Clinical trial NCT01589445: Efficacy Study of Pioglitazone and Metformin and Association Between Pioglitazone Response and Peroxisome Proliferator-activated Receptor Gamma Gene Variants in Bangladeshi Type 2 Diabetes Mellitus Subjects
Official title: Modulation of Insulin Secretion and Insulin Sensitivity in Bangladeshi Type 2 Diabetic Subjects by an Insulin Sensitizer Pioglitazone and T2DM Association With PPARG Gene Polymorphism.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Keywords: Bangladesh
T2DM
Pioglitazone
Metformin
Insulin secretion and Sensitivity
Lead sponsor: University of Dhaka
Sponsor class: OTHER
Collaborators: name: Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders
name: University of Dundee
First posted: 2012-05-02
Enrollment: 77
Sex: ALL
Minimum age (years): 40
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: * The present study was undertaken to assess the efficacy and safety of two different insulin sensitizers (namely Pioglitazone and Metformin) among subjects with type 2 diabetes mellitus (T2DM) in Bangladesh.
* A prospective, double-blind, single group, 'within-subject' designed clinical trial of 77 diagnosed T2DM patients out of 130 patients with glycosylated haemoglobin (HbA1c) ≥7.2±1.5%, aged 46±6.4 years and registered for diabetes treatment in Bangladesh Institute of Research and Rehabilitation in Diabetes Endocrine and Metabolic Disorders (BIRDEM) was carried out.
* The study was conducted between November 2008 and September 2010.
* Baseline data, included case history of the patients,anthropometric measurement, biomedical parameters psychosocial factors, were collected from each subject and then enrolled to receive treatment with 001 drug once daily for three months, then the patients were left for wash out with metformin 850mg once daily for one month; then they received 002 drug once daily for further three months.
* Dietary chart was remained as before.
* DNA was isolated by Chelex method using the primers and control DNA,restriction Digestion Enzyme Endonuclease Hae 111 for genotyping PPARγ-(Peroxisome Proliferator Activated Receptor gamma)Pro12Pro

  * (Proline12Proline)/Pro12Ala-(Proline12 Alanine))/Ala12Ala-(Alanine12Alanine).
* The blinded drugs were decoded after analyzing results, 001 tablet was pioglitazone (30 mg once daily) and 002 tablets was metformin (850mg once daily). Bio-medical outcomes were measured to assess the efficacy of both the drugs each month. After finishing the treatment period the effects of two drugs were compared using SPSS.And the association between the pioglitazone drug effects and genetic polymorphism was also assessed.
* The metformin effects was assessed also using the response rate of HbA1c \<7.0% after 3 months treatment to the patients.

Detailed description: 1. Introduction Thiazolidinediones and metformin are known drugs and especially metformin is widely used medicine to treat people with T2DM. Though pioglitazone has been suspended in many countries, its safety and efficacy is a matter of research for the drug investigators. Thiazolidinediones had been introduced in 1997 as an oral anti-diabetic drug (OAD). Metformin has been used as the key compound to treat T2DM for many years and is the most prescribed OAD worldwide. Both metformin and thiazolidinediones are considered as "insulin sensitizer". The ß-cell dysfunction and insulin resistance are the core defects in the progression of T2DM with associated metabolic syndrome. Evidence suggests that pioglitazone lowers glucose in blood by increasing glucose uptake into cell and metformin by decreasing glucose production. However, there are many controversies in clinical study specially about the improvement of insulin action of metformin. In contrast, a research recommended pioglitazone as the most appropriate OAD for the South Asian population. The key to this argument is that since pioglitazone is a proliferator-activated receptor gamma (PPAR-γ or PPARG) \[a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes\] agonist and decreases insulin resistance, overall glycemic control seems to be better with this thiazolidinedione. However, there are very few published documents on the efficacy and safety of these drugs in South Asians. To the best of our knowledge, there is no published paper that examined and compared the efficacy and safety of these two drugs in Bangladeshi patients T2DM. This double-blind trail therefore examined the efficacy and safety of pioglitazone and metformin in T2DM individuals and also the association of the effects of pioglitazone and the variants of PPARG. We have compared the effects of pioglitazone with metformin on biomedical variables in T2DM patients who were eligible for oral hypoglycaemic therapy and then we also analyzed the association among the effects of pioglitazone and PPARG variants.
2. Methodology

