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Probiotics in Metformin Intolerant Patients With Type 2 Diabetes (ProGasMet)

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ClinicalTrials.gov Identifier: NCT04089280
Recruitment Status : Recruiting
First Posted : September 13, 2019
Last Update Posted : September 26, 2019
Sponsor:
Collaborator:
Sanprobi Sp. z o.o., Sp. k., Szczecin, Poland
Information provided by (Responsible Party):
Medical University of Silesia

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).


Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Metformin Adverse Reaction Dietary Supplement: Sanprobi Barrier-multispecies probiotic Other: Placebo Comparator Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: prospective, single center , interventional
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Quadruple
Primary Purpose: Treatment
Official Title: The Effect of Multi-strain Probiotics on Gastrointestinal Symptoms in Patients With Type 2 Diabetes and Metformin Intolerance. A 32-week Prospective, Single Center, Randomized, Placebo Controlled, Cross-over Clinical Trial.
Actual Study Start Date : October 16, 2018
Estimated Primary Completion Date : October 16, 2020
Estimated Study Completion Date : May 16, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sanprobi Barrier-multispecies probiotic
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
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).

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




Primary Outcome Measures :
  1. Adverse gastrointestinal symptoms related to metformin treatment [ Time Frame: 32 weeks ]

    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)



Secondary Outcome Measures :
  1. Intestinal barrier permeability and inflammation - zonulin blood concentration [ Time Frame: 32 weeks ]
    blood concentration of zonulin

  2. Intestinal barrier permeability and inflammation - immunoglobulins (IG) against zonulin [ Time Frame: 32 weeks ]
    immunoglobulins against zonulin

  3. Intestinal barrier permeability and inflammation - CRP [ Time Frame: 32 weeks ]
    C-reactive protein

  4. Intestinal barrier permeability and inflammation - stool concentration of zonulin [ Time Frame: 32 weeks ]
    stool concentration of zonulin

  5. Intestinal barrier permeability and inflammation - blood concentration of calprotectin [ Time Frame: 32 weeks ]
    blood concentration of calprotectin

  6. Intestinal barrier permeability and inflammation - stool concentration of calprotectin [ Time Frame: 32 weeks ]
    stool concentration of calprotectin

  7. Faecal microbiota composition [ Time Frame: 32 weeks ]
    16S rRNA sequencing

  8. Short chain fatty acids (SCFAs) [ Time Frame: 32 weeks ]
    assessment of short chain fatty acids in stool (gas chromatography)

  9. Cardiometabolic state - lipid parameters [ Time Frame: 32 weeks ]
    lipid parameters

  10. Cardiometabolic state - Body Mass Index [ Time Frame: 32 weeks ]
    Body Mass Index (BMI)

  11. Cardiometabolic state - blood pressure [ Time Frame: 32 weeks ]
    blood pressure

  12. Cardiometabolic state - heart rate [ Time Frame: 32 weeks ]
    heart rate measurements

  13. Cardiometabolic state - HbA1c [ Time Frame: 32 weeks ]
    blood haemoglobin A1c (HbA1c)

  14. Oxidative stress markers - SOD [ Time Frame: 32 weeks ]
    superoxide dismutase

  15. Oxidative stress markers - GPx [ Time Frame: 32 weeks ]
    glutathione peroxidase

  16. Oxidative stress markers - CAT [ Time Frame: 32 weeks ]
    glutathione catalase

  17. Oxidative stress markers - GR [ Time Frame: 32 weeks ]
    glutathione reductase

  18. Oxidative stress markers - TOC [ Time Frame: 32 weeks ]
    total oxidant capacity

  19. Oxidative stress markers - LHP [ Time Frame: 32 weeks ]
    lipid hydroperoxides

  20. Oxidative stress markers - LPS [ Time Frame: 32 weeks ]
    lipofuscin concentration

  21. Oxidative stress markers - PSH [ Time Frame: 32 weeks ]
    protein sulphydryl concentration

  22. Oxidative stress markers - MDA [ Time Frame: 32 weeks ]
    malondialdehyde concentration

  23. Oxidative stress markers - GSH [ Time Frame: 32 weeks ]
    glutathione concentration

  24. Oxidative stress markers - TAS [ Time Frame: 32 weeks ]
    total antioxidant status



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent for participation in the clinical trial
  2. Age 18-75 years
  3. Type 2 diabetes mellitus diagnosed at minimum 6 months prior to the study
  4. 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.
  5. Metformin treatment in the daily dose not higher than 1500 mg
  6. Stable metformin dose in the last 3 months before inclusion to the study

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04089280


Contacts
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Contact: Katarzyna Nabrdalik, MD, PhD 0048697592954 knabrdalik@sum.edu.pl
Contact: Hanna Kwiendacz, MD, PhD 0048509774849 hanna.kwiendacz@gmail.com

Locations
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Poland
Department of Internal Diseases, Diabetology and Nephrology Recruiting
Zabrze, Poland, 41-800
Contact: Hanna Kwiendacz, MD,PhD    0048509774849    hanna.kwiendacz@gmail.com   
Contact: Katarzyna Nabrdalik, Md,PhD    0048697592954    knabrdalik@sum.edu.pl   
Principal Investigator: Katarzyna Nabrdalik, MD, PhD         
Sub-Investigator: Janusz Gumprecht, MD,PhD,Prof         
Sub-Investigator: Hanna Kwiendacz, MD         
Sub-Investigator: Karolina Drożdż, MD         
Sponsors and Collaborators
Medical University of Silesia
Sanprobi Sp. z o.o., Sp. k., Szczecin, Poland
Investigators
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Principal Investigator: Katarzyna Nabrdalik Medical University of Silesia

Publications:

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Responsible Party: Medical University of Silesia
ClinicalTrials.gov Identifier: NCT04089280     History of Changes
Other Study ID Numbers: SilesianMU2
First Posted: September 13, 2019    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Medical University of Silesia:
diabetes type 2
probiotics
metformin intolerance
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs