Clinical trial NCT06032988: Effect of Probiotic Supplements on Metabolic Control of People With Type 2 Diabetes Mellitus in Greece
Official title: The Effect of Probiotic Supplements on Metabolic Control of People With Type 2 Diabetes in Greece. A Randomized, Double-blind, Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes mellitus type 2
Probiotics
Gut microbiota
Lead sponsor: National and Kapodistrian University of Athens
Sponsor class: OTHER
Collaborators: name: Uni-Pharma
First posted: 2023-09-13
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The present study will be a single-center, randomized, double-blind, placebo-controlled trial of a 6-month duration involving persons with T2D. Participants will receive either a multi-strain probiotic supplement (in the form of a capsule) or a matching placebo capsule once a day.
Primary purpose: TREATMENT

Brief summary: The goal of this interventional clinical study is to examine if there will be a change in metabolic indices (glycemic and lipid parameters) among persons with type 2 diabetes (T2D) who will receive a probiotic dietary supplement capsule for 6 months compared to those not receiving such a treatment (they will receive a matching placebo capsule that does not contain active ingredients).

The main questions to answer are:

1. Will glycemic indices, i.e., glycated hemoglobin (HbA1c) and fasting blood glucose, be different in people taking the probiotic treatment, compared to those not taking it, after 6 months?
2. Will other metabolic indices, mostly blood lipid levels (total cholesterol, triglycerides, HDL- and LDL-cholesterol) and liver function tests, be different in people taking the probiotic treatment compared to those not taking it after 6 months?
3. Will adiposity measures (weight, waist circumference) be affected by probiotic treatment in the two groups? Studies in animals and humans, mostly of shorter duration (\<12 weeks) so far, have shown a possible trend towards improvement with probiotic treatment in all these parameters, but longer-term studies are scarce, and in Greece, there is none. Since diabetes treatment is complex (usually involving many medications) and expensive, developing cost-effective functional healthcare products for regulating blood glucose more efficiently has been recognized as a beneficial alternative.

Participants will be adult individuals (\>18 years old) with T2D, followed at the outpatient Diabetes Center of the Laiko General Hospital, National and Kapodistrian University of Athens Medical School, in Athens, Greece, who will be randomized to receive either a probiotic dietary supplement or a matching placebo capsule, once a day. They will be followed every 3 months (as is customary for diabetic patients). They will be monitored regarding their glycemic control (HbA1c and fasting blood glucose), lipid parameters, liver and renal function, and anthropometric changes (weight, waist circumference, and blood pressure). Furthermore, participants will be asked to give a stool sample at the study's beginning and end (6 months) for gut microbiota analysis. A questionnaire will also be administered at the last visit (6 months) asking about patients' tolerance and satisfaction with the treatment (frequency of constipation, diarrhea, bowel function, bloating, gas production, and abdominal pain).

Detailed description: Eligible participants will be randomized using a computer generator (www.randomization.com), which randomizes each subject to a single treatment by using the method of randomly permuted blocks, to receive either a multi-strain probiotic supplement (in the form of a capsule \[LactoLevure\^R\]) or a matching placebo capsule, once a day. The probiotic capsule contains the species: Lactobacillus Acidophilus, Lactobacillus plantarum, Bifidobacterium lactis, Saccharomyces boulardii (in the following quantities of colony-forming units \[CFU\]: Lactobacillus Acidophilus 1.75x10\^9 CFU, Lactobacillus plantarum 0.5x10\^9 CFU, Bifidobacterium lactis 1.75x10\^9 CFU, Saccharomyces boulardii 1.5x10\^9 CFU). The capsules (probiotics brand name LactoLevure\^R and placebo) are prepared and donated to the study personnel by an unrestricted research grant from Uni-Pharma Greece, the producer of LactoLevure\^R (Uni-Pharma Pharmaceutical Laboratories S.A., Kifisia, Greece), who will have no other interference with the planning, the conduction, or the analysis of the results of the study. The probiotic and placebo capsules will have an identical appearance and packaging. Neither the participants nor the investigators will be aware of the treatment assignments in this double-blinded study. Additionally, participants will be asked not to change their diet and exercise habits and to refrain from consuming yoghurt or other similar dietary supplements during the study. Care will be taken not to change the other pharmaceutical medicines during the study (participants who will have to initiate insulin treatment will be excluded from further follow-up and analysis in the study).

