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

Primary Purpose

Polycystic Ovary Syndrome (PCOS), Insulin Resistance

Status

Completed

Phase

Phase 3

Locations

Indonesia

Study Type

Interventional

Intervention

DLBS3233

Metformin XR

Placebo metformin

Placebo DLBS3233

About this trial

This is an interventional treatment trial for Polycystic Ovary Syndrome (PCOS) focused on measuring Polycystic ovarium syndrome, DLBS3233, metformin, insulin resistance, Female

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

Treatment I : DLBS3233

Treatment II : Metformin

Treatment III : Combination DLBS3233 and Metformin

Arm Description

DLBS3233 100 mg capsule once daily, and Placebo metformin caplet twice daily; orally, for 6 months

Metformin XR 750 mg caplet twice daily, and Placebo DLBS3233 once daily; orally, for 6 months

DLBS3233 100 mg capsule once daily, and Metformin XR 750 mg caplet twice daily; orally, for 6 months.

Outcomes

Primary Outcome Measures

HOMA-IR reduction

HOMA-IR reduction from baseline to Month 6th (end of study)

Secondary Outcome Measures

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)

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)

Change of waist circumference

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.

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

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.

Improvement in Ferriman-Gallwey Score

Improvement in Ferriman-Gallwey Score from baseline to Month 3rd and Month 6th (the end of study)

Reduction of free testosterone level

Reduction of free testosterone level from baseline to Month 6th (end of study)

Change of luteinizing hormone (LH) level

Change of luteinizing hormone (LH) level from baseline to Month 6th (end of study)

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)

Liver function

Liver function (levels of serum AST, ALT, alkaline phosphatase) will be measured at baseline and Month 6th (end of study)

Renal function

Renal function (levels of serum creatinine, BUN) will be measured at baseline and Month 6th (end of study)

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

Full Information

NCT ID

NCT01999686

First Posted

November 26, 2013

Last Updated

May 24, 2019

Sponsor

Dexa Medica Group

1. Study Identification

Unique Protocol Identification Number

NCT01999686

Brief Title

PCOS Treatment Using DLBS3233, Metformin, and Combination of Both

Acronym

POSITIF

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2019

Overall Recruitment Status

Completed

Study Start Date

October 2014 (undefined)

Primary Completion Date

February 2019 (Actual)

Study Completion Date

May 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Dexa Medica Group

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Polycystic Ovary Syndrome (PCOS), Insulin Resistance

Keywords

Polycystic ovarium syndrome, DLBS3233, metformin, insulin resistance, Female

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

186 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment I : DLBS3233

Arm Type

Experimental

Arm Description

DLBS3233 100 mg capsule once daily, and Placebo metformin caplet twice daily; orally, for 6 months

Arm Title

Treatment II : Metformin

Arm Type

Active Comparator

Arm Description

Metformin XR 750 mg caplet twice daily, and Placebo DLBS3233 once daily; orally, for 6 months

Arm Title

Treatment III : Combination DLBS3233 and Metformin

Arm Type

Experimental

Arm Description

DLBS3233 100 mg capsule once daily, and Metformin XR 750 mg caplet twice daily; orally, for 6 months.

Intervention Type

Drug

Intervention Name(s)

DLBS3233

Other Intervention Name(s)

Inlacin

Intervention Type

Drug

Intervention Name(s)

Metformin XR

Other Intervention Name(s)

Glumin XR

Intervention Type

Drug

Intervention Name(s)

Placebo metformin

Intervention Description

Placebo metformin has the same ingredients with Metformin XR caplet, except that it does not contain the active substance (metformin).

Intervention Type

Drug

Intervention Name(s)

Placebo DLBS3233

Intervention Description

Placebo DLBS3233 has the same ingredients with DLBS3233 capsule, except that it does not contain the active substance (DLBS3233).

Primary Outcome Measure Information:

Title

HOMA-IR reduction

Description

HOMA-IR reduction from baseline to Month 6th (end of study)

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Lipid profile improvement

Description

Lipid profile improvement (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides level) from baseline to Month 3rd and Month 6th (end of study)

Time Frame

3 and 6 months

Title

Improvement of glucose tolerance

Description

Improvement of glucose tolerance (reduction of FPG and 2-hour PPPG) from baseline to Month 3rd and Month 6th (end of study)

Time Frame

3 and 6 months

Title

Change of waist circumference

Description

1, 2, 3, 4, 5, and 6 months

Time Frame

1, 2, 3, 4, 5, and 6 months

Title

Response rate: presence of ovulation

Description

Time Frame

menstrual cycle of Month 3rd up to that of Month 6th

Title

Change of endometrium thickness

Description

Change of endometrium thickness will be measured by using trans-vaginal USG at basal condition and at the day/period of ovulation

Time Frame

3 to 6 months

Title

Improvement of S/A ratio

Description

Time Frame

3 to 6 months

Title

Improvement in Ferriman-Gallwey Score

Description

Improvement in Ferriman-Gallwey Score from baseline to Month 3rd and Month 6th (the end of study)

Time Frame

3 and 6 months

Title

Reduction of free testosterone level

Description

Reduction of free testosterone level from baseline to Month 6th (end of study)

Time Frame

6 months

Title

Change of luteinizing hormone (LH) level

Description

Change of luteinizing hormone (LH) level from baseline to Month 6th (end of study)

Time Frame

6 months

Title

Change of luteinizing hormone (LH) / follicle stimulating hormone (FSH) ratio

Description

Change of luteinizing hormone (LH) / follicle stimulating hormone (FSH) ratio from baseline to Month 6th (end of study)

Time Frame

6 months

Title

Liver function

Description

Liver function (levels of serum AST, ALT, alkaline phosphatase) will be measured at baseline and Month 6th (end of study)

Time Frame

6 months

Title

Renal function

Description

Renal function (levels of serum creatinine, BUN) will be measured at baseline and Month 6th (end of study)

Time Frame

6 months

Title

Number of adverse events and subjects with events

Description

Time Frame

During 6 months

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials: