waist circumference | 1, 2, 3, 4, 5, and 6 months | 1, 2, 3, 4, 5, and 6 months | 
| Response rate: presence of ovulation | Presence of ovulation will be evaluated using trans-vaginal USG to find dominant follicle(s), at the day/period of ovulation, starting from menstrual cycle of Month 3rd up to Month 6th. Measurement of progesterone level will be performed 7 days after the finding of dominant follicle on USG examination to confirm the presence of ovulation. | menstrual cycle of Month 3rd up to that of Month 6th | 
| Change of endometrium thickness | Change of endometrium thickness will be measured by using trans-vaginal USG at basal condition and at the day/period of ovulation | 3 to 6 months | 
| Improvement of S/A ratio | Improvement from baseline of the S/A ratio (defined as the ratio between stromal and total area of median ovarian section) will be measured using trans-vaginal USG (trans-longitudinal measurement) at Baseline, menstrual cycle of Month 3rd, and menstrual cycle of Month 6th at basal condition. | 3 to 6 months | 
| Improvement in Ferriman-Gallwey Score | Improvement in Ferriman-Gallwey Score from baseline to Month 3rd and Month 6th (the end of study) | 3 and 6 months | 
| Reduction of free testosterone level | Reduction of free testosterone level from baseline to Month 6th (end of study) | 6 months | 
| Change of luteinizing hormone (LH) level | Change of luteinizing hormone (LH) level from baseline to Month 6th (end of study) | 6 months | 
| Change of luteinizing hormone (LH) / follicle stimulating hormone (FSH) ratio | Change of luteinizing hormone (LH) / follicle stimulating hormone (FSH) ratio from baseline to Month 6th (end of study) | 6 months | 
| Liver function | Liver function (levels of serum AST, ALT, alkaline phosphatase) will be measured at baseline and Month 6th (end of study) | 6 months | 
| Renal function | Renal function (levels of serum creatinine, BUN) will be measured at baseline and Month 6th (end of study) | 6 months | 
| Number of adverse events and subjects with events | Adverse events as well as number of events and subjects experiencing the events will be observed and evaluated throughout study period (6 months) and until all adverse events have been recovered or stabilized | During 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polycystic ovarium syndrome, DLBS3233, metformin, insulin resistance, Female