PCOS Treatment Using DLBS3233, Metformin, and Combination of Both (POSITIF)

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

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.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance; Polycystic Ovary Syndrome (PCOS)
• Intervention / Treatment: Drug: Metformin XR; Drug: DLBS3233; Drug: Placebo metformin; Drug: Placebo DLBS3233

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 Type: Interventional
• Enrollment (Actual): 186
• Phase: Phase 3

Contacts and Locations

Study Locations

• Indonesia
  • Banjarmasin, Indonesia
    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Lambung Mangkurat, Ulin Banjarmasin Hospital
  • Denpasar, Indonesia
    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Udayana, Sanglah Hospital
  • Makasar, Indonesia
    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Hasanuddin, Dr. Wahidin Sudirohusodo Hospital
  • Malang, Indonesia
    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Brawijaya, Dr. Saiful Anwar Hospital
  • Manado, Indonesia
    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Sam Ratulangi, Prof. Dr. Kandou Hospital
  • Semarang, Indonesia
    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital
  • Surabaya, Indonesia
    • Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Airlangga, Dr. Soetomo Hospital.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment I : DLBS3233; DLBS3233 100 mg capsule once daily, and Placebo metformin caplet twice daily; orally, for 6 months	Drug: DLBS3233; Other Names: Inlacin; Drug: Placebo metformin; Placebo metformin has the same ingredients with Metformin XR caplet, except that it does not contain the active substance (metformin).
Active Comparator: Treatment II : Metformin; Metformin XR 750 mg caplet twice daily, and Placebo DLBS3233 once daily; orally, for 6 months	Drug: Metformin XR; Other Names: Glumin XR; Drug: Placebo DLBS3233; Placebo DLBS3233 has the same ingredients with DLBS3233 capsule, except that it does not contain the active substance (DLBS3233).
Experimental: Treatment III : Combination DLBS3233 and Metformin; DLBS3233 100 mg capsule once daily, and Metformin XR 750 mg caplet twice daily; orally, for 6 months.	Drug: Metformin XR; Other Names: Glumin XR; Drug: DLBS3233; Other Names: Inlacin

What is the study measuring?

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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Dexa Medica Group
• Investigators: Principal Investigator: Soehartono Ds, Prof. dr., SpOG-K, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Airlangga, Dr. Soetomo Hospital, Surabaya, Indonesia.; Principal Investigator: Arsana Wiyasa IW, Dr. dr., SpOG-K, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Brawijaya, Dr. Saiful Anwar Hospital, Malang, Indonesia.; Principal Investigator: Putu Doster Mahayasa, dr., SpOG-K, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Udayana, Sanglah Hospital, Denpasar, Indonesia.; Principal Investigator: Syarief Taufik, dr., SpOG-K, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital, Semarang, Indonesia.; Principal Investigator: Nusratuddin Abdullah, Dr. dr., SpOG-K, MARS, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Hasanuddin, Dr. Wahidin Sudirohusodo Hospital, Makasar, Indonesia.; Principal Investigator: Iwan Darma Putra, dr., SpOG-K, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Lambung Mangkurat, Ulin Banjarmasin Hospital, Banjarmasin, Indonesia.; Principal Investigator: Eddy Suparman, Prof. Dr. dr., SpOG-K, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Sam Ratulangi, Prof. Dr. Kandou Hospital, Manado, Indonesia.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): February 1, 2019
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: November 26, 2013
• First Submitted That Met QC Criteria: December 2, 2013
• First Posted (Estimate): December 3, 2013

Study Record Updates

• Last Update Posted (Actual): May 28, 2019
• Last Update Submitted That Met QC Criteria: May 24, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: insulin resistance; metformin; Female; DLBS3233; Polycystic ovarium syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Hyperinsulinism; Polycystic Ovary Syndrome; Syndrome; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: DLBS3233-1013