Mode of Action (MoA) Study of TOTUM-63 in Individuals at Increased Cardio-metabolic Risk

Study Overview
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Brief Summary
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This clinical study aims to investigate the effects of TOTUM-63, a mix of 5 plant extracts, consumed at the daily regimen of three times per day, on cardiometabolic health and gut microbiota profile in overweight-obese individuals.

Detailed Description
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In 2019, over 460 million adults had diabetes worldwide. Moreover, it was estimated by the International Diabetes Federation that about 700 million adults will have type 2 diabetes (T2D) by 2045. Valbiotis is a research & development company dedicated to scientific innovation for preventing and reducing the risk of metabolic and cardiovascular disease (CVD) using specific combinations of plant-based molecules. Valbiotis developed a formula (TOTUM-63) which is composed by the association of five plant extracts. Given the results obtained in pre-clinical studies, as well as the good tolerance and first efficacy results of TOTUM-63 in two clinical trials on human subjects, this research aims to investigate the effects of TOTUM-63 on cardiometabolic health and gut microbiota profile in overweight-obese individuals. TOTUM-63 will be tested (5g acutely and 5g/d over 8 weeks of supplementation) on energy metabolism, post-prandial nutrients metabolism and hepatic health in overweight and obese subjects. Blood and feces samples collected before, and after the supplementation will allow to perform metabolomic, transcriptomic and metagenomics analyses to further explore the potential mechanisms of action of TOTUM-63.

Official Title
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An Open-label, Single Arm, Clinical Trial to Explore the Consumption Effects of TOTUM-63 on Metabolic Signatures, Microbiome, Energy Metabolism and Post-prandial Nutrient Processing in Individuals at Increased Cardio-metabolic Risk

Conditions
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Prediabetic State, Dysglycemia, Overweight and Obesity

Intervention / Treatment
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* Dietary Supplement: TOTUM-63


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Body mass index (BMI) between ≥ 27 and < 40 kg/m2 kg/m²; Waist circumference > 94 cm for men and > 80 cm for women; Weight stable within ± 5% in the last three months; Fasting plasma TG ≥ 1.35 OR fasting glycemia ≥ 5.6 and ≤ 6.9 mmol/L OR HbA1c ≥ 5.6 and ≤ 6.4 % Main Exclusion Criteria: Any metabolic disorder requiring pharmacological treatment and susceptible to affect glucose metabolism or plasma lipid levels or that might affect the study outcomes according to the investigator; Taking medication which may affect the study outcomes (or a medication modification less than 3 months prior to the study); To have taken regularly natural health products or enriched foods susceptible to modify the parameters followed by the investigator within the 3 months prior to the study; With a known or suspected food allergy, intolerance or hypersensitivity to any of the study products' ingredient as well as the non-medicinal ingredients of the product; Consuming more than 4 drinks of alcohol per week; Having a lifestyle deemed incompatible with the study according to the investigator including high level of physical activity (defined as more than 10 hours of intense physical activity a week, walking excluded); Pregnant or lactating women or intending to become pregnant within the timeframe of the study; Fasting blood triglycerides (TG) > 2.5 mmol/L; Fasting blood LDL-C > 4.9mmol/L or non-HDL-C > 5.7 mmol/L; Blood AST ≥ 45 U/L for men; and blood AST ≥ 35 U/L for women; Blood ALT ≥ 60 U/L for men; and blood ALT ≥ 50 U/L for women; Blood GGT ≥ 75 U/L for men; and blood GGT ≥ 50 U/L for women; Blood creatinine concentration > 125 μmol/L AND Estimated Glomerular Filtration Rate (eGFR) (calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) < 60 mL/min/1.73m²; Complete blood count (CBC) with hemoglobin < 120 g/L or leucocytes < 3000 /mm3 or leucocytes > 16000 /mm3 or clinically significant abnormality according to the investigator.

Ages Eligible for Study
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Minimum Age: 30 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: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, single center, single arm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TOTUM-63<br>Experimental active are supplemented with TOTUM-63, taken 3 times per day. | Dietary Supplement: TOTUM-63<br>* 5-g per day dose of TOTUM-63 supplement, a mix of 5 plant extracts. Daily dose for 8 weeks followed by a 4 weeks follow-up period without supplementation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of blood pressure | Systolic blood pressure, diastolic blood pressure (in mmHg) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of heart rate | Heart rate (in BPM) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of weight | Weight (in kg) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of waist circumference | Waist circumference (in cm) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of body mass index | Body mass index (in kg/m2) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of fasting glycemia | Fasting glycemia (in mmol/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of insulin secretion | Fasting insulinemia and C-peptide (in pmol/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of HbA1c | Fasting HbA1c (in %) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of satiety hormones | Peptide tyrosine tyrosine (PYY), cholecystokinin (in pg/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of adipokines | Adiponectin, leptin, plasminogen activator inhibitor 1 (in ng/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of inflammatory response (fibrinogen) | Fibrinogen (in ng/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of inflammatory response (IL6, TNFa) | Interleukin 6, tumour necrosis factor alpha (in pg/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of inflammatory response (hs-CRP) | High-sensitivity C-reactive protein (in mg/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of incretin response | Glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 (in pg/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of blood lipid profile (lipid profile) | Triglycerides, total cholesterol, HDL-C, non-HDL-C, LDL-C, free-fatty-acids (in mmol/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of blood lipid profile (oxidized-LDL) | Oxidized-LDL (in ng/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of blood lipid profile (ketones) | Ketones (in umol/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of fecal and plasma bile acid profiles | Primary and secondary bile acids profiles (fecal and plasma) (in uM) | Baseline and V3 (8 weeks of intervention) | 
| Evolution of metagenomic parameters (whole metagenome shotgun sequencing) | Whole metagenome shotgun sequencing | Baseline and V3 (8 weeks of intervention) | 
| Evolution of metagenomic parameters (microbiota diversity) | Microbiota diversity measurements (Shannon index) | Baseline and V3 (8 weeks of intervention) | 
| Evolution of metagenomic parameters (microbiota richness) | Microbiota richness measurements (Simpson index) | Baseline and V3 (8 weeks of intervention) | 
| Evolution of liver MRI | Liver fat content | Baseline and V3 (8 weeks of intervention) | 
| Evolution of FIB-4 index | FIB-4 index (FIB-4 index < 1.45 in the context of steatosis allows the exclusion of a clinically significant fibrosis) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of BARD score | BARD score (from 0 to 4, with a score of 4 resulting in a higher risk of advanced fibrosis) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of NAFLD fibrosis score | NAFLD fibrosis score (< -1.455 low fibrosis probability; -1.455 to 0.676 intermediate score; > 0.676 high probability of fibrosis) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution in kinetics of glucose metabolism | Evaluation of glucose concentrations during a 6-hours mixed-meal tolerance test (in mmol/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution in kinetics of insulin secretion | Evaluation of blood insulin and C-peptide during a 6-hours mixed-meal tolerance test (in pmol/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution in kinetics of blood lipid profile | Evaluation of triglycerides, total cholesterol, HDL-C, non-HDL-C and LDL-C during a 6-hours mixed-meal tolerance test (in mmol/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of kinetics of incretin parameters | Evaluation of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 during a 2-hours mixed-meal tolerance test (in pg/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of inflammatory parameters (fibrinogen) | Evaluation of fibrinogen before and after a 6-hours mixed-meal tolerance test (in ng/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of inflammatory parameters (IL6, TNFA) | Evaluation of interleukin 6, tumour necrosis factor alpha before and after a 6-hours mixed-meal tolerance test (in pg/ml) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of inflammatory parameters (hs-CRP) | Evaluation high-sensitivity C-reactive protein before and after a 6-hours mixed-meal tolerance test (in mg/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of energy metabolism (respiratory quotient) | Evaluation of respiratory quotient before and after a 6-hours mixed-meal tolerance test (in carbon dioxide (CO2) eliminated / dioxygen (O2) consumed) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of energy metabolism (resting metabolic rate) | Evaluation of resting metabolic rate before and after a 6-hours mixed-meal tolerance test (in kcal/day) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of energy metabolism (energy expenditure) | Evaluation of energy expenditure before and after a 6-hours mixed-meal tolerance test (in kcal/kg/h) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of Safety parameters (hepatic enzymes) | Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) (in U/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of Safety parameters (AST/ALT ratio) | AST/ALT ratio | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of Safety parameters (albumin) | Albumin (in g/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of Safety parameters (creatinine) | Creatinine (in umol/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of complete blood count (red and white blood cells, platelet) | Red blood cells, white blood cells, platelet (in cells/mm3) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of complete blood count (hemoglobin) | Hemoglobin (in g/L) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of complete blood count (hematocrit) | Hematocrit (in %) | Baseline, V2 (4 weeks of intervention), V3 (8 weeks of intervention) and V4 (8 weeks of intervention + 4 weeks of follow-up) | 
| Evolution of transcriptomics | RNA sequencing | Baseline and V3 (8 weeks of intervention) | 
| Evolution of metabolomics (amino acids, fatty acids and acylcarnitine species) | Evolution of amino acids, fatty acids and acylcarnitine species (in uM) | Baseline and V3 (8 weeks of intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dysglycemia, Prediabetes, Diabetes risk, Cardio-metabolic risk, Diet supplement, Plant extracts, Polyphenols, Microbiota, Magnetic Resonance Imaging