PCOS Treatment Using DLBS3233, Metformin, and Combination of Both

Phase 3

Completed

• Conditions: Polycystic Ovary Syndrome (PCOS); Insulin Resistance
• Interventions: Drug: Metformin XR; Drug: DLBS3233; Drug: Placebo metformin; Drug: Placebo DLBS3233

• Registration Number: NCT01999686
• Lead Sponsor: Dexa Medica Group

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2013-11-26
• Study First Submitted QC: 2013-12-02
• Study First Posted: 2013-12-03
• Study Start: 2014-10
• Primary Completion: 2019-02
• Status Verified: 2019-05
• Study Completion: 2019-05
• Last Update Submitted: 2019-05-24
• Last Update Posted: 2019-05-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 186

Inclusion Criteria

1. Signed written informed consent prior to participation in the study.

2. Female subjects in reproductive age (i.e. 18-40 years) willing to conceive.

3. 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).

4. Subject with insulin resistance defined by : HOMA-IR of > 2.00.

5. Subject with body mass index (BMI) of 19-35 inclusive.

6. Able to take oral medication.

Exclusion Criteria

1. Pregnant or lactating women (urinary pregnancy test will be applied at screening).

2. 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.

3. Known to have the following medical condition:

   • Diabetes mellitus,
   • Uncontrolled hypertension
   • Symptomatic cardiovascular diseases:
   • Acute or chronic infections at baseline.
   • Any known malignancies.

4. History of gynecological surgery.

5. Impaired renal function

6. Impaired liver function

7. Medically-assisted weight loss with medications or surgical procedures.

8. Currently having laparoscopic ovarian diathermy (LOD).

9. Currently under treatment with in vitro fertilization (IVF) techniques.

10. 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

11. Participating in other clinical trial within 30 days prior to screening.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment II : Metformin	Metformin XR	Metformin XR 750 mg caplet twice daily, and Placebo DLBS3233 once daily; orally, for 6 months
Treatment III : Combination DLBS3233 and Metformin	Metformin XR	DLBS3233 100 mg capsule once daily, and Metformin XR 750 mg caplet twice daily; orally, for 6 months.
Treatment I : DLBS3233	Placebo metformin	DLBS3233 100 mg capsule once daily, and Placebo metformin caplet twice daily; orally, for 6 months
Treatment II : Metformin	Placebo DLBS3233	Metformin XR 750 mg caplet twice daily, and Placebo DLBS3233 once daily; orally, for 6 months
Treatment I : DLBS3233	DLBS3233	DLBS3233 100 mg capsule once daily, and Placebo metformin caplet twice daily; orally, for 6 months
Treatment III : Combination DLBS3233 and Metformin	DLBS3233	DLBS3233 100 mg capsule once daily, and Metformin XR 750 mg caplet twice daily; orally, for 6 months.

Primary Outcome Measures

Name	Time	Method
HOMA-IR reduction	6 months	HOMA-IR reduction from baseline to Month 6th (end of study)

Secondary Outcome Measures

Name	Time	Method
Change of waist circumference	1, 2, 3, 4, 5, and 6 months	1, 2, 3, 4, 5, and 6 months
Renal function	6 months	Renal function (levels of serum creatinine, BUN) will be measured at baseline and Month 6th (end of study)
Lipid profile improvement	3 and 6 months	Lipid profile improvement (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides level) from baseline to Month 3rd and Month 6th (end of study)
Improvement of glucose tolerance	3 and 6 months	Improvement of glucose tolerance (reduction of FPG and 2-hour PPPG) from baseline to Month 3rd and Month 6th (end of study)
Response rate: presence of ovulation	menstrual cycle of Month 3rd up to that of Month 6th	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.
Change of endometrium thickness	3 to 6 months	Change of endometrium thickness will be measured by using trans-vaginal USG at basal condition and at the day/period of ovulation
Reduction of free testosterone level	6 months	Reduction of free testosterone level from baseline to Month 6th (end of study)
Change of luteinizing hormone (LH) level	6 months	Change of luteinizing hormone (LH) level from baseline to Month 6th (end of study)
Improvement of S/A ratio	3 to 6 months	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.
Improvement in Ferriman-Gallwey Score	3 and 6 months	Improvement in Ferriman-Gallwey Score from baseline to Month 3rd and Month 6th (the end of study)
Change of luteinizing hormone (LH) / follicle stimulating hormone (FSH) ratio	6 months	Change of luteinizing hormone (LH) / follicle stimulating hormone (FSH) ratio from baseline to Month 6th (end of study)
Liver function	6 months	Liver function (levels of serum AST, ALT, alkaline phosphatase) will be measured at baseline and Month 6th (end of study)
Number of adverse events and subjects with events	During 6 months	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

Trial Locations

Locations (7)

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Udayana, Sanglah Hospital; 🇮🇩 Denpasar, Indonesia

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Lambung Mangkurat, Ulin Banjarmasin Hospital; 🇮🇩 Banjarmasin, Indonesia

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Hasanuddin, Dr. Wahidin Sudirohusodo Hospital; 🇮🇩 Makasar, Indonesia

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Brawijaya, Dr. Saiful Anwar Hospital; 🇮🇩 Malang, Indonesia

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Sam Ratulangi, Prof. Dr. Kandou Hospital; 🇮🇩 Manado, Indonesia

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital; 🇮🇩 Semarang, Indonesia

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Airlangga, Dr. Soetomo Hospital.; 🇮🇩 Surabaya, Indonesia