Trial Title:
Metabolic Responses of Metformin and Genetic Polymorphisms of SLC22A1 Gene in PCOS
NCT ID:
NCT05680805
Condition:
Polycystic Ovary Syndrome
Metformin
Conditions: Official terms:
Polycystic Ovary Syndrome
Syndrome
Metformin
Conditions: Keywords:
Metformin
solute carrier family 22 member 1
Polycystic ovary syndrome
Metabolic response
Study type:
Interventional
Study phase:
Phase 4
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Metformin Hydrochloride
Description:
Metformin 1500 mg/day in 3 divided dose for 24 weeks
Arm group label:
PCOS
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.
Criteria for 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)
Gender:
Female
Minimum age:
18 Years
Maximum age:
35 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University
Address:
City:
Dhaka
Zip:
1000
Country:
Bangladesh
Status:
Recruiting
Contact:
Last name:
Muhammad A Hasanat, MPhil, MD
Phone:
+88 01711-670735
Email:
aryansowgat@gmail.com
Investigator:
Last name:
Md S Morshed, MD
Email:
Sub-Investigator
Investigator:
Last name:
Hurjahan Banu, FCPS
Email:
Sub-Investigator
Investigator:
Last name:
Shaheda Anwar, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Ahmed A Saleh, MPhil
Email:
Sub-Investigator
Investigator:
Last name:
Sharif Akhteruzzaman, PhD
Email:
Sub-Investigator
Start date:
May 27, 2023
Completion date:
May 31, 2025
Lead sponsor:
Agency:
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Agency class:
Other
Collaborator:
Agency:
Department of Genetic Engineering and Biotechnology, Dhaka University
Agency class:
Other
Source:
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05680805
