A Diabetes Improvement in Medical Therapy Versus SADJB Study

Study Overview
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Brief Summary
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The incidence of diabetes mellitus is increasing annually in Asia. It is the leading cause of blindness, chronic renal insufficiency, and amputations, multiplying the risks of heart disease and stroke. Ninety percent of diabetic patients are type 2 diabetes mellitus (T2DM), which is usually associated with overweight and obese. Single Anastomosis Duodeno-Jejunal Bypass with Sleeve Gastrectomy (SADJB-SG) is a type of bariatric surgery whereby food is bypassed into the distal jejunum, and the duodenum is excluded. Sleeve gastrectomy offers the restrictive component by reducing the capacity of the stomach. In short, this combined technique results in food restriction and malabsorption. A total of 84 patients will be recruited in this study. An equal number of patients will be allocated into two groups. There will be an intensive medical therapy group (IMT) and SADJB-SG group. The patients in IMT group will be subjected to strict adherence to diet, optimization of diabetic medications and close monitoring of blood glucose and glycated haemoglobin (HbA1c) level. The SADJB-SG group will be undergoing surgery. The variables that will be studied include body mass index (BMI), fasting blood glucose (FBG), glycated haemoglobin (HbA1c), C- peptide, plasma insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Biochemical markers are important in this research as the development of T2DM involves both multi-organ insulin resistance and inadequate insulin secretion by pancreatic β-cells, leading to high blood sugar during fasting and post meal. Other mechanisms proposed in this study are leptin, adipokines, incretins, amino acids, and diabetic dyslipidaemia. The raw data will be analysed using the SPSS statistical software. At the end of the study, the investigator will evaluate and determine the role of SADJB-SG in glycaemic control and BMI in T2DM patients compared to IMT. The investigator hypothesized that there is an improvement in HbA1c level in T2DM patients in SADJB-SG group compare to IMT group.

Detailed Description
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Recruitment will be a prospective study in patients with body mass index (BMI) of 23.5-30 kg/m2, aged between 18 and 65 years old. Each patient will be preoperatively screened (including psychologist assessment) and evaluated by the study multidisciplinary team before recruitment. The study will involve two groups with equal allocation of patients in the intensive medical therapy (IMT) group and Single Anastomosis Duodeno Jejunal Bypass with Sleeve Gastrectomy (SADJB-SG) group with stratification by use of insulin at screening. All patients who agree to participate in this study will be assigned to one of the treatment groups by the doctor without randomization. Before making a final decision for treatment, every patient will undergo a detailed and up-to-date evaluation by the doctor regarding the suitability, the pros and cons, risk and benefits, the potential postoperative complications and the likelihood of requiring postoperative nutritional supplementation. Patients that are eligible to take part in this study will be informed, and the final decision will solely be made based on patients' willingness. The patients will also be made aware that this is an experimental trial and both verbal and written informed consent will be taken before treatment. In addition, the patients will be informed regarding the use of the clinical and analytical data for publication purposes. Initial assessment of the patient's social demographic data, history of present illness (duration of diabetes, oral hypoglycemic agent used), medical and surgical history, family history, anthropometric measurements (height, weight, BMI, calculated as weight (kg)/height (m2), waist, hip and neck circumference), history of weight loss attempt, diet and lifestyle assessment, quality of life assessment and biochemical measures including fasting blood glucose (FBG), glycated haemoglobin (HbA1c), C- peptide, plasma insulin and HOMA-IR, assessment for obstructive sleep apnea, depression and sleep quality will be obtained upon approval of participation in the study or before any form of treatment. An additional pre-operation questionnaire will be given to the SADJB-SG group during initial assessment to ensure understanding of the patients towards the surgery. Adverse events will be monitored closely at 1, 2, 3, and 4 weeks after surgery. In any occurrence of an adverse event, it will be documented and reported within 14 days.The study will be terminated if there are life-threatening or severe adverse events associated with SADJB-SG group or IMT group. Patients will not be given access to the study data however the patients will be informed regarding their progress during every follow-up visit. All medical records and research data will be kept in the investigator's hard disk and web-based storage (i-cloud and i-drive) for two years. Study data will be held even after the study period as there will still be a continuous follow-up with the patients for life. However, all patients' information obtained from this study will be kept and handled in a confidential manner, by applicable laws and regulations. When publishing or presenting the study results, the identity of patients will not be revealed without patient's expressed consent. Participants will also be covered under clinical trial insurance from the institution during the study period. In the case of emergency, all patients will be given the contact number of the investigator as the investigators are contactable throughout the day. This study will begin after receiving the approval of Medical Research & Ethics Committee, Ministry of Health Malaysia. Sample size: The sample size was estimated with the help of PS software (power and sample size calculation software) 3.1.2 with a power of 80% and a significant level of 0.05. The estimation was based on the diabetic remission in a few study done on bariatric surgery on one arm and intensive medical treatment on the other and it was detected a range of 57% to 73% diabetic remission among the bariatric surgery group. Another study by Lee WJ et al., 2014 found a diabetic remission rate of 64% (HbA1C<6.0%) with the SADJB-SG group one year after surgery. The total estimated sample size is 34 patients in each arm for this study. However, with the inclusion of 20% dropout rate, the total number of patients needed for this study is 42 patients in each arm. Laboratory investigations: 15 ml of fasting blood samples will be taken early in the morning for the following blood tests stated below in Ethylenediaminetetraacetic acid (EDTA), fluoride oxalate and plain tubes, depending on the respective test. Samples will be further centrifuged for the serum to be stored in 3 aliquots (1 ml each) for batch analysis. This serum will be stored at - 80°C pending further analysis. The analysis will be done at the Chemical Pathology Laboratory, Faculty of Medicine & Health Sciences, UPM.3.6.1. Baseline preoperative biochemical markers and profiles for all bariatric surgery T2DM candidates, and other nutrients 'at risk' related to medication usage or poor dietary quality include: Blood investigations on automated analyser: Full blood count Renal profile (urea, creatinine, sodium, potassium) Liver function test (total protein, albumin, bilirubin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, gamma-glutamyl transferase) Thyroid function test (TSH, free T4) Cortisol Fasting plasma glucose, HbA1c Fasting lipid profile (total cholesterol, triglyceride, LDL, HDL) Bone profile [calcium, phosphate, magnesium, parathyroid hormone, 25-OH vitamin D] Iron, ferritin, vitamin B12, folate Urine investigations Urinalysis (dipstick) & urine FEME (automated analyser) Urine microalbumin (automated analyser) These investigations will be repeated in 24 months but more frequently if clinically indicated. Apart from that, studying the following parameters at baseline, 6 and 12 months post-surgery will allow us to explore the hypothesis that a modulatory effect on incretin production could lead to better glycaemic control independent of weight loss. Insulin, C-peptide (automated analyser), HOMA-IR (calculated value) Lipoprotein Subfractionation on Lipoprint LDL system. Incretins (GLP-1, GIP) Adipokines such as leptin Adiponectin FGF19 (Fibroblast Growth Factor 19) Tumor necrosis factor-alpha (TNF-alpha) Genetic Analysis: DNA Extraction- Laboratory analyses will be obtained after an overnight fast and the plasma will be separated by centrifugation and storage at -20ºC. The available commercial DNA extraction methods will be utilized to get a good DNA regarding quantity and quality. DNA Quantification- The quality of the extracted DNA will be evaluated using electrophoresis and the concentration of the extracted DNA will be estimated using the spectrophotometer. Genotyping analysis- Standardization of Polymerase chain reaction (PCR) will be carried out for the respective genes. Identification and analysis of candidate genes polymorphisms of GCG, GLP1R, DPP4, GIP, GIPR and PCSK1 genes by conventional PCR, PCR-RFLP, Real time- PCR High Resolution Analysis. Staining and Visualizing of Genomic DNA- Agarose electrophoresis will be carried out to determine the PCR products by staining with