   1. Study Setting:

      The study was conducted between November 2008 and September 2010. The participants for this study were recruited from the outdoor, BIRDEM Hospital in Dhaka,Bangladesh.
   2. Subjects I.Individuals who had been diagnosed with T2DM treating with diet/exercise or Metformin 850 mg or Pioglitazone 30mg once daily, and were attending Outdoor Patient Department (OPD) of BIRDEM for consultation were approached by the researcher and invited to participate in the study. The patients were diagnosed already and registered in BIRDEM. T2DM was ascertained based on World Health Organization recommended criteria two repeated measures of fasting (plasma glucose ≥7.0 mmol ⁄ l or 2-h plasma glucose ≥11.1 mmol ⁄ l.)

      II.We screened a total of 130 patients for eligibility and selected 80 patients for enrollment based of our inclusion and exclusion criteria. But 77 T2DM patients with HbA1c level \< 7.5 %, BMI kg/m2 ≥ 25, SGPT≤ 100 IU/L , creatinine ≤ 1.2 mg/dl) of both sexes, aged between 40-50, treated by monotherapy of pioglitazone or metformin received the drug for the trial according to inclusion and exclusion criteria. 53 patients were screening failure as some did not match eligibility criteria (n=39), some refused to take part(n=11)and some were unable to take part (n=03)due to unknown cause.
   3. Patient Preparation:

      I.Written informed consent was obtained from all participants before study entry. Patients were instructed to follow adhere to a disease- and weight-orientated diet throughout the study as before.

      II.Each case history was documented in the case report form. The study was approved by the National Medical Ethics Review Boards (NMERB) of Bangladesh Medical Research Council (BMRC).The investigations were carried out in accordance with the principles of the Declaration of Helsinki as revised in 2000.
   4. Treatment:

      The patients were to receive treatment pioglitazone tablet 001 (30mg once per day) for 3 months followed by one month "metformin wash-out period", then to the alternative treatment regimen for further 3 months with metformin tablet 002 (850mg once per day). The drugs were supplied by the Aristopharma Pharmaceutical Ltd., Bangladesh.
   5. Anthropometric Measurements I.Height: Standing height was measured using appropriate scales (Detect-Medic, Detect scales INC, USA) without shoes.

      II.Weight: Weight was measured with the balance was placed on a hard flat surface and checked for zero balance before measurement. The subjects were in the center of the platform wearing light cloths without shoes.

      III.BMI: Body mass indexes (BMI) of the subjects were calculated using standard formula: BMI= Weight (kg)/\[Height (m)\] 2.

      IV.Blood Pressure: Systemic and Diastolic pressure was measured according to WHO-IHS.
   6. Blood Sample Collection for Biochemical analysis :

      I. During the appointed date the patients came in the fasting condition. Fasting blood samples (10 ml) were drawn from the antecubital vein. The time was mentioned as 0 hour. Then the patients received drug. They were requested to swallow the tablet and have their breakfast according to their diet charts. Next blood sample had been drawn at 30 min and 2 hour and then they were provided the drugs for the whole month.

      II.The patients were requested to take the drug just before the breakfast every day for 29 days.

      III.From the fasting blood sample 1ml of blood was transferred in an EDTA containing tube for measurement of HbA1C and the rest of the blood was taken in an EDTA containing tube and centrifuged immediately.

      IV.Samples after processing were divided into two aliquots under sterile condition;one aliquot was sent for biochemical analysis for Fasting glucose, Lipid profile, Cholesterol, ALT, Insulin, Creatinine and another one was stored at -80 0C for further verification of results in case of any necessity.
   7. Biochemical Test Methods:

      I. Serum glucose (fasting, 1 and 2 hours) by Glucose Oxidase (GOD-PAP) method (Randox Laboratories Ltd., UK).

      II.Serum triglyceride by enzymatic colorimetric (GPO-PAP) method (Randox Laboratories Ltd., UK).

      III.Serum total cholesterol by enzymatic endpoint (Cholesterol Oxidase/ Peroxidase) method (Randox Laboratories Ltd., UK).

      IV.Serum HDL cholesterol by enzymatic colorimetric (Cholesterol CHOD-PAP) method (Randox Laboratories Ltd., UK) using micro-plate reader (Bio-Tec, ELISA).

      V.Serum creatinine by enzymatic colorimetric (GPO-PAP) method (Randox Laboratories Ltd., UK).

      VI.Serum alanine amino transferase (ALT) by UV method using ALT (GPT) opt.kit (Randox Laboratories Ltd., UK).

      VII.Serum insulin by enzyme linked immunosorbent assay (ELISA) method (Linco Research Inc., USA).

      VIII.Glycosylated Haemoglobin (HbA1c) by High Performance Liquid Chromatographic (HPLC) method.
   8. Blood sample collection for DNA analysis (PPARG gene):

   I.At the end of 3rd month of each treatment 1.5 ml of blood was taken in EDTA containing tube for genetic analysis and the whole blood specimen was collected in the vacuum collection tube containing EDTA, stored at -20 0C to - 80 0C.

   II.DNA was isolated by Chelex method, identified by electrophoresis method and amplified by using primers. We used a published document to select the primers for genotyping PPARγ Pro12Ala/Pro12Pro. The primers for the Pro12Ala SNP genotype, we amplified exon B using the reverse primer 5' CTG GAA GAC AAA CTA CAA GAG 3' and the forward primer 5' ACT CTG GGA GAT TCT CCT ATT GGC 3'. (Sigma product, Order No. SIGMA 03/11/09 4152936-F/185 PPARG-R 8006875247-1).

   III.Control DNA: Professor Colin Palmer Laboratory, Biomedical Research Institute ,University of Dundee Medical School, University of Dundee, Scotland, UK sent six control samples of 3 types control DNA genotyped for PPARG SNP rs 1801282 (Pro12Ala).

   IV.Restriction Digestion Enzyme Endonuclease Hae 111 was used to identify the cutting site(Sigma Product No. R 5628).
3. Response Rate:

1. The response rate was defined by the decrease of ≥10% FBG or by the decrease of ≥1% HbA1c from the baseline values.

ll.There was another response group was defined by the the HbA1c rate \<7.0% after 3 months treatment with metformin only to find out the secondary failure rate of metformin.

4) Statistical Analysis: I.Statistical analysis was performed using SPSS (Statistical Package for Social Science) software for Windows version 18 (SPSS Inc, Chicago, Illinois, USA). Data were expressed as mean + SD (Standard Deviation).

II. Effects of drugs after 3 months treatment were analyzed using t pair tests. The groups were compared using one way ANOVA. If the p value was \<0.05, the groups were compared using the student's t test for unpaired samples or χ2 test through univariate analysis for further verification. Correlation coefficient among the variables was tested using Pearson's test. Multivariate logistic regression analysis was performed to obtain the odds ratios and independent influencing factor for finding possible association between PPARγ genotypes and drug response in case of genetic analysis.

III.A p value \<0.05 was considered significant for all tests. lv. The statistical analysis for within group study like PPARG response group and metformin secondary failure group has not been displayed here.

