Clinical trial NCT02358668: BTI320 (SUGARDOWN®) on Post-Prandial Hyperglycaemia in Subjects With Pre-Diabetes
Official title: A Study to Evaluate the Effect of BTI320 (SUGARDOWN®) on Post-Prandial Hyperglycaemia in High Risk Chinese Subjects With Pre-Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pre-Diabetes
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Sugardown Company Limited
First posted: 2015-02-09
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Adult subjects ≥ 18-70 years inclusive
2. Chinese ethnicity
3. High risk subject with pre-diabetes as defined by meeting at least 2 of the following criteria from (a), (b) and (c):

   1. FPG ≥ 5.6-6.9 mmol/l and/or 2-hour PG ≥ 7.8-11.0 mmol/l during 75 gram OGTT
   2. HbA1c ≥ 5.7-6.4%
   3. 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.
4. Subject is capable of giving informed consent prior to the initiation of any study related procedures
5. 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.
6. The subject is able and willing to consistently record food diary to facilitate CGMS evaluation.

Exclusion Criteria:

1. Subject has received anti-diabetic agents within 6 weeks prior to screening visit.
2. On dietary supplement known to affect glucose or galactose metabolism.
3. History of acute cardiovascular disease including myocardial infarction, acute coronary syndrome or stroke which required hospitalization in the last 12 months.
4. Significant renal impairment with estimated glomerular filtration rate (eGFR) \< 60ml/min/1.73m2
5. Known lactose or galactose intolerance.
6. History of eating disorder.
7. Pregnant or lactating female subjects.
8. Subjects with gastrointestinal disease that may interfere with absorption of the investigational product.
9. Subject has received any investigational product within 30 days of randomization visit.
10. Reduced life expectancy or any condition considered by the investigator as unsuitable for enrolment.

Primary outcomes:
measure: Change in Serum Fructosamine in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo
timeFrame: From baseline to Week 4
Secondary outcomes:
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Mean Blood Glucose on Continuous Glucose Monitoring System
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Standard Deviation of Glucose on Continuous Glucose Monitoring System
timeFrame: From baseline to Week 16
measure: Changes in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo in Percent Coefficient of Variation on Continuous Glucose Monitoring System
timeFrame: From baseline to Week 16
measure: Changes in HbA1c in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo
timeFrame: From baseline to Week 16
measure: Changes in Fructosamine in Subjects Treated With Low Dose and High Dose BTI320 Compared With Placebo
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: Proportion of Subjects With Impaired Fasting Glucose or Impaired Glucose Tolerance in Low Dose BTI320, High Dose BTI320 and Placebo Group
timeFrame: From baseline to 30 days post-treatment
measure: Changes in Blood Pressures in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in Waist Circumference in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in Body Weight in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in Lipids in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in High-sensitivity C-reactive Protein in Subjects Treated With High Dose and Low Dose BTI320 Compared Placebo
timeFrame: From baseline to Week 16
measure: Changes in Urate in Subjects Treated With High Dose and Lose Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in Quality of Life Measures in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in Measures of Food Satiety in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in Measures of Nutritional Intake in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in Measures of Exercise in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
measure: 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
timeFrame: From baseline to Week 16
Other outcomes:
measure: Changes in Serum Creatinine in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 16
measure: Changes in Measures of Liver Function in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 4, Week 8, Week 12, and Week 16
measure: Changes in Complete Blood Count in Subjects Treated With High Dose and Low Dose BTI320 Compared to Placebo
timeFrame: From baseline to Week 4, Week 8, Week 12, and Week 16
Locations:
city: Shatin
country: Hong Kong
facility: The Chinese University of Hong Kong
Study officials:
affiliation: Chinese University of Hong Kong
name: Andrea OY Luk, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Luk AOY, Zee BCY, Chong M, Ozaki R, Rausch CW, Chan MHM, Ma RCW, Kong APS, Chow FCC, Chan JCN. A proof-of-concept study to evaluate the efficacy and safety of BTI320 on post-prandial hyperglycaemia in Chinese subjects with pre-diabetes. BMC Endocr Disord. 2018 Aug 31;18(1):59. doi: 10.1186/s12902-018-0288-5.