Probiotics in Metformin Intolerant Patients With Type 2 Diabetes

NCT04089280 | Completed

• 1 other identifier: SilesianMU2
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

Metformin, the first-line drug in the treatment of type 2 diabetes (T2DM), may cause dose dependent undesirable side-effects like diarrhea, abdominal pain, nausea or bloating which may affect up to 20 % of patients treated with this drug. The mechanism of the gastrointestinal intolerance in patients treated with metformin is poorly understood. The number of studies on this topic increases and data are mounting that metformin treatment is associated with changes in gut bacterial composition. Among other drugs, metformin also leads to enrichment of short chain fatty acids (SCFAs) producing microbiota which exert positive influence on the human metabolic state. It has been shown that the therapeutic effect of metformin depends on the microbiota and metformin's main site of action in humans is the intestine. It is also known that patients with T2DM, in general, show evidence of gut dysbiosis followed by alterations of an intestinal barrier leading to an increase in intestinal permeability and elevated inflammatory state. Therefore, it has been speculated that metformin's versatile effect mediated through the gut microbiota is responsible not only for its therapeutic effect but also for its undesirable digestive symptoms. Probiotics, defined as "live microorganisms, that when administered in adequate amounts, confer a health benefit on the host", may have the potential to modulate the gut bacterial composition. This is why the investigators hypothesize that it may also reduce the intensity of adverse effects associated with metformin use. The investigators have chosen Sanprobi Barrier multi-strain formula probiotic because it is identical, in relation to bacterial strains and number, to Ecologic® BARRIER which has been proven in in vitro studies to improve the function of epithelial barrier of the intestine. It was also shown that 12-week administration of strains included in Ecologic® BARRIER in obese postmenopausal women improved intestinal barrier permeability marker (lipopolysaccharide) and cardiometabolic risk factors (waist, fat mass, subcutaneous fat, uric acid, total cholesterol, triglycerides, low-density lipoprotein cholesterol, glucose, insulin, and homeostatic model assessment - insulin resistance (HOMA-IR).

Conditions

Diabetes Mellitus, Type 2; Metformin Adverse Reaction

Keywords

diabetes type 2; probiotics; metformin intolerance

Outcome Measures

Primary Outcomes (1)

• Adverse gastrointestinal symptoms related to metformin treatment

  Questionnaire to Assess Character and Severity of Metformin Intolerance (adapted from Laura J. Mc Creight et al.). The score indicates how the patient tolerates metformin. Score interpretation: 0 - 10 = tolerant (T) 11-20 = mild intolerance (MI) 21-30 = intolerant (I) 31-50 = severely intolerant (SI)

  32 weeks

Secondary Outcomes (24)

• Intestinal barrier permeability and inflammation - zonulin blood concentration

  32 weeks

• Intestinal barrier permeability and inflammation - immunoglobulins (IG) against zonulin

  32 weeks

• Intestinal barrier permeability and inflammation - CRP

  32 weeks

• Intestinal barrier permeability and inflammation - stool concentration of zonulin

  32 weeks

• Intestinal barrier permeability and inflammation - blood concentration of calprotectin

  32 weeks

Study Arms (2)

Sanprobi Barrier-multispecies probiotic

EXPERIMENTAL

A randomized placebo-controlled, parallel-group study, crossover-design. Intervention: Sanprobi Barrier-multispecies probiotic product, 2,5 x10 9 cfu/gram or placebo, cross-over design

Dietary Supplement: Sanprobi Barrier-multispecies probiotic

carrier material of Sanprobi Barrier-multispecies probiotic

PLACEBO COMPARATOR

A randomized placebo-controlled, parallel-group study, crossover-design. Intervention: placebo comparator (carrier material of Sanprobi Barrier-multispecies probiotic product , not containing bacterial strains,similar appearance as the probiotic, cross-over design

Other: Placebo Comparator

Interventions

Sanprobi Barrier-multispecies probiotic DIETARY_SUPPLEMENT

Multi-strain probiotic Sanprobi Barrier (Bifidobacterium lactis W52, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus lactis W19, Lactobacillus lactis W58, Lactobacillus acidophilus W37, Bifidobacterium bifidum W23, Lactobacillus salivarius W24) or placebo. Patients will be randomized to one of the two products ("A" or "B") each containing probiotic/placebo and administered for 12 weeks. After 12 weeks of supplementation, the probiotic/placebo product "A" or "B" will be discontinued and reintroduced again after next 4 weeks - patients will be switched to the other "A or B" group of probiotic/placebo arm. Patients will be administered with 4 capsules per day for 24 weeks (12 weeks for group A probiotic/placebo and 12 weeks for group B probiotic/placebo allowing 4 weeks washout between the group assignment).