Sample size calculation will be based on previous similar studies considering 80% power at α = 0.05 to detect a difference in metabolic indices. All participants will be given verbal and written information about the study and will sign an informed consent form according to the recommendations of the Declaration of Helsinki.

Participants will be seen every 3 months in the outpatient Diabetes center of the Laiko General Hospital, National and Kapodistrian University of Athens Medical School, in Athens, Greece (as is customary for diabetic patients) and will be monitored regarding their glycemic control (HbA1c and fasting blood glucose), lipid parameters, liver and renal function, and anthropometric variables changes (weight and waist circumference, blood pressure). Furthermore, participants will be asked to give a stool sample at the study's beginning and end (6 months) for gut microbiota analysis. A questionnaire will also be administered at the last visit (6 months) asking about patients' tolerance and satisfaction with the treatment (frequency of constipation, diarrhea, bowel function, bloating, gas production, and abdominal pain).

Eligibility criteria: Inclusion Criteria:

* T2D diagnosis of \>6 months' duration
* Age 18-90 years
* A body-mass index (BMI) \>18.5 kg/m\^2
* HbA1c level \>6 percent (%)
* on stable antidiabetic medications (oral or injectable glucagon-like peptide 1 receptor agonists \[GLP-1 RAs\]) for 8 weeks before the screening

Exclusion Criteria:

* Type 1 or other type of diabetes
* Pregnancy or wishing to become pregnant during the study
* End-stage kidney failure on dialysis, presence of other diseases, including cancer or severe hepatic insufficiency (transaminases \>3.5x above normal)
* The use of other probiotic products or antibiotics over the previous 6 months
* Participation in other clinical trials
* Insulin administration
* The presence of other medical conditions that in the opinion of the investigators could jeopardize compliance with the protocol (e.g., malabsorption syndrome or an inability to take orally administered medications)

Primary outcomes:
measure: Effects of probiotics supplementation on glycemic control (HbA1c)
timeFrame: 6 months
Secondary outcomes:
measure: Effects of probiotics supplementation on fasting blood glucose (FBG)
timeFrame: 6 months
measure: Effects of probiotics supplementation on lipid parameters (Total cholesterol, Triglycerides, HDL-C, LDL-C)
timeFrame: 6 months
measure: Effects of probiotics supplementation on liver function tests (AST, ALT, γGT, Alkaline Phosphatase)
timeFrame: 6 months
measure: Effects of probiotics supplementation on adiposity measures (BMI, Waist circumference)
timeFrame: 6 months
measure: Effects of probiotics supplementation on changes in gut microbiota diversity (alpha- and beta-diversity)
timeFrame: 6 months
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Laiko General Hospital
state: Attica
Study officials:
affiliation: National and Kapodistrian University of Athens
name: KONSTANTINOS MAKRILAKIS, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bock PM, Telo GH, Ramalho R, Sbaraini M, Leivas G, Martins AF, Schaan BD. The effect of probiotics, prebiotics or synbiotics on metabolic outcomes in individuals with diabetes: a systematic review and meta-analysis. Diabetologia. 2021 Jan;64(1):26-41. doi: 10.1007/s00125-020-05295-1. Epub 2020 Oct 13.
citation: Rittiphairoj T, Pongpirul K, Janchot K, Mueller NT, Li T. Probiotics Contribute to Glycemic Control in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Adv Nutr. 2021 Jun 1;12(3):722-734. doi: 10.1093/advances/nmaa133.
citation: Vallianou NG, Stratigou T, Tsagarakis S. Microbiome and diabetes: Where are we now? Diabetes Res Clin Pract. 2018 Dec;146:111-118. doi: 10.1016/j.diabres.2018.10.008. Epub 2018 Oct 18.