- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05680805
Metabolic Responses of Metformin and Genetic Polymorphisms of SLC22A1 Gene in PCOS
Metabolic Responses of Metformin and Genetic Polymorphisms (rs628031 and rs2282143) of Solute Carrier Family 22 Member 1 Gene in Polycystic Ovary Syndrome
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 4
Contacts and Locations
Study Contact
- Name: Muhammad A Hasanat, MPhil, MD
- Phone Number: +88 01711-670735
- Email: aryansowgat@gmail.com
Study Locations
-
-
-
Dhaka, Bangladesh, 1000
- Recruiting
- Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University
-
Contact:
- Muhammad A Hasanat, MPhil, MD
- Phone Number: +88 01711-670735
- Email: aryansowgat@gmail.com
-
Sub-Investigator:
- Md S Morshed, MD
-
Sub-Investigator:
- Hurjahan Banu, FCPS
-
Sub-Investigator:
- Shaheda Anwar, PhD
-
Sub-Investigator:
- Ahmed A Saleh, MPhil
-
Sub-Investigator:
- Sharif Akhteruzzaman, PhD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: PCOS
Participants with PCOS
|
Metformin 1500 mg/day in 3 divided dose for 24 weeks
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Homeostasis model assessment of insulin resistance (HOMA-IR)
Time Frame: 24 weeks
|
Insulin resistance
|
24 weeks
|
Lipid profile
Time Frame: 24 weeks
|
Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglyceride, all in mg/dL
|
24 weeks
|
Weight
Time Frame: 24 weeks
|
Weight (Kg)
|
24 weeks
|
C-peptide
Time Frame: 24 weeks
|
Beta cell secretory capacity, ng/ml
|
24 weeks
|
SLC22A1 (rs628031)
Time Frame: 24 weeks
|
AA, AT, TT- frequency
|
24 weeks
|
SLC22A1 (rs2282143)
Time Frame: 24 weeks
|
CC, CG, GG- frequency
|
24 weeks
|
Glycemic status
Time Frame: 24 weeks
|
Fasting plasma glucose (mmol/L), 2 hours after OGTT (2H-OGTT) glucose (mmol/L)
|
24 weeks
|
Height
Time Frame: 24 weeks
|
Height (meter)
|
24 weeks
|
Waist circumference
Time Frame: 24 weeks
|
waist circumference (cm)
|
24 weeks
|
Systolic blood pressure
Time Frame: 24 weeks
|
Systolic blood pressure (mm-Hg)
|
24 weeks
|
Diastolic blood pressure
Time Frame: 24 weeks
|
Diastolic blood pressure (mm-Hg)
|
24 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of participants with side-effects
Time Frame: 24 weeks
|
Number of participants with nausea, vomiting, diarrhea, loose motion, and others
|
24 weeks
|
Collaborators and Investigators
Investigators
- Principal Investigator: Muhammad A Hasanat, MPhil, MD, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms
- Endocrine System Diseases
- Disease
- Ovarian Cysts
- Cysts
- Ovarian Diseases
- Adnexal Diseases
- Gonadal Disorders
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Genital Diseases
- Genital Diseases, Female
- Polycystic Ovary Syndrome
- Syndrome
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Metformin
Other Study ID Numbers
- BSMMU/2022/9559-768
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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