Clinical Trial to Evaluate the Efficacy and Safety of the Probiotic Strains Limosilactocillus Reuteri DSM 32910 and Lacticaseibacillus Paracasei DSM 32851 on Glucose Homeostatis in Prediabetic Adults

Study Overview
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Brief Summary
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The aim of this international, randomized, parallel arms, double-blind, placebo-controlled clinical trial is to investigate the safety and efficacy of a combination of the two Lactobacillus strains (NZ-GHMH-01) on glucose and insulin metabolism, in prediabetic subjects. This trial will include prediabetic (insulin resistant) subjects with excessive body weight (over-weight or obese, showing abdominal or visceral obesity) to be able to investigate the effect of the probiotic NZ-GHMH-01 on glycaemic control.

Official Title
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Double-blind, Placebo-controlled, Randomized Pilot Clinical Trial to Evaluate the Efficacy and Safety of the Probiotic Strains Limosilactocillus Reuteri DSM 32910 and Lacticaseibacillus Paracasei DSM 32851 on Glucose Homeostatis in Prediabetic Adults

Conditions
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Prediabetic State, Dysglycemia

Intervention / Treatment
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* Dietary Supplement: NZ-GHMH-01
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 18 and 75 years (limits included) Having BMI between 18,5 and 40 kg/m² (limits included) Prediabetic For women: Non menopausal with the same reliable contraception or menopausal without or with hormone replacement therapy Agreeing to keep his lifestyle habits unchanged throughout the study With stable weight within ± 5% in the last three months Having a good general and mental health with in the opinion of the investigator Having signed informed consent form Affiliated with a social security scheme (for French sites only) Agreed to be registered on the subjects in the VRB (biomedical research file (for French sites only)) Having HbA1c level ≥ 5.7% and ≤ 6.4% Exclusion Criteria: Metabolic disorder such as diabetes or uncontrolled thyroidal trouble or other metabolic disorder; Having a history of medication for diabetes and dyslipidemia Uncontrolled hypertension Severe chronic disease or gastrointestinal disorders Having done the second injection of COVID-19 vaccination or between the first and the second injection within the last 2 weeks prior to V1 visit Food allergy or intolerance or hypersensitivity to any of the study products' ingredient Pregnant or lactating women or intending to become pregnant within 3 months ahead Smoking subject (more than 5 cigarettes per day) Having a history of bariatric surgery Having a history of any surgery in the 3 months before V1 visit or having scheduled any surgery within 6 months ahead Under dietary supplement except fibers, omega 3 and vitamins (other than Vitamin D3) if the subject agrees to keep his/her intake unchanged throughout the study; Under treatment which could significantly affect parameter(s) followed during the study Under antibiotic treatment in the 3 to 6 months before V1 visit With significant change in food habits or in physical activity in the 3 months before V1 visit or not agreeing to keep them unchanged throughout the study With a current or planned in the next 5 months specific diet (hyper or hypocaloric, vegan…) or putted in place since less than 3 months before the inclusion visit With a personal history of anorexia nervosa, bulimia or significant eating disorders according to the investigator Abuse of alcohol, defined as more than 21 alcohol units per week for men and 14 units for women, or unwillingness to refrain from alcohol intake the day before V2 and V5 visits Having a lifestyle deemed incompatible with the study according to the investigator Taking part in another clinical trial or having taken part in another clinical trial in the 3 months before the inclusion visit; Having received, during the last 12 months, indemnities for clinical trial higher or equal to 4500 Euros (for French sites only); Under legal protection (guardianship, wardship) or deprived from his rights following administrative or judicial decision; Presenting a psychological or linguistic incapability to sign the informed consent; Impossible to contact in case of emergency. Having blood ASAT, ALAT or GGT levels out of range and clinically significant according to the investigator Having CBC with hemoglobin < 11 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: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NZ-GHMH-01<br>Dietary supplement in shape of capsule to be taken once per day in the evening. | Dietary Supplement: NZ-GHMH-01<br>* Each randomized subject will consume 1 capsule daily bringing 100 mg (≥ 2 x 109 CFU) of active ingredient during 16 weeks (from V2 to V5 visits).<br>|