Sanprobi Barrier-multispecies probiotic

Placebo Comparator OTHER

Carrier material of Sanprobi Barrier-multispecies probiotic product, not containing bacterial strains,similar appearance as the probiotic

carrier material of Sanprobi Barrier-multispecies probiotic

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent for participation in the clinical trial
• Age 18-75 years
• Type 2 diabetes mellitus diagnosed at minimum 6 months prior to the study
• Metformin intolerance defined as gastrointestinal adverse effects occurrence at the daily metformin dose higher than 1500 mg assessed by the Questionnaire adapted from Laura J. McCreight et al., which disappeared or decreased to the accepted tolerable level after dose reduction to 1500 mg per day.
• Metformin treatment in the daily dose not higher than 1500 mg

You may not qualify if:

• Estimated Glomerular Filtration Rate (eGFR) \< 60 ml /min/ 1.73m2
• Elevation of ALT and aspartate aminotransferase (AST) activity in the blood serum, three times above the reference value
• Chronic bowel disease
• Any other acute or chronic disease that may cause gastrointestinal symptoms
• Acute or chronic pancreatitis
• Chronic alcohol consumption \>30 g/day for men and \> 20 g/day for women
• Antibiotic therapy in the last 6 months prior to the study
• Probiotics use in the last 3 months before the study
• Chronic use of steroid drugs or other immunomodulators
• Heart failure (New York Heart Association (NYHA) III and IV)
• Pregnancy or breast feeding

Sponsors & Collaborators

• Medical University of Silesia: lead
• Sanprobi Sp. z o.o., Sp. k., Szczecin, Poland: collaborator

Study Sites (1)

Department of Internal Diseases, Diabetology and Nephrology

Zabrze, 41-800, Poland

Location

Related Publications (11)

• Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017 Sep;60(9):1577-1585. doi: 10.1007/s00125-017-4342-z. Epub 2017 Aug 3.

  PMID: 28776086 BACKGROUND

• Bonnet F, Scheen A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes Metab. 2017 Apr;19(4):473-481. doi: 10.1111/dom.12854. Epub 2017 Feb 22.

  PMID: 27987248 BACKGROUND

• McCreight LJ, Stage TB, Connelly P, Lonergan M, Nielsen F, Prehn C, Adamski J, Brosen K, Pearson ER. Pharmacokinetics of metformin in patients with gastrointestinal intolerance. Diabetes Obes Metab. 2018 Jul;20(7):1593-1601. doi: 10.1111/dom.13264. Epub 2018 Mar 23.

  PMID: 29457876 BACKGROUND

• Elbere I, Kalnina I, Silamikelis I, Konrade I, Zaharenko L, Sekace K, Radovica-Spalvina I, Fridmanis D, Gudra D, Pirags V, Klovins J. Association of metformin administration with gut microbiome dysbiosis in healthy volunteers. PLoS One. 2018 Sep 27;13(9):e0204317. doi: 10.1371/journal.pone.0204317. eCollection 2018.

  PMID: 30261008 BACKGROUND

• Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, Prifti E, Vieira-Silva S, Gudmundsdottir V, Pedersen HK, Arumugam M, Kristiansen K, Voigt AY, Vestergaard H, Hercog R, Costea PI, Kultima JR, Li J, Jorgensen T, Levenez F, Dore J; MetaHIT consortium; Nielsen HB, Brunak S, Raes J, Hansen T, Wang J, Ehrlich SD, Bork P, Pedersen O. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015 Dec 10;528(7581):262-266. doi: 10.1038/nature15766. Epub 2015 Dec 2.

  PMID: 26633628 BACKGROUND

• Bordalo Tonucci L, Dos Santos KM, De Luces Fortes Ferreira CL, Ribeiro SM, De Oliveira LL, Martino HS. Gut microbiota and probiotics: Focus on diabetes mellitus. Crit Rev Food Sci Nutr. 2017 Jul 24;57(11):2296-2309. doi: 10.1080/10408398.2014.934438.

  PMID: 26499995 BACKGROUND

• Szulinska M, Loniewski I, van Hemert S, Sobieska M, Bogdanski P. Dose-Dependent Effects of Multispecies Probiotic Supplementation on the Lipopolysaccharide (LPS) Level and Cardiometabolic Profile in Obese Postmenopausal Women: A 12-Week Randomized Clinical Trial. Nutrients. 2018 Jun 15;10(6):773. doi: 10.3390/nu10060773.

  PMID: 29914095 BACKGROUND

• de Roos NM, Giezenaar CG, Rovers JM, Witteman BJ, Smits MG, van Hemert S. The effects of the multispecies probiotic mixture Ecologic(R)Barrier on migraine: results of an open-label pilot study. Benef Microbes. 2015;6(5):641-6. doi: 10.3920/BM2015.0003. Epub 2015 Apr 22.

  PMID: 25869282 BACKGROUND

• Fasano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol. 2012 Oct;10(10):1096-100. doi: 10.1016/j.cgh.2012.08.012. Epub 2012 Aug 16.

  PMID: 22902773 BACKGROUND

• Catalan V, Gomez-Ambrosi J, Rodriguez A, Ramirez B, Rotellar F, Valenti V, Silva C, Gil MJ, Fernandez-Real JM, Salvador J, Fruhbeck G. Increased levels of calprotectin in obesity are related to macrophage content: impact on inflammation and effect of weight loss. Mol Med. 2011;17(11-12):1157-67. doi: 10.2119/molmed.2011.00144. Epub 2011 Jul 5.

  PMID: 21738950 BACKGROUND

• Zamani B, Sheikhi A, Namazi N, Larijani B, Azadbakht L. The Effects of Supplementation with Probiotic on Biomarkers of Oxidative Stress in Adult Subjects: a Systematic Review and Meta-analysis of Randomized Trials. Probiotics Antimicrob Proteins. 2020 Mar;12(1):102-111. doi: 10.1007/s12602-018-9500-1.

  PMID: 30666617 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• Katarzyna Nabrdalik

  Medical University of Silesia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Quadruple
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: prospective, single center , interventional

Study Record Dates

• First Submitted: August 27, 2019
• First Posted: September 13, 2019
• Study Start: October 16, 2018
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: May 6, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1)