Clinical trial NCT04423302: Effect of Totum-63 on Glucose and Lipid Homeostasis in Subjects With Dysglycemia (REVERSE-IT)
Official title: Randomized Placebo-controlled Double-blinded Study of the Effect of TOTUM-63 on Glucose and Lipid Homeostasis in Subjects With Dysglycemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Prediabetic State
Diabetes type2
Dysglycemia
Keywords: Dysglycemia
Prediabetes
Type 2 diabetes
Hyperglycemia
Insulinemia
Diabetes risk
Diet supplement
Plant extracts
Health condition
Hygiene and dietary recommendations
Diet
Lead sponsor: Valbiotis
Sponsor class: INDUSTRY
Collaborators: name: Biofortis Mérieux NutriSciences
First posted: 2020-06-09
Enrollment: 636
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This clinical study aims to assess the efficacy of TOTUM-63, a mix of 5 plant extracts, consumed at the daily regimen of three times per day on glucose and lipid homeostasis in dysglycemic subjects. The hypothesis is that TOTUM-63, consumed 3 times per day, is superior to placebo for decrease of fasting plasma glucose (FPG) concentration after 24 weeks of consumption.


Eligibility criteria: Inclusion Criteria:

* I1. From 18 to 70 years (including ranges);
* I2. Dysglycemic, prediabetic or newly diagnosed type 2 diabetes, subject without any clinical symptoms of diabetes (e.g. polyuria, polydipsia, blurred vision...) and not requiring immediate anti-diabetic treatment;
* I3. Body mass index (BMI) between 25 and 40 kg/m² (including ranges);
* I4. Waist circumference \> 102 cm for men and \> 88 cm for women (-2% margin allowed, respectively ≥ 100 cm and ≥ 86.5 cm);
* I5. Weight stable within ± 5% in the last three months;
* I6. No significant change in food habits or in physical activity in the 3 months before the randomization and agreeing to follow hygiene and dietary (HD) recommendations given during the study;
* I7. 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 (estrogenic replacement therapy begun from less than 3 months excluded);
* I8. Good general and mental health according to the opinion of the investigator: no clinically significant and relevant abnormalities of medical history or physical examination;
* I9. Able and willing to participate to the study by complying with the protocol procedures as evidenced by his dated and signed informed consent form;
* I10. Affiliated with a social security scheme;
* I11. Agreeing to be registered on the volunteers in biomedical research (applicable only for French centers).

At V0 biological analysis, the subjects will be eligible to the study on the following criteria:

* I12. Fasting plasma glucose concentration ≥ 110 mg/dL.

Exclusion Criteria:

* E1. Suffering from a metabolic disorder such as treated diabetes, uncontrolled thyroidal dysfunction or other metabolic disorder needing a dose adjustment in drug intervention according to the professional recommendations;
* E2. Suffering from an uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg);
* E3. With a history of retinopathy, ischemic cardiovascular event, having undergone recent surgical procedure in the past 6 months or in the 9 months to come;
* E4. 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);
* E5. Under antidiabetic drug (e.g. biguanides, sulfonylureas, glinides, gliptins, glitazones, gliflozins, α-glucosidase inhibitors, incretins and insulin);
* E6. Under lipid-lowering treatment (e.g. statins, fibrates, ezetimibe, bile acid sequestrants, niacin, etc.) since less than 3 months or modification of the treatment dose since less than 3 months before the randomization. Subject with a stable lipid-lowering treatment since at least three months can be included in the study;
* E7. Under medication which could affect glucose and/or lipid homeostasis parameters or stopped less than 3 months before randomization (e.g. beta 2 agonists 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 agonists like salbutamol, ACE inhibitors, beta blockers, thiazide diuretics, SSRIs, MAOIs are tolerated only if stable since more than 3 months before the randomization and maintained during the whole study;
  * 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;
* E8. Regular intake of dietary supplements or "health foods", or products rich in plant stanol or sterol (like Pro-Activ® or Danacol® products), rich in long chain omega-3 fatty acids (especially soft gels containing fish oils), or in other substances intended to reduce glycemia (e.g. beta-glucans, konjac, olive leaf extract, berberine, cinnamon, etc.) or stopped less than 3 months before the randomization;
* E9. 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 (for example consumed in the month before the randomization);
* E10. With a known or suspected food allergy or intolerance or hypersensitivity to any of the study products' ingredient;
* E11. Consuming more than 3 standard drinks daily 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;
* E12. With extreme and/or unbalanced eating habits (e.g. vegetarian, vegan, skipping meals regularly);
* E13. With a personal history of anorexia nervosa, bulimia or significant eating disorders according to the investigator;
* E14. Smoking more than 20 cigarettes daily or not agreeing to keep his smoking habits unchanged throughout the study. The subject should be able not to smoke during the visits (maximum 4 hours);
* E15. 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);
* E16. Pregnant (as evidenced by a positive test for β-HCG (Human Chorionic Gonadotropin), i.e. \> 5 mUI/mL, realized at V0) or lactating women or intending to become pregnant within 9 months ahead;
* E17. Who made a blood donation in the 3 months before the randomization or intending to make it within 9 months ahead;
* E18. Taking part in another clinical trial or being in the exclusion period of a previous clinical trial;
* E19. Having received, during the last 12 months, indemnities for clinical trial higher or equal to 4500 Euros (applicable only for French centers);
* E20. Under legal protection (guardianship, wardship) or deprived from his rights following administrative or judicial decision;
* E21. Presenting a psychological or linguistic incapability to sign the informed consent;
* E22. Impossible to contact in case of emergency;
* E23. Any condition assessed by the investigator which could endanger patient safety or the conduct of the study (e.g. device related contraindication for impedancemetry and/or DEXA (Dual-Energy X-ray Absorptiometry) such as pacemaker or electronic implant);

