Effect of Pasteurized Akkermansia Muciniphila on Insulin Resistance in Otherwise Healthy Subjects With Dysglycaemia

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate the efficacy of pasteurized Akkermansia muciniphila (pAKK) in improving insulin sensitivity in hyperglycaemic, but otherwise healthy persons with metabolic syndrome. This is the primary objective of this study. Secondary objectives consist of evaluation of the effects of next generation beneficial microbes on metabolic health, anthropometry and body composition, and safety. Therefore, the trial is designed as a phase 2, randomized, double-blind, placebo-controlled, parallel group, multi-center trial comparing pAKK with placebo in restoring insulin sensitivity in dysglycaemic but otherwise healthy subjects with metabolic syndrome. In total, 144 enrolled participants will attend 6 study visits in total. Study visits may be conducted in the clinic, at home by a Healthcare Professional, or by telephone / telemedicine.

Detailed Description
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Overweight and obesity have reached worldwide epidemic level. Observation of elevated glycaemia like impaired fasting glucose and impaired glucose tolerance are reflecting pre-diabetic states often occurring in the context of development of insulin resistance in persons with metabolic syndrome. Moreover, this status is associated with the risk for developing type 2 diabetes as well as cardiovascular disease. In a proof of concept study the supplementation with A. muciniphila was safe and improved metabolic health in persons with metabolic syndrome. The purpose of this study is to demonstrate the efficacy of pasteurized Akkermansia muciniphila (pAKK) in improving insulin sensitivity in hyperglycaemic, but otherwise healthy persons with metabolic syndrome. This is the primary objective of this study. Secondary objectives consist of evaluation of the effects of next generation beneficial microbes on metabolic health, anthropometry and body composition, and safety. Therefore, the trial is designed as a phase 2, randomized, double-blind, placebo-controlled, parallel group, multi-center trial comparing pAKK with placebo in restoring insulin sensitivity in dysglycaemic but otherwise healthy subjects with metabolic syndrome. In total, 144 enrolled participants will attend 6 study visits in total. Study visits may be conducted in the clinic, at home by a Healthcare Professional, or by telephone / telemedicine.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Investigate the Effects of 'Next Generation Beneficial Microbes', Akkermansia Muciniphila (AMF-01), on Long-term Improvements in Insulin Resistance in Otherwise Healthy Hyperglycaemic Adults

Conditions
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Metabolic Syndrome, Pre-diabetes, Overweight and Obesity