| Placebo Comparator: Placebo<br>The placebo is in shape of capsule to be taken once per day in the evening and in which only the active ingredients are not present. | Dietary Supplement: Placebo<br>* Each randomized subject will consume 1 capsule with no active ingredient daily during 16 weeks (from V2 to V5 visits).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycated Hemoglobin A1c (HbA1c) | Change from Baseline of HbA1c level between V2 and V5 visits (in %) between both groups. | V2 (randomization) and V5 (16 weeks of intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycated Hemoglobin A1c (HbA1c) | Change from baseline of HbA1c level | V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Glucose kinetic parameters: ΔPeak and Cmax | Change from baseline of ΔPeak (g/L) and Cmax (g/L) | V2 (randomization) and V5 (16 weeks of intervention) | 
| Glucose kinetic parameters: T max | Change from baseline of T max (min) | V2 (randomization) and V5 (16 weeks of intervention) | 
| Incremental Area Under the Curve (iAUC) of glucose | Change from baseline of the value of the iAUC of glucose, obtained during OGTT (iAUC0-120min) | V2 (randomization) and V5 (16 weeks of intervention) | 
| Incremental Area Under the Curve (iAUC) of insulinemia | Change from baseline of the value of the iAUC of insulinemia, obtained during OGTT (iAUC0-120min) | V2 (randomization) and V5 (16 weeks of intervention) | 
| Homeostasis Model of Assessment - insulin resistance (HOMA-IR) | Change from baseline of HOMA-IR index | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Quantitative Insulin sensitivity Check Index (QUICKI) | Change from baseline of QUICKI index | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Insulin Sensitivity Index (ISI) | Change from baseline of ISI index | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Fasting Plasma Glucose (FPG) | Change from baseline of FPG levels | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Fasting insulinemia | Change from baseline of fasting insulinemia levels | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Glycemia | Change from baseline of glycemia level | V2 (randomization) and V5 (16 weeks of intervention) | 
| Glucagon Like Peptide 1 (GLP-1) | Change from baseline of GLP-1 level | V2 (randomization) and V5 (16 weeks of intervention) | 
| Weight | Change from baseline of weight(in kg) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Body Mass Index (BMI) | Change from baseline of BMI (in kg/m2) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Waist and Hip | Change from baseline of Waist measurement (in cm) and Hip Circumference (in cm) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Anthropometric ratios | Change from baseline of Waist to Hip ratio and Waist to Height ratio | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Liver function | Change from baseline of Aspartate Amino Transferase (ASAT), Alanine Amino Transferase (ALAT) and Gamma Glutamyl Transpeptidase (GGT) levels (expressed in ukat/L) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Total bilirubin | Change from baseline of Total bilirubin levels (expressed in umol/L) | V1 (screening) and V5 (16 weeks of intervention) | 
| Triglycerides | fasting blood concentrations of triglycerides (expressed in g/L) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Lipid homeostasis | fasting blood concentrations of total cholesterol, High Density Lipoprotein cholesterol (HDLc), non-HDLc and Low Density Lipoprotein cholesterol (LDLc) (expressed in mmol/L) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| high-sensitivity C-reactive Protein (CRPhs) | Change from baseline of the CRPhs | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Cytokines | Change from baseline of the Cytokines IL-1alpha, IL-1beta, IL-6, IL-10, IL-12p70 and monocyte chemoattractant protein 1 (MCP1) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Tumor Necrosis Factors alpha (TNFα) | Change from baseline of the TNFα | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Overall health | Change from baseline of participant overall health (evaluated with SF36 questionnaire) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) | 
| Blood metabolites | Change from baseline of Cholic acid, Chenodeoxycholic acid, Deoxycholic acid, Lithocholic acid, Ursodeoxy cholic acid, Taurocholic acid and Glycochenodeoxycholic acids | V2 (randomization) and V5 (16 weeks of intervention) | 
| Gastrointestinal Symptoms | Change from baseline of gastrointestinal symptoms (evaluated with Gastrointestinal Symptom Rating Scale) | V2 (randomization), V3 (4 weeks of intervention), V4 (12 weeks of intervention) and V5 (16 weeks of intervention) |