At V0 biological analysis, the subjects will be considered as non-eligible to the study on the following criteria:

* E24. Fasting glucose plasma concentration \> 220 mg/dL;
* E25. Fasting blood triglycerides \> 2.2 g/L;
* E26. TSH (Thyroid Stimulating Hormone) outside the laboratory normal values;
* E27. Fasting blood LDL (Low Density Lipoprotein) cholesterol \> 1.9 g/L or non HDLc (High Density Lipoprotein cholesterol) \> 2.2 g/L or any condition requiring a therapeutic dose adjustment during the trial according to the professional recommendations;
* E28. Blood AST (ASpartate amino Transferase), ALT (ALanine amino Transferase) or GGT (Gamma Glutamyl Transpeptidase) \> 3 x ULN (Upper Limit of Normal);
* E29. Blood creatinine concentration \> 125 μmol/L;
* E30. eGFR estimated Glomerular Filtration Rate, calculated by CKD-EPI (Chronic Kidney Disease-EPIdemiology collaboration) formula) \< 60 mL/min/1.73m²;
* E31. Complete blood count (CBC) with hemoglobin \< 11 g/dL or leucocytes \< 3000 /mm3 or leucocytes \> 16000 /mm3 or clinically significant abnormality according to the investigator.

Primary outcomes:
measure: Fasting plasma glucose concentration at V3 with a 3 times a day regimen
timeFrame: V3 (24 weeks of intervention)
Secondary outcomes:
measure: Evolution of the fasting plasma glucose concentration
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the HbA1c
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the glycemia at 120 minutes following the 75g glucose intake
timeFrame: V1 (baseline), V2 (12 weeks of intervention), V3 (24 weeks of intervention) and V4 (12 weeks and the end of intervention)
measure: Evolution of the fasting insulinemia
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the HOMA-IR (HOmeostasis Model Assessment of Insulin Resistance) index
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the HOMA-β (Homeostasis Model Assessment of Beta cells) index
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the QUICKY (QUantitative Insulin sensitivity ChecK Index) index
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the fasting blood concentrations of triglycerides
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the fasting blood concentrations of total cholesterol
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the fasting blood concentrations of HDL cholesterol
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the fasting blood concentrations of non-HDL cholesterol
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the fasting blood concentrations of LDL cholesterol
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the fasting blood concentrations of free fatty acids
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of atherogenic index
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of atherogenic coefficient
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of Cardiac risk ratio 1
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of cardiac risk ratio 2
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the fasting blood concentrations of hsCRP
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the body weight
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the waist circumference
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the hip circumference
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the waist to hip ratio
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Evolution of the body composition assessed by impedancemeter
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Delay of occurence of pharmacological treatment requirement for type 2 diabetes from V1
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
measure: Proportion of subjects having an improvement or a deterioration of their glycemic status from V1