Intervention / Treatment
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* Dietary Supplement: Pasteurized A. muciniphila
* Dietary Supplement: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent; BMI between >25 and <40 Kg/m2; Qualifying for the diagnosis of metabolic syndrome according to the International Diabetes Federation (IDF 2006) criteria. At least any three of five citeria, with the modification that the criterion FPG≥100 mg/dL (5.6 mmol/L) is required among at least three of five: Increased waist circumference: for Europid, sub-Saharan African, Eastern and Middle-Eastern ≥94 cm (men) or ≥80 cm (women), with ethnic-specific waist circumference cut-points: for South Asian and Chinese patients, waist ≥90 cm (men) or ≥80 cm (women); for Japanese patients, waist ≥90 cm (men) or ≥80 cm (women); Triglycerides ≥150 mg/dL (1.7 mmol/L) (exception: triglycerides ≥100 mg/dL (1.13mmol/L) for sub-Saharan African) or treatment for elevated triglycerides; HDL cholesterol <40 mg/dL (1.03 mmol/L) in men or <50 mg/dL (1.29 mmol/L) in females, or treatment for low HDL; Systolic blood pressure ≥130, diastolic blood pressure ≥85 mmHg, or treatment for hypertension; FPG ≥100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes; an oral glucose tolerance test is recommended for patients with an elevated FPG, but it is not required. If participant has a prior diagnosis of pre-diabetes or Type II diabetes, and has been unmedicated for 3-months prior to screening; If female, must meet all the following criteria: Not pregnant or breastfeeding If of childbearing potential (including peri-menopausal women who have had a menstrual period within one year) must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as double barrier methods [male condom with spermicide, with or without cervical cap or diaphragm], implants, injectable or oral contraceptives [must have been using for at least the last 3 months], some intrauterine contraceptive devices, tubal ligation, or in an established relationship with a vasectomized partner) during the entire duration of the study Be willing to maintain stable dietary habits and physical activity levels throughout the trial period; Be able to communicate well with the Investigator, to understand and comply with the requirements of the study and be judged suitable for the study in the opinion of the Investigator. Within 3 months following to the exit of the study for failure to comply with one or more of the inclusion criteria listed above, a re-screening could be performed. Exclusion Criteria: Uncontrolled hyperglycemia assessed by HbA1c ≥ 6.5%; Suffering from a metabolic disorder such as diabetes mellitus that requires lifesyle and dietary recommendations or a medication according to the recommendations, uncontrolled thyroidal trouble (Confirmed by clinical significant abnormal TSG/T4 and/or stabled medication for >3 months) or other metabolic disorder; Suffering from a severe chronic disease (e.g., cancer, HIV, renal failure, hepatic or biliary disorders ongoing, chronic inflammatory digestive disease, inflammatory bowel disease, irritable bowel syndrome, arthritis or other chronic respiratory trouble, etc.) or gastrointestinal disorders found to be inconsistent with the conduct of the study by the investigator (e.g., celiac disease); With a history of retinopathy, microalbuminuria, ischemic cardiovascular event during the previous 6 months; Consumption of more than 30 g of dietary fibre per day, as measured by the Block Fibre Screener Prior diagnosis of Type I diabetes mellitus (i.e., a clinical diagnosis made before the screening visit of this study); Alcohol consumption (>21 units per week); Smoking more than 10 cigarettes per day; Previous bariatric surgery; Any surgery in the 3 months before the study or planned for 6 months after enrolling; Pregnancy or pregnancy planned in the 6 months after enrolling or lactating women; Consumption of dietary supplements (omega-3 fatty acids, probiotics, prebiotics, plant stanols/sterols) in the 4-weeks before the study; Presence or history of significant and diagnosed gastrointestinal diseases that, in the opinion of the investigator, could be associated with disturbed gastrointestinal absorption (e.g., resections, diverticula, active and diagnostically confirmed irritable bowel syndrome, malabsorption syndrome); Present or recent (within 3-months of screening) use of any other medication which, in the opinion of the investigator, could interfere with the outcome of the study, including but not limited to antithrombotic agents, anti-inflammatory agents and chronic NSAID use (except low-dose prophylactic, proton pump inhibitors (PPIs), antihistamines, if ongoing (3-months) and on a stable dose throughout study period); Steroids (over the counter (OTC) NSAIDS, topical steroids and inhalers are allowed) Current or planned participation in a weight-loss regimen (including intermediate fasting), including extreme dietary practices or exercise; Anorexia nervosa, bulimia or significant eating disorders according to the investigators; Having lost >5% of their body weight within 3-months prior to screening; Lactose intolerance or milk protein allergy; Gluten intolerance; Current treatment with medications influencing the parameters of interest (glucose-lowering drugs such as metformin, DPP4 inhibitors, GLP-1 receptor agonists, acarbose, sulfonylureas, glinides, thiazolidinediones, sodium-glucose cotransporter -2 inhibitors, insulin, lactulose, glucocorticoids, immunosuppressive agents, , orlistat, cholestyramine or ezetimibe); Antibiotic use in the 3 months before the study; Participant has a known allergy to inactive or active ingredients in the study products; Participation in other clinical research trials within 90 days prior to randomization; Any other condition which in the Investigator's opinion may adversely affect the subject's ability to complete the study or its measures or which may pose significant risk to the subject.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: randomized, double-blind, placebo-controlled, parallel group, multi-center trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group receiving pasteurized Akkermansia muciniphila<br>Experimental group receiving pasteurized Akkermansia muciniphila. | Dietary Supplement: Pasteurized A. muciniphila<br>* Daily oral dose<br>|
| Placebo Comparator: Control group<br>Control group receiving placebo, identical to verum regarding the form, size, taste, color and intake. | Dietary Supplement: placebo<br>* Placebo = identical to verum regarding the form, size, taste, color and intake<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity by Matsuda Index | Absolute change from baseline to day 120 in treatment group as compared to placebo in insulin sensitivity as determined by Matsuda. | From baseline to day 120 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity by homeostasis model assessment-estimated (HOMA) insuline sensitivity | change in treatment group as compared to placebo by measuring fasting glucose and insulin values | From baseline to day 120 | 
| fasting blood glucose | change in treatment group as compared to placebo | From baseline to day 120 | 
| 3-hour blood glucose incremental Area Under the Curve (AUC) as measured by Oral Glucose Tolerance Test (OGTT) | change in treatment group as compared to placebo | From baseline to day 120 | 
| Peak Plasma Concentration (Cmax) of blood glucose as measured by OGTT | change in treatment group as compared to placebo | From baseline to day 120 | 
| 3-hour blood insulin incremental Area Under the Curve (AUC) as measured by OGTT | change in treatment group as compared to placebo | From baseline to day 120 | 
| Peak Plasma Concentration (Cmax) of blood insulin as measured by OGTT | change in treatment group as compared to placebo | From baseline to day 120 | 
| Glycosylated hemoglobin (HbA1c) | change in treatment group as compared to placebo | From baseline to day 120 | 
| Postprandial triglyceride (TG) response as incremental Area Under the Curve (AUC) as measured by OGTT | change in treatment group as compared to placebo | From baseline to day 120 | 
| Peak Plasma Concentration (Cmax) of blood TG as measured by OGTT | change in treatment group as compared to placebo | From baseline to day 120 | 
| Blood lipid profile by total cholesterol, TG, low density lipoprotein, high density lipoprotein, non-esterified fatty acids | change in treatment group as compared to placebo | From baseline to day 120 | 
| Liver enzymes (ALT, AST, GGT, bilirubin, alkaline phosphatase) | change in treatment group as compared to placebo | From baseline to day 120 | 
| Anthropometry by Height (m) and body weight (kg) combined into BMI (kg/m2) | change in treatment group as compared to placebo | From baseline to day 120 | 
| Circumference (cm) of waist, hip and neck and waist, hip and height measurement will be combined into Waist-to-Hip ratio (W:H) and Waist-to-Height ratio (WHtR) | change in treatment group as compared to placebo | From baseline to day 120 | 
| Body composition by measurement of body fat mass by DEXA measurement | change in treatment group as compared to placebo | From baseline to day 120 | 
| Body composition by measurement of lean mass by DEXA measurement | change in treatment group as compared to placebo | From baseline to day 120 | 
| Body composition by measurement of trunk fat mass by DEXA measurement | change in treatment group as compared to placebo | From baseline to day 120 | 
| Vital signs: heart rate | evaluation of heart rate | From baseline to day 120 | 
| Vital signs: blood pressure | evaluation of Systolic blood pressure (SBP) (mmHg) and diastolic blood pressure (DBP) (mmHg) | From baseline to day 120 | 
| Vital signs: body temperature | evaluation of body temperature | From baseline to day 120 | 
| Vital signs: respiratory rate | evaluation of respiratory rate | From baseline to day 120 | 
| Adverse events | evaluation of occurrence of the nature, frequency, severity and relatedness of adverse events as well as clinically significant laboratory values | From baseline to day 120 |