ethidium bromide. The genomic DNA, PCR amplified products and the restricted fragments will be visualized under ultraviolet light and the image will be captured by Alpha Imager. Validation- Nearly 10% of the samples will be randomly chosen and the samples will be genotyped on the same assay for the second time and the results will be scored by the other researcher. Positive and Negative Controls PCR amplified products from the respective gene will be sequenced to identify the genotypes. Those samples will be used as a positive control for the respective genes and the PCR grade water lacking the DNA template will be used as a negative control. DNA Sequencing methods- DNA sequencing will be done to confirm the polymorphism of the respective genes. The sequencing results will be subjected to BLAST (www.ncbi.nlm.nig.gov/BLAST) and it has been verified against the published gene sequence for the respective gene. Data Analysis: Statistical calculations will be performed using the standard statistical software package, IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. Results will be expressed as mean values and standard deviation for normally distributed variables. Median and interquartile range (IQR) will be calculated for all not normally distributed continuous variables. Non-parametric tests such as Mann-Whitney U test and/or Kruskall-Wallis test will be used for non-normal distribution of variables. Associations between qualitative variables will be determined by Chi-square test, Fisher's exact test and SAS Exact Contingency Table. In all statistical analyses, p-value of < 0.05 (95% confidence interval) was considered to be statistically significant. Analysis of variance (ANOVA) will be used to test for significant differences between means. Univariate logistic regression analysis will be used to determine the synergistic effect of the genetic variants The Hardy-Weinberg equilibrium for genotypic distribution will be evaluated using the Hardy-Weinberg equilibrium exact test. Rotor-Gene 6000 software (software version 1.7, built 87) will be used for the HRM analysis for certain gene polymorphisms by generating a normalized melting curve, a difference graph and a derivative plot. The categorical variables from this study such as Body Mass Index (BMI), fasting glucose, HbA1c, C- peptide levels, Plasma insulin and HOMA-IR will be reported as counts and percent and compared between SADJB-SG group and IMT group by SPSS method. Study Ethics: Ethical clearance will be obtained from the Ethics Committee for Research Involving Human Subjects Universiti Putra Malaysia (JKEUPM) and Kuala Lumpur General Hospital. This study will be submitted to National Medical Research Register (NMRR) for Medical Research and Ethics Committee, Ministry of Health Malaysia (MREC) clearance. Informed consent will be obtained from each participant of the study. Conflict of Interest: There is no conflict of interest among the investigators.

Official Title
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Single Anastomosis Duodeno Jejunal Bypass With Sleeve Gastrectomy (SADJB-SG) Versus Intensive Medical Therapy (IMT) in the Treatment of Type 2 Diabetes Mellitus Among Asian Patients With BMI 23.5 - 30 kg/m2: A Clinical Trial

Conditions
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Diabetes Mellitus, Type 2, Overweight

Intervention / Treatment
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* Procedure: SADJB-SG group
* Procedure: IMT group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 years. BMI 23.5 - 30 kg/m2. Diabetes more than two years and less than ten years. American Society of Anesthesiologists (ASA) classification < 4 Able to give informed consent Exclusion Criteria: Age: below 18 and above 65. Inability to informed consent. Patients on GLP-1 agonist and insulin two weeks before admission into the trial. Diabetes more than ten years or less than two years. C-Peptide level < 2.0 ng/mL American Society of Anesthesiologists (ASA) classification > 3 Logistic issue where patient come from rural area and has difficulty in complying with the post-operation close monitoring and follow-up Patient who has psychiatric disorder (depression, substance abuse, eating disorder, alcoholism, dementia etc.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will involve two groups with equal allocation of patients in the intensive medical therapy (IMT) group and Single Anastomosis Duodeno Jejunal Bypass with Sleeve Gastrectomy (SADJB-SG) group with stratification by use of insulin at screening. All patients who agree to participate in this study will be assigned to one of the treatment groups by the doctor without randomization.