timeFrame: V1 (baseline), V2 (12 weeks of intervention) and V3 (24 weeks of intervention)
Other outcomes:
Locations:
city: Botevgrad
country: Bulgaria
facility: MHAT-Botevgrad EOOD, Botevgrad
city: Plovdiv
country: Bulgaria
facility: MHAT Sveta Karidad, First department of Internal Diseases
city: Plovdiv
country: Bulgaria
facility: Ambulatory for IPSOC in Endocrynology and Metabolic Diseases ENDO MED-CONSULT EOOD
city: Plovdiv
country: Bulgaria
facility: Diagnostic-consultative center 7 EOOD, Plovdiv
city: Sofia
country: Bulgaria
facility: Diagnostic Consultative Center "ALEXANDROVSKA"
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for active treatment "Alexandrovska" EAD Clinic of Endocrinology and metabolic diseases
city: Sofia
country: Bulgaria
facility: 4th Multiprofile Hospital for active treatment - EAD, Internal Diseases Departement
city: Sofia
country: Bulgaria
facility: Diagnostic Consultative Center
city: Amiens
country: France
facility: CHU Amiens
city: Arras
country: France
facility: CH Arras
city: Clermont-Ferrand
country: France
facility: CIC Clermont Ferrand
city: Dijon
country: France
facility: CEN Nutriment
city: Gières
country: France
facility: Eurofins Optimed
city: Grenoble
country: France
facility: CHU Grenoble
city: Lille
country: France
facility: Institut Pasteur de Lille
city: Lille
country: France
facility: CHU Lille
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice
city: Paris
country: France
facility: Unité d'Investigation Clinique Biofortis Mérieux NutriSciences
city: Pierre-Bénite
country: France
facility: Unité de Recherche Clinique en Immunologie Lyon Sud
city: Rouen
country: France
facility: CHU Rouen
city: Saint-Herblain
country: France
facility: Biofortis Mérieux NutriSciences
city: Berlin
country: Germany
facility: Analyze & Realize
city: Dresden
country: Germany
facility: Klinische Forschung Dresden
city: Essen
country: Germany
facility: Medizentrum Essen Borbeck
city: Esslingen
country: Germany
facility: Biotesys
city: Hamburg
country: Germany
facility: Klinische Forschung Hamburg
city: Hannover
country: Germany
facility: Klinische Forschung Hannover-Mitte
city: Karlsruhe
country: Germany
facility: Klinische Forschung Karlsruhe
city: Künzing
country: Germany
facility: Gemeinschaftspraxis Dr. Med C. Klein/J Minnich
city: Sankt Ingbert
country: Germany
facility: Zentrum fur Klinische Studien
city: Schwerin
country: Germany
facility: Klinische Forschung Schwerin
city: Stuttgart
country: Germany
facility: Zentrum für Klinische Ernährung Stuttgart
city: Balatonfüred
country: Hungary
facility: Drug Resesarch Center (DRC)
city: Budapest
country: Hungary
facility: ClinExpert Medical Center
city: Békéscsaba
country: Hungary
facility: Trial Pharma Ltd
city: Eger
country: Hungary
facility: Agria - Study Ltd
city: Gyula
country: Hungary
facility: Trial Pharma Ltd
city: Győr
country: Hungary
facility: Trial Pharma Ltd
city: Miskolc
country: Hungary
facility: Clinical Research Unit (CRU)
city: Orosháza
country: Hungary
facility: Trial Pharma Ltd
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Universitaria "Mater Domini"
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Palermo
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone"
city: Roma
country: Italy
facility: Policlinico Umberto I
city: Bydgoszcz
country: Poland
facility: Vitamed
city: Katowice
country: Poland
facility: Grupowa Praktyka Lekarska s.c
city: Kraków
country: Poland
facility: Centrum Medyczne Linden
city: Bucarest
country: Romania
facility: Sana Monitoring
city: Caracal
country: Romania
facility: Spitalul Municipal Caracal
city: Călăraşi
country: Romania
facility: Ames Research Cente
city: Reșca
country: Romania
facility: Clintrial Medical Center
Study officials:
affiliation: Biofortis Mérieux NutriSciences
name: Isabelle METREAU, MD
role: PRINCIPAL_INVESTIGATOR
References: