Effect of Totum-63, Active Ingredient of Valedia, on Glucose and Lipid Homeostasis on Subjects With Prediabetes

Given the data on the active ingredients of Totum-63, this research aims to evaluate the effect of its chronic consumption (24 weeks) on glucose and lipid homeostasis and especially on fasting plasma glucose in volunteers with abdominal obesity associated with impaired glucose tolerance or untreated type 2 diabetes and hypertriglyceridemia. This clinical study is designed to estimate the effect of Totum-63, active ingredient of Valedia, on several glucose and lipid homeostasis related parameters since these data are still unknown for this specific dietary supplement formula. Collected data will provide more reliable information which may be used to plan a subsequent larger main study.

Primary objective:

The primary objective of the present trial is to assess the beneficial effect of Totum-63 compared to a placebo on glucose homeostasis assessed by the fasting plasma glucose level in prediabetics or untreated type 2 diabetics after 24 weeks of consumption.

Secondary objectives:

Secondary objectives of the study are to assess the efficacy of Totum-63 compared to a placebo in prediabetics or untreated type 2 diabetics after 12 and 24 weeks of consumption through the following criteria:

* Glucose homeostasis assessed by fasting plasma glucose level (after 12 weeks of consumption only), fasting blood HbA1c and fructosamine levels, OGTT (Oral Glucose Tolerance Test after 24 weeks of consumption only), insulinemic and glycemic parameters.
* Pancreatic beta-cells function and insulin sensitivity assessed by fasting blood insulin level, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance), HOMA-β, QUICKI (Quantitative Insulin sensitivity Check Index), ISI-M (Matsuda-DeFronzo Insulin Sensitivity Index after 24 weeks of consumption only), OGIS (Oral Glucose Insulin Sensitivity after 24 weeks of consumption only) and PREDIM (PREDIcted M after 24 weeks of consumption only) indexes.
* Lipid homeostasis assessed by fasting blood levels of triglycerides (TG), Total Cholesterol (TC), HDL-cholesterol, LDL-cholesterol and NEFA (Non-Esterified Fatty Acids).
* Oxidation mechanism of circulating lipids assessed by the ratio fasting blood LDLox / fasting blood LDLc and the PON-1 (paraoxonase-1, arylesterase activity) activity in blood.
* Low grade inflammation assessed by fasting blood hsCRP level.
* Hepatic function assessed by fasting blood total bilirubin level, GGT, ASAT and ALAT activities in blood.
* Hemodynamics assessed by Heart Rate (HR), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP).
* Anthropometrics assessed by Body Weight (BW), Waist Circumference (WC), Hip Circumference (HC) and Waist to Hip Ratio (WHR).
* Satiety assessed by the three-day food diary energy and nutrient intake parameters.

Safety objectives:

The following criteria assessed after 24 weeks of study product consumption participate to the objectives of safety check:

* Renal function assessed by fasting blood creatinine and urea level;
* Complete blood count.

Eligibility Criteria:
Inclusion Criteria:

I1. Fasting glycemia \> 6,1 mmol/L. (1,1 g/L). I2. 2 hours glycemia (OGTT) \> 7,8 mmol/L (1,4 g/L). I3. HbA1c \< 7% I4. Triglyceridemia \> 1,5 g/L. I5. Prediabetic or type-2 diabetic but not requiring immediate drug therapy according to the current recommendations (HAS, 2013).

I6. Waist circumference \> 94 cm for men or \> 80 cm for women. I7. With reported body weight variation \< 5% in the 3 months prior the randomization.

I8. Without significant change in food habits or in physical activity in the 3 months before randomization and agreeing to keep them unchanged throughout the study (no hyper-hypocaloric diet nor start-stop of sport activity planned in the next 7 months).

I9. For women: Non menopausal with the same reliable contraception since at least three months before the beginning of the study and agreeing to keep it during the entire duration of the study (hormonal contraception, intra uterine device or surgical intervention) or menopausal with or without hormone replacement therapy (oestrogenic replacement therapy begun from less than 3 months excluded).

I10. Good general and mental health with in the opinion of the investigator: no clinically significant and relevant abnormalities of medical history or physical examination.

I11. Able and willing to participate to the study by complying with the protocol procedures as evidenced by his dated and signed informed consent form.

I12. Affiliated with a social security scheme. I13. Agree to be registered on the volunteers in biomedical research file.

