BTI320 (SUGARDOWN®) on Post-Prandial Hyperglycaemia in Subjects With Pre-Diabetes

Study Overview
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Brief Summary
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This is a single-centre, 16-week, randomized, double-blind, placebo-controlled, 3-treatment arm pilot study to evaluate the efficacy and safety of BTI320 in the treatment of high risk subjects with pre-diabetes. This is a pilot study aiming to test whether taking a medicine named BTI320 that slows down carbohydrate absorption in the gut, will lower blood sugar. The study aims to recruit 60 individuals in Hong Kong. To take part in the study, subjects must have pre-diabetes, that is, they have blood sugar levels that are above normal but not reaching diabetes range. The medicine BTI320 is currently licensed as a health supplement in Hong Kong and is known alternatively as SUGARDOWN®. The investigators are comparing the effectiveness of BTI320 against a dummy tablet. Both tablets look and taste identical and during the study, subjects will not know which of these tablets they are taking. There is a 4 in 5 chance of receiving active medication and 1 in 5 chance of receiving placebo. Subjects will be followed up closely every 2 to 4 weeks for a period of time up to 22 weeks. The study visits will take between 30 minutes to 3 hours, depending on additional checks that are required on a particular visit including oral glucose tolerance test and meal tolerance test. At visits involving meal tolerance test, subjects will be required to stay for approximately 3 hours. In addition, at Visit 2, Visit 4 and 3 days before Visit 7, a continuous glucose monitoring system device will be installed. Throughout the study period, subjects will return to the study center for check-ups including careful enquiry about whether they have developed any side-effects from taking the medication, physical examination, as well as blood tests.

Detailed Description
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In a recent national survey, 11% of adults in China have diabetes and 50% have pre-diabetes defined by fasting plasma glucose (FPG) 5.6-6.9 mmol/l and/or 2-hour post glucose (PG) 7.8-11.0 mmol/L using 75 gram oral glucose tolerance test (75g OGTT) and/or glycated haemoglobin (HbA1c) 5.7-6.4%. Depending on the presence of other risk factors, the annual conversion rate of pre-diabetes averages 3-10% with pre-diabetes associated with 1.5-2.0 fold increased risk for cardiovascular disease. Once diabetes is established, life expectancy is reduced by 6 years if not diagnosed, treated or controlled, especially in young-to-middle aged subjects who will face long disease duration of diabetes. In the Hong Kong Diabetes Registry, depending on control of glucose and other risk factors, 3-10% of Chinese subjects with diabetes may die or develop a major event every year including heart disease, stroke, kidney failure and /or all-site cancer. Besides glycaemic control as defined by HbA1c, post prandial hyperglycaemia and glycaemic variability have also been shown to predict cardiovascular and renal events in both pre-diabetic and diabetic patient. Genetic variants discovered in large-scale epidemiological studies including those from China and Hong Kong have been found to be associated with beta cell dysfunction which can be further exacerbated by glucotoxicity and lipotoxicity, often due to co-existing obesity giving rise to early onset diabetes. Several studies including those from Asian populations indicated that subjects with pre-diabetes exhibit reduced early phase insulin secretion resulting in postprandial hyperglycaemia which can impose metabolic stress on the beta cells leading to eventual beta cell failure. BTI320, also known as SUGARDOWN®, is derived from galactomanan which acts by blocking the key carbohydrate hydrolyzing enzymes including amylase, maltose, lactose and sucrose in the gastrointestinal tract. It also acts to bind to ingested polysaccharides and slow their absorption with each meal thereby reducing post prandial glucose excursion. The mechanism of action for BTI320 is similar to Acarbose®, an alpha glucosidase inhibitor, which has been shown to improve glycaemic control and has been approved for prevention of diabetes in China. 24-hour continuous glucose monitoring system (CGMS) measures mean blood glucose (MBG), mean area under the curve for blood glucose above 10mmol/l (180mg/dl) (AUC-180), mean postprandial maximum glucose (MPMG), mean amplitude of glucose excursion (MAGE) over 72 hours. These parameters correlate well with plasma fructosamine (FA) alternatively known as glycated albumin, which reflects short-term glycaemic control during the preceding 2 weeks.