5) List of Abbreviations

AEs Adverse Events

ALT Alanine aminotransferase

BMI Body Mass Index

BMRC Bangladesh Medical Research Council

BIRDEM Bangladesh Institute of Research and Rehabilitation in Diabetes,Endocrine and Metabolic Disorder

BP Blood Pressure

DNA Deoxynucleic Acid

DBP Diastolic Blood Pressure

DM Diabetes Mellitus

EASD European Association for the Study of Diabetes

EDTA Ethylene Diamine Tetra Acetic acid

ELISA Enzyme Linked Immunosorbent Assay

FBG/FSG Fasting Blood Glucose/Fasting Serum Glucose

FSI Fasting Serum Insulin

2hBG 2 hours Blood Glucose

HbA1c Glycosylated Haemoglobin

HOMA percent B Homeostasis Model Assessment percentage of beta cell function HOMA percent S Homeostasis Model Assessment percentage of sensitivity

HOMA IR Homeostasis Model Assessment Insulin Resistance

HDL-C High Density Lipid Cholesterol

IU/L International Unit/Litre

LDL-C Low Density Lipid Cholesterol

ml millilitre

mm millimetre

mg/dl milligram/ decilitre

MLR Multiple Logistic Regression

OPD Outdoor Patient Department

OMIM Online Mendelian Inheritance in Man

OR Odds Ratio

PPARγ Peroxisome Proliferator Activated Receptor gamma

Pro12Pro Proline12Proline

Pro12Ala Proline 12 Alanine

Ala12Ala Alanine12Alanine

PCR Polymerase Chain Reaction

QUICKI Quantitative Insulin sensitivity Check Index

SD Standard Deviation

SPSS Statistical Package for Social Science

SBP Systolic Blood Pressure

TC Total Cholesterol

TG Triglyceride

T2DM Type 2 Diabetes Mellitus

TZD Thiazolidinedione

µl Microliter

WHO World Health Organization

Eligibility criteria: Inclusion Criteria:

* Type 2 DM patients (with HbA1c level \< 8.5 %, BMI kg/m2 ≥ 25, SGPT ≤ 100 IU/L , creatinine ≤ 1.2 mg/dl) of both sexes,
* Aged between 40-50,
* Treated by monotherapy of pioglitazone or metformin.

Exclusion Criteria:

* Patients with diabetes secondary to another cause.
* Patients suffering from serious incurrent illness requiring systemic treatment.
* Patients suffering from any other infectious diseases.
* Patients with impaired kidney function (serum creatinine level more than 1.2mg/dl)
* Patients with impaired hepatic function (SGPT ≥ 100 IU/L).
* Patients with pulmonary insufficiency with hypoxaemia.
* Triglyceriadiamea (TG ≥ 150mg/dl).
* Bloodpressure \> 180 mmHg (Systolic) or \> 110 mmHg (diastolic).
* Positive history of drug or alcohol abuse.
* Pregnant women and willing to be pregnant shortly.

Primary outcomes:
measure: Comparison of Changes in Fasting Serum Glucose (FSG)With Pioglitazone and Metformin
timeFrame: 3 months for each drug
measure: Comparison of Changes in Glycosylated Hemoglobin (HbA1c)With Pioglitazone and Metformin
timeFrame: 3 months for each drug
measure: Comparison of Changes in Insulin Levels (HOMA IR,QUICKI) With Pioglitazone and Metformin
timeFrame: 3 months for each drug
measure: Comparison of Changes in HOMA Percent B and HOMA Percent S With Pioglitazone and Metformin
timeFrame: 3 months for each drug
measure: Comparison of Changes in Fasting Serum Insulin (FSI)With Pioglitazone and Metformin
timeFrame: 3 months for each drug
Secondary outcomes:
measure: Comparison of Changes in Lipid Profiles With Pioglitazone and Metformin
timeFrame: 3 months for each drug
Other outcomes:
Locations:
city: Dhaka
country: Bangladesh
facility: Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM)
Study officials:
affiliation: University of Dhaka, Bangladesh
name: AK Azad Chowdhury, PhD
role: STUDY_CHAIR
affiliation: University of Dhaka, Bangladesh
name: Masuma Parvin, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: BIRDEM,Dhaka,Bangladesh
name: Begum Rokeya, PhD
role: STUDY_DIRECTOR
affiliation: University of Dundee
name: Colin Palmer, PhD
role: STUDY_DIRECTOR
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