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Metabolic Responses of Metformin and Genetic Polymorphisms of SLC22A1 Gene in PCOS

Primary Purpose

Polycystic Ovary Syndrome, Metformin

Status
Recruiting
Phase
Phase 4
Locations
Bangladesh
Study Type
Interventional
Intervention
Metformin Hydrochloride
Sponsored by
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Polycystic Ovary Syndrome focused on measuring Metformin, solute carrier family 22 member 1, Polycystic ovary syndrome, Metabolic response

Eligibility Criteria

18 Years - 35 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria: • Newly diagnosed women of reproductive age (18 - 35 years) PCOS patients Exclusion Criteria: • Patients having known similar endocrine disorders (hypothyroidism, hyperprolactinemia, androgen producing tumor, congenital adrenal hyperplasia, etc) Planning to conceive within next six months, pregnant/ lactating mother Patients with known diabetes mellitus, ischemic heart disease, chronic liver (serum ALT >2 × upper limit of normal) and renal disease (eGFR <60 ml/minute/1.73 m2 body surface area) Patients taking oral contraceptive, steroid or drugs affecting insulin resistance (metformin, pioglitazone)

Sites / Locations

  • Department of Endocrinology, Bangabandhu Sheikh Mujib Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

PCOS

Arm Description

Participants with PCOS

Outcomes

Primary Outcome Measures

Homeostasis model assessment of insulin resistance (HOMA-IR)
Insulin resistance
Lipid profile
Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglyceride, all in mg/dL
Weight
Weight (Kg)
C-peptide
Beta cell secretory capacity, ng/ml
SLC22A1 (rs628031)
AA, AT, TT- frequency
SLC22A1 (rs2282143)
CC, CG, GG- frequency
Glycemic status
Fasting plasma glucose (mmol/L), 2 hours after OGTT (2H-OGTT) glucose (mmol/L)
Height
Height (meter)
Waist circumference
waist circumference (cm)
Systolic blood pressure
Systolic blood pressure (mm-Hg)
Diastolic blood pressure
Diastolic blood pressure (mm-Hg)

Secondary Outcome Measures

Number of participants with side-effects
Number of participants with nausea, vomiting, diarrhea, loose motion, and others

Full Information

First Posted
October 27, 2022
Last Updated
July 29, 2023
Sponsor
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Collaborators
Department of Genetic Engineering and Biotechnology, Dhaka University
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1. Study Identification