Official Title
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A Study to Evaluate the Effect of BTI320 (SUGARDOWN®) on Post-Prandial Hyperglycaemia in High Risk Chinese Subjects With Pre-Diabetes

Conditions
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Pre-Diabetes

Intervention / Treatment
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* Drug: BTI320
* Drug: BTI320 matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects ≥ 18-70 years inclusive Chinese ethnicity High risk subject with pre-diabetes as defined by meeting at least 2 of the following criteria from (a), (b) and (c): FPG ≥ 5.6-6.9 mmol/l and/or 2-hour PG ≥ 7.8-11.0 mmol/l during 75 gram OGTT HbA1c ≥ 5.7-6.4% At least one of the following risk factors:- History of gestational diabetes Family history of diabetes in first degree relative 2 components or more of the metabolic syndrome (triglyceride ≥ 1.7 mmol/L, blood pressure (BP) ≥ 130/80 mmHg, high density-lipoprotein (HDL) cholesterol <1.3 mmol/L in women or <1.1 in men and waist circumference ≥ 80 cm in women or ≥ 90 cm in men). Patients on anti-hypertensive agent for treatment of hypertension or lipid lowering drug for the treatment of hyperlipidaemia will respectively be considered to have one component of the metabolic syndrome. Subject is capable of giving informed consent prior to the initiation of any study related procedures A female subject of childbearing potential who is sexually active with a non-sterilized male partner agrees to use routinely adequate and effective contraception to avoid pregnancy during the study period and up to 30 days after the final visit. The subject is able and willing to consistently record food diary to facilitate CGMS evaluation. Exclusion Criteria: Subject has received anti-diabetic agents within 6 weeks prior to screening visit. On dietary supplement known to affect glucose or galactose metabolism. History of acute cardiovascular disease including myocardial infarction, acute coronary syndrome or stroke which required hospitalization in the last 12 months. Significant renal impairment with estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2 Known lactose or galactose intolerance. History of eating disorder. Pregnant or lactating female subjects. Subjects with gastrointestinal disease that may interfere with absorption of the investigational product. Subject has received any investigational product within 30 days of randomization visit. Reduced life expectancy or any condition considered by the investigator as unsuitable for enrolment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BTI320 4 grams<br>three times daily, oral for 16 weeks | Drug: BTI320<br>* BTI320, also known as SUGARDOWN®, is derived from galactomanan which blocks key enzymes that break down carbohydrate in the gut. BTI320 therefore helps to slow down the absorption of carbohydrates to lower post-meal blood sugar.<br>* Other names: SUGARDOWN®;|
| Experimental: BTI320 8 grams<br>three times daily, oral for 16 weeks | Drug: BTI320<br>* BTI320, also known as SUGARDOWN®, is derived from galactomanan which blocks key enzymes that break down carbohydrate in the gut. BTI320 therefore helps to slow down the absorption of carbohydrates to lower post-meal blood sugar.<br>* Other names: SUGARDOWN®;|
| Placebo Comparator: BTI320 matching placebo<br>2 tablets three times daily, oral for 16 weeks | Drug: BTI320 matching placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Fructosamine in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo |  | From baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Post-prandial Glucose Incremental Area Under Curve on Continuous Glucose Monitoring System | Changes in 3-hour post-prandial glucose incremental area under curve on continuous glucose monitoring system from baseline to Week 16. Note that this is not a pharmacokinetic study and this is not pharmacokinetic data as we are not measuring drug levels. Here we are examining glucose levels after meals as one of the anticipated glycemic outcomes of using glucose-lowering therapy (BTI320 in this case). With data-analysis based on continuous glucose monitoring, it is conventional to present post-prandial (i.e. post-meal) glucose incremental area under curve at up to 3 hours. It is not meaningful to look at post-meal glucose changes at more than 3 hours after meal for the obvious reason that subject might have taken another meal by then. | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose BTI320 and High Dose BTI320 Compared With Placebo in Mean Post-meal Maximum Glucose on Continuous Glucose Monitoring System |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Amplitude of Glucose Excursion on Continuous Glucose Monitoring System |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Blood Glucose on Continuous Glucose Monitoring System |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Area Under Curve for Glucose Levels >180mg/dL on Continuous Glucose Monitoring System | Area under curve for glucose levels >180 mg/dL over 72 hours | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Glucose on Continuous Glucose Monitoring System |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation on Continuous Glucose Monitoring System |  | From baseline to Week 16 | 