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SADJB-SG group<br>Patients in this group will undergo bariatric surgery. There are two parts to this procedure. One is the restrictive type of weight loss surgery, which reduces the stomach size. The other type prevents the body from absorbing fats and sugar properly, as the small intestine will be attached to the small stomach, bypassing most of the stomach and upper part of the small intestine. This surgery will be performed using a minimally invasive technique known as laparoscopic keyhole surgery. | Procedure: SADJB-SG group<br>* Patients will undergo bariatric surgery. A clear liquid high protein diet will be started in the first two postoperative days. If no complications were detected by physical examination, patients will be stimulated to walk and will be dismissed from the hospital on postoperative day 3. Patients will be subjected to a strict adherence to diet and close monitoring of their blood glucose and HbA1c levels during the study period. Standard follow-up includes a visit to the outpatient clinic at 1, 2, 3, 4 weeks after surgery, then 3, 6, 9, 12, 18, 24 months and after that, a life-long annual visit. Glycaemic control at home will be maintained as in the preoperative period and patients will need to inform the results of their blood glucose levels to the doctor during each follow-up visits.<br>|
| Experimental: IMT group<br>Patients in this group will be subjected to strict adherence to diet, optimisation of diabetic medications and close monitoring of blood glucose and HbA1c. | Procedure: IMT group<br>* Patients will be subjected to strict adherence to their diet, optimisation of their diabetic medications and close monitoring of their blood glucose and HbA1c levels at 0, 6, 12, 24 months. The endocrinologist will be monitoring the patients in this group. Detailed individualized lifestyle and dietary counseling will be given by a dietitian emphasizing on nutrition knowledge, the timing of meal with medication, portion control, and increasing daily physical activity level.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Type 2 Diabetes Mellitus (T2DM) patients in SADJB-SG group achieving glycated hemoglobin (HbA1c) level of less than 7% (with or without diabetes medications) in 2 years as compare to patients in IMT group. | The HbA1c level is measured in percentage | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T2DM patients in SADJB-SG group achieving mean fasting blood glucose level of 4.4-7.0 mmol/l in 2 years as compare to patients in IMT group. | Fasting blood glucose level is measured in mmol/l | 24 months | 
| T2DM patients in SADJB-SG group achieving lower body mass index (BMI) in 2 years as compare to IMT group. | BMI is calculated as weight (kg)/height (m^2) | 24 months | 
| Changes in serum level of lipids. | Fasting blood samples will be taken early in the morning. In the study, serum concentrations of the following lipids will be measured using automated clinical chemistry analyzer: triglycerides, total cholesterol, HDL, LDL. LDL-Subfractionation will be done using Quantrimetrix Lipoprint system. The measurements will be performed before the planned intervention and then at intervals of 6, 12 and 24 months. The results will be presented in respective units (mmol/L). | 24 months | 
| Assessment of NAFLD associated morbidities by detecting the metabolic changes after SADJB-SG. | In the study, serum concentrations of the following analytes will be measured on an automated clinical chemistry analyzer: total protein (g/L), albumin (g/L), bilirubin (umol/L), alkaline phosphatase (U/L), alanine transaminase (U/L), aspartate aminotransferase (U/L), gamma-glutamyl transferase (U/L). ELISA Technique will be used to analyze the following parameters in serum: leptin (pg/mL), adiponectin, FGF19 (pg/mL), and TNF-alpha (pg/mL). The measurements will be performed before the planned intervention and then at intervals of 6, 12 and 24 months. | 24 months | 
| Identification of proposed mechanism for improvement in glycemic control following SADJB-SG. | In the study, serum incretins GLP-1 (pmol/L) and GIP (pmol/L) will be analyzed using ELISA technique. The measurements will be performed before the planned intervention and then at intervals of 6, 12 and 24 months. | 24 months | 
| Identification of genetic biomarkers. | The genotypic and allelic frequencies of genetic polymorphisms of GCG, GLP1R, DPP4, GIP, GIPR, PCSK1 gene are analyzed by PCR method. The significant association (p<0.05) of genetic polymorphisms between the subjects is considered as the genetic risk factors/genetic marker for the development of T2DM. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleeve Gastrectomy, Duodeno Jejunal Bypass, Single Anastomosis, Intensive Medical Therapy, Diabetes Mellitus