Unique Protocol Identification Number
NCT05680805
Brief Title
Metabolic Responses of Metformin and Genetic Polymorphisms of SLC22A1 Gene in PCOS
Official Title
Metabolic Responses of Metformin and Genetic Polymorphisms (rs628031 and rs2282143) of Solute Carrier Family 22 Member 1 Gene in Polycystic Ovary Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 27, 2023 (Actual)
Primary Completion Date
October 31, 2024 (Anticipated)
Study Completion Date
May 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Collaborators
Department of Genetic Engineering and Biotechnology, Dhaka University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The aim of this study is to see the associations of metabolic responses of metformin with single nucleotide polymorphisms (SNPs) (rs628031 and rs2282143) of solute carrier family 22 member 1 (SLC22A1) gene in women with polycystic ovary syndrome (PCOS). This prospective clinical study will be conducted in the department of Endocrinology, Bangabandhu Sheikh Mujib Medical University (BSMMU) from February 2023 to September 2024 over a period of two years. A total of at least 100 women with PCOS (18 - 35 years) diagnosed based on International Evidence-based Guideline for PCOS 2018, will be included consecutively by convenient sampling. After taking informed written consent, relevant clinical history will be taken and physical examinations will be done at baseline. Following a run in phase of three weeks, patients will visit thrice after 1, 12 & 24 weeks of metformin maintenance therapy with a window period of 14 days both ways. Blood samples will be collected in fasting state at baseline and after 24 weeks of treatment to measure glycemic status, lipid profile, fasting insulin, c-peptide and detection of SLC22A1 gene (rs628031 and rs2282143) polymorphisms. Glucose will be measured by glucose oxidase method, lipids by glycerol phosphate dehydrogenase peroxidase method, insulin by chemiluminescent microparticle immunoassay, c-peptide by enzyme-linked immunosorbent assay (ELISA) and genetic analysis of rs628031 and rs2282143 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Detailed Description
Objectives of the Study General objective Determination of the association of metabolic responses to metformin with SLC22A1 gene polymorphisms (rs628031 and rs2282143) in women with PCOS Specific objectives To see the changes of metabolic profile (body mass index, waist circumference, blood pressure, glycemic status, insulin resistance, c-peptide and lipid) in 24 weeks of metformin therapy in women with PCOS Determination of frequency of SLC22A1 gene polymorphisms (rs628031 and rs2282143) in women with PCOS Categorization of PCOS patients according to SLC22A1 gene polymorphisms (rs628031 and rs2282143) into wild and variant groups Comparison of metabolic changes of 24 weeks of metformin therapy between wild vs. variant group of SLC22A1 gene polymorphisms (rs628031 and rs2282143) in women with PCOS Others: Determination of the short-term side-effects of metformin in women with PCOS Comparison of metformin side-effects in women with PCOS with or without SLC22A1 gene polymorphisms (rs628031 and rs2282143) Materials and Methods: Type of study: Prospective clinical study Place of study: Department of Endocrinology, BSMMU Study period: October 2022 to September 2024 Study population: Reproductive aged (18 - 35 years) women of PCOS Sampling method: Consecutive purposive/convenient sampling Sample size: The sample size will be calculated from following formula: n= {(Zα + Zβ)^2 × (σ1^2 + σ2^2)} ÷ (μ1 - μ2)^2 From a previous similar study, the 2 hours OGTT glucose/insulin ratio (GIR) before and after 24 weeks of metformin therapy were 2.3±2.5 and 3.2±3.2 in variant genotype and 2.0±1.9 and 3.9±2.9 respectively in wild genotype of SLC22A1 rs628031. The mean differences in variant and wild genotype were 0.9±0.7 and 1.9±1.0 respectively. Here, Zα= 1.96 at 95% confidence level, Zβ= 1.28 at 90% power, μ1= mean changes of GIR after metformin in variant genotype of rs628031 (AG/GG) = 0.9, μ2 = mean of GIR after metformin in wild genotype of rs628031(AA) = 1.9, Assuming standard deviation (SD)= 1.5 (σ1=σ2) in both groups Minimum number of sample to be studied in each group, n= {(1.96 + 1.28)^2 × (1.52 + 1.52)} ÷ (0.9 - 1.9)^2 {(3.24)^2 × (2.25 + 2.25)} ÷ (1.0)^2 {10.50 × 4.50} ÷ 1 = 47.25 ÷ 1 = 47.25 At least 94 patients with PCOS are required for this study. However considering dropout, at least 100 patients with PCOS will be taken for the study. Sample size may be increased if required. Study procedure Newly diagnosed at least 100 women of reproductive age (18 - 35 years) PCOS patients will be consecutively recruited from the department of Endocrinology, BSMMU. Informed written consent will be taken from patients and asked to come in fasting state on particular day, time and place twice a week. Related history (reproductive, personal and family history) will be taken and physical examination (height, weight, waist circumference, hip circumference, acne, hirsutism, acanthosis nigricans) will be done and all data will be documented in a pretested semi-structured questionnaire. Blood sample collection at baseline: About 10 ml of venous blood will be drawn from each participant with 8 - 12 hours of fasting. Then a 75 gm oral glucose tolerance test (OGTT) will be done and another five ml of blood will be collected after two hours. About two ml of blood collected during fasting and two hours after OGTT will be kept in fluorinated tube for blood glucose measurement on the same day of collection. Additional two ml of whole blood will be preserved at -70 degree Celcius in the department of Endocrinology for polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) after completing all biochemical analysis to avoid bias. Remaining six ml blood collected during fasting and three ml of blood collected after OGTT will be kept standing for 15 minutes to allow clotting. After centrifugation, serum will be separated and kept into eppendorf. After proper labeling, they will be preserved in a -700C refrigerator. Biochemical analysis (glucose and lipid profile) of the serum will be done on the same day and insulin and c-peptide within seven days of collection. Interventions Lifestyle modifications Patients will be counseled at the time of diagnosis and a written document will be provided. Diet An individualized diet chart prepared by dietitian will be provided Overweight/obese: An energy deficit of 500 Kcal/day diet from weight maintenance diet Others: Weight maintenance diet Physical activity A minimum of 150 minutes/week of moderate intensity physical activity (brisk walking at a rate of 6 km/h) with muscle strengthening activities on 2 non-consecutive days/week activity be performed in at least 10-minute bouts or around 1000 steps, aiming to achieve at least 30 minutes daily at least 5 days a week Metformin prescription Ingredients of each tablet of metformin Each tablet of metformin contains metformin 500 mg HCl, BP along with inactive ingredients of povidone, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In addition, the coating for the tablets contains polyethylene glycol, polyvinyl alcohol, titanium dioxide, talc, gum acacia, maltodextrin, propylene glycol and natural flavors. Inventory All the tablets of metformin will be dispensed periodically to the study participants by the researcher at baseline and 1st visit (after week 1) and 2nd follow up visit after 12 weeks of metformin maintenance therapy (1500 mg/day). Metformin tablets will be preserved as per the instructions of manufacturer. Expiry date and quality of the drugs will be checked periodically. Run-in phase Metformin will be prescribed at 500 mg once daily after dinner and will increase to 1500 mg/day in three divided doses after main meals within two weeks of initiation. Patients will be asked to come with a chart of drug compliance and side-effects one week after initiation of 1500 mg/day of metformin. Patients who will not able to tolerate 1500 mg/day, be excluded from the study for analysis of metabolic responses. Maintenance dose: 1500 mg/day in three divided dose for 24 weeks Follow up: Patients will be requested to come for three follow up visits after 1, 12 and 24 weeks of maintenance metformin therapy with a window period of two weeks both ways. During 1st follow up visit (after 1 week) patients' drug compliance and side-effects will be monitored; clinical status along with lifestyle and drug's compliance and adverse effects will be documented after 12 weeks (2nd follow up visit). After 24 weeks (3rd visit), patient's biochemical metabolic profiles will also be done with above mentioned clinical information. Blood sample collection after 24 weeks About eight ml of venous blood after 24 weeks of metformin therapy with 8 - 12 hours of fasting will be collected to measure FBG, HbA1C, insulin, c-peptide and lipid profile and a 75 gm OGTT followed by five ml of blood will be collected for measurement of glucose and insulin. Drug compliance: It will be monitored over phone weekly for the first two weeks and then each visit to the researcher. Patients will be requested to come with empty blisters of metformin. A record book will be maintained to monitor compliance properly. Patients with drug compliance <95% at any time of the study will be excluded from the analysis for metabolic responses. Adverse events monitoring: On each visit patients will be provided with an adverse event (AE) diary for noting pre-specified gastro-intestinal (GI) events. They will also be asked for any serious adverse effect (SAE) or other AE apart from GI event. All AE and SAE will be recorded in given AE form and will be preserved in patients' files. Patients will be advised to strictly use barrier contraception. Serum ALT and creatinine will be measured after 24 weeks of metformin therapy also.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycystic Ovary Syndrome, Metformin
Keywords
Metformin, solute carrier family 22 member 1, Polycystic ovary syndrome, Metabolic response