| Changes in HbA1c in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo |  | From baseline to Week 16 | 
| Changes in Fructosamine in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Area Under Curve of Glucose During Standard Meal Tolerance Test From 0 Minute to 120 Minutes | Changes in area under curve of glucose from 0 minute to 120 minutes from baseline to Week 16 | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Area Under Curve of Insulin During Standard Meal Tolerance Test From 0 Minute to 120 Minutes | Changes in area under curve of insulin from 0 minute to 120 minutes from baseline to Week 16 | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Area Under Curve of C-peptide During Standard Meal Tolerance Test From 0 Minute to 120 Minutes | Changes in area under curve of C-peptide from 0 minute to 120 minutes from baseline to Week 16 | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Glucagon-like Peptide 1 During Standard Meal Tolerance Test From 0 Minute to 120 Minutes | Changes in area under curve of glucagon-like peptide-1 from 0 minute to 120 minutes from baseline to Week 16 | From baseline to Week 16 | 
| Proportion of Subjects With Impaired Fasting Glucose or Impaired Glucose Tolerance in Low Dose BTI320, High Dose BTI320 and Placebo Group | Proportion of subjects with impaired fasting glucose, impaired glucose tolerance, both impaired fasting glucose and impaired glucose tolerance, HbA1c 5.7-6.4%, or type 2 diabetes at 30 days post-treatment | From baseline to 30 days post-treatment | 
| Changes in Blood Pressures in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo | Changes in systolic blood pressures from baseline to Week 16 | From baseline to Week 16 | 
| Changes in Waist Circumference in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo |  | From baseline to Week 16 | 
| Changes in Body Weight in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo |  | From baseline to Week 16 | 
| Changes in Lipids in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo | Changes in total cholesterol from baseline to Week 16. | From baseline to Week 16 | 
| Changes in High-sensitivity C-reactive Protein in Subjects Treated With High Dose and Low Dose BTI320 Compared Placebo |  | From baseline to Week 16 | 
| Changes in Urate in Subjects Treated With High Dose and Lose Dose BTI320 Compared to Placebo |  | From baseline to Week 16 | 
| Changes in Quality of Life Measures in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo | Changes in WHOQOL-BREF physical health domain score from baseline to Week 16. This is a sub-scale of the WHOQOL-BREF. Possible scores range from minimal of 4 to maximum of 20. Higher score indicate better physical health domain. | From baseline to Week 16 | 
| Changes in Measures of Food Satiety in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo | Changes to question of how full do you feel in the Appetite Questionnaire adopted from Hill and Blundell from baseline and Week 16. Scale score ranges from minimum of 0 to maximum of 10. 10 being the most full and 0 being the least full. | From baseline to Week 16 | 
| Changes in Measures of Nutritional Intake in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo | Changes in daily calories intake from baseline to Week 16 | From baseline to Week 16 | 
| Changes in Measures of Exercise in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo | Changes in the number of days per week that the subject spent walking for at least 10 minutes from baseline to Week 16 | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean 1 Hour Post-prandial Glucose Incremental Area Under Curve on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean 2 Hour Post-prandial Glucose Incremental Area Under Curve on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean 3 Hour Post-prandial Glucose Incremental Area Under Curve on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in 1 Hour Post-prandial Mean Blood Glucose on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in 2 Hour Post-prandial Mean Blood Glucose on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in 3 Hour Post-prandial Mean Blood Glucose on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Blood Glucose During 24 Hours on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Post-prandial Maximum Glucose on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Post-prandial Maximum Glucose During 24 Hours on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Blood Glucose During 1 Hour Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Blood Glucose During 2 Hours Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Blood Glucose During 3 Hours Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Blood Glucose Over 24 Hours on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation of Blood Glucose Over 1 Hour Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation of Blood Glucose Over 2 Hours Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation of Blood Glucose Over 3 Hours Post-prandial on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 | 
| Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation of Blood Glucose Over 24 Hours on Continuous Glucose Monitoring System Repeated Measures Analysis |  | From baseline to Week 16 |