Exclusion Criteria:

E1. Fasting blood triglycerides \> 3,5 g/L. E2. TSH outside the laboratory normal values. E3. Fasting blood TC \> 4,5 g/L or HDLc \< 0,1 g/L with an abnormality judged as clinically significant according to the investigator.

E4. Blood AST, ALT or GGT \> 3xULN (laboratory Upper Limit of Normal). E5. Blood urea \> 12 mmol/L or creatinine \> 125 µmol/L. E6. Complete blood count with hemoglobin \< 11 g/L or leucocytes \< 3000 / mm3 or leucocytes \> 16000 / mm3 or clinically significant abnormality according to the investigator.

E7. Suffering from a metabolic disorder such as treated diabetes, uncontrolled thyroidal trouble or other metabolic disorder.

E8. Suffering from an uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg).

E9. With a history of retinopathy, microalbuminuria, ischemic cardiovascular event or, during the previous 6 months a surgical procedure.

E10. Suffering from a severe chronic disease (e.g. cancer, HIV, renal failure, hepatic or biliary disorders ongoing, chronic inflammatory digestive disease, 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).

E11. Under antidiabetic drug (e.g. biguanides, sulfonylureas, glinides, gliptines, glitazones, gliflozines, α-glucosidase inhibitors, incretins and insulin).

E12. Under lipid-lowering treatment (e.g. statins, fibrates, ezetimibe, bile acid sequestrants, niacin, etc.) or stopped less than 3 months before the randomization.

E13. Requiring cholesterol lowering by immediate pharmacologic intervention according to the current recommendations (AFSSAPS 2005).

E14. Under medication which could affect glucose and/or lipid homeostasis parameters or stopped less than 3 months before randomization (e.g. beta 2 agoniste like salbutamol, Angiotensin Converting Enzyme (ACE) inhibitors, beta blockers, thiazide diuretics, Selective Serotonin Reuptake Inhibitors (SSRIs), Mono-Amine Oxidase Inhibitors (MAOIs), neuroleptics, long-term corticosteroid systemic drugs, systemic antibodies, androgens, phenytoin, interferons, immunosuppressants, antivirals and antiretrovirals, etc.). Beta 2 agoniste like salbutamol, ACE inhibitors, beta blockers, thiazide diuretics, SSIRs, MAOIs begun more than 3 months before the randomization and maintained stable during the whole study are tolerated. The others drugs (neuroleptics, long-term corticosteroid systemic drugs, systemic antibodies, androgens, phenytoin, interferons, immunosuppressants, antivirals and antiretrovirals, etc.) are not allowed during the study.

E15. Regular intake of dietary supplements or "health foods" rich in plant stanol or sterol (like PRO-ACTIV or DANACOL products), in long chain omega-3 fatty acids (especially sofgels containing fish oils), or in other substances intended to lower LDLc, TG or glycemia (e.g. beta-glucans, konjac, cinnamon, olive leaf extract, berberine, red yeast rice, policosanol, etc.) or stopped less than 3 months before the randomization.

E16. Under treatment or dietary supplement which could significantly affect parameter(s) followed during the study according to the investigator or stopped in a too short period before the randomization.

E17. Under dietary supplement in the month before V1. E18. With a known or suspected food allergy or intolerance or hypersensitivity to any of the study products' ingredient.

E19. Consuming more than 3 standard drinks of alcoholic beverage for men or 2 standard drinks daily for women or not agreeing to keep his alcohol consumption habits unchanged throughout the study.

E20. With extreme eating habits (e.g. vegetarian or vegan). E21. With a personal history of anorexia nervosa, bulimia or significant eating disorders according to the investigator.

E22. Smoking more than 10 cigarettes daily or not agreeing to keep his smoking habits unchanged throughout the study.

E23. Having a lifestyle deemed incompatible with the study according to the investigator including high level physical activity (defined as more than 10 hours of significant physical activity a week, walking excluded).

E24. Pregnant or lactating women or intending to become pregnant within 7 months ahead.

E25. Who made a blood donation in the 3 months before the randomization or intending to make it within 7 months ahead.

E26. Taking part in another clinical trial or being in the exclusion period of a previous clinical trial.

E27. Having received, during the last 12 months, indemnities for clinical trial higher or equal to 4500 Euros.

E28. Under legal protection (guardianship, wardship) or deprived from his rights following administrative or judicial decision.

E29. Presenting a psychological or linguistic incapability to sign the informed consent.

E30. Impossible to contact in case of emergency.