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
PCOS
Arm Type
Experimental
Arm Description
Participants with PCOS
Intervention Type
Drug
Intervention Name(s)
Metformin Hydrochloride
Intervention Description
Metformin 1500 mg/day in 3 divided dose for 24 weeks
Primary Outcome Measure Information:
Title
Homeostasis model assessment of insulin resistance (HOMA-IR)
Description
Insulin resistance
Time Frame
24 weeks
Title
Lipid profile
Description
Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglyceride, all in mg/dL
Time Frame
24 weeks
Title
Weight
Description
Weight (Kg)
Time Frame
24 weeks
Title
C-peptide
Description
Beta cell secretory capacity, ng/ml
Time Frame
24 weeks
Title
SLC22A1 (rs628031)
Description
AA, AT, TT- frequency
Time Frame
24 weeks
Title
SLC22A1 (rs2282143)
Description
CC, CG, GG- frequency
Time Frame
24 weeks
Title
Glycemic status
Description
Fasting plasma glucose (mmol/L), 2 hours after OGTT (2H-OGTT) glucose (mmol/L)
Time Frame
24 weeks
Title
Height
Description
Height (meter)
Time Frame
24 weeks
Title
Waist circumference
Description
waist circumference (cm)
Time Frame
24 weeks
Title
Systolic blood pressure
Description
Systolic blood pressure (mm-Hg)
Time Frame
24 weeks
Title
Diastolic blood pressure
Description
Diastolic blood pressure (mm-Hg)
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Number of participants with side-effects
Description
Number of participants with nausea, vomiting, diarrhea, loose motion, and others
Time Frame
24 weeks

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: • Newly diagnosed women of reproductive age (18 - 35 years) PCOS patients Exclusion Criteria: • Patients having known similar endocrine disorders (hypothyroidism, hyperprolactinemia, androgen producing tumor, congenital adrenal hyperplasia, etc) Planning to conceive within next six months, pregnant/ lactating mother Patients with known diabetes mellitus, ischemic heart disease, chronic liver (serum ALT >2 × upper limit of normal) and renal disease (eGFR <60 ml/minute/1.73 m2 body surface area) Patients taking oral contraceptive, steroid or drugs affecting insulin resistance (metformin, pioglitazone)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Muhammad A Hasanat, MPhil, MD
Phone
+88 01711-670735
Email
aryansowgat@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Muhammad A Hasanat, MPhil, MD
Organizational Affiliation
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University
City
Dhaka
ZIP/Postal Code
1000
Country
Bangladesh
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Muhammad A Hasanat, MPhil, MD
Phone
+88 01711-670735
Email
aryansowgat@gmail.com
First Name & Middle Initial & Last Name & Degree
Md S Morshed, MD
First Name & Middle Initial & Last Name & Degree
Hurjahan Banu, FCPS
First Name & Middle Initial & Last Name & Degree
Shaheda Anwar, PhD
First Name & Middle Initial & Last Name & Degree
Ahmed A Saleh, MPhil
First Name & Middle Initial & Last Name & Degree
Sharif Akhteruzzaman, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Only group data
Citations:
PubMed Identifier
20660041
Citation
Gambineri A, Tomassoni F, Gasparini DI, Di Rocco A, Mantovani V, Pagotto U, Altieri P, Sanna S, Fulghesu AM, Pasquali R. Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 2010 Oct;95(10):E204-8. doi: 10.1210/jc.2010-0145. Epub 2010 Jul 21.
Results Reference
result
PubMed Identifier
30959948
Citation
Chang HH, Hsueh YS, Cheng YW, Ou HT, Wu MH. Association between Polymorphisms of OCT1 and Metabolic Response to Metformin in Women with Polycystic Ovary Syndrome. Int J Mol Sci. 2019 Apr 7;20(7):1720. doi: 10.3390/ijms20071720.
Results Reference
result
PubMed Identifier
24533710
Citation
Schweighofer N, Lerchbaum E, Trummer O, Schwetz V, Pieber T, Obermayer-Pietsch B. Metformin resistance alleles in polycystic ovary syndrome: pattern and association with glucose metabolism. Pharmacogenomics. 2014 Feb;15(3):305-17. doi: 10.2217/pgs.13.223.
Results Reference
result

Learn more about this trial

Metabolic Responses of Metformin and Genetic Polymorphisms of SLC22A1 Gene in PCOS

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