Effect of Sinbiotic With Multispecies Probiotics on Liver Parameters Liver Enzymes, Ultrasound, Elastography and Adipokines in Same Cases) in Patients With Metabolic Associated Steatotic Liver Disease.

NCT07025980 | Not Yet Recruiting Phase 2

• 1 other identifier: 01-22682/1-23
• Study Type: interventional
• Target: 114
• Locations: 1 country
• Sites: 1

Brief Summary

Scientific hypothesis: the use of a synbiotic preparation with a multi-strain probiotic in patients with MASLD can lead to a decrease in non-invasive elastographic parameters of hepatic steatosis and fibrosis and an improvement in liver function. The main objective of this study is to examine whether the test product affects the improvement of liver function measured by elastographic parameters or at least the prevention of further disease progression. The goal of this clinical trial is to learn if sinbiotics works to improve liver function in adult patients with MASLD The main questions it aims to answer are: Does sinbiotic lowers elastographic parameters od steatosis and fibrosis? Does it change liver function by lowering liver enzymes, blood lipids and sugar? Can sinbiotics lower CV risks and improve quality of life? Researchers will compare sinbiotic to a placebo (a look-alike substance that contains no drug) to see if sinbiotic works in MASLD patients. Participants will: Take sinbiotic or a placebo every day (td) for 9 months Visit the clinic once every 3 months for checkups, and at the begining and after 9 months for blood tests and US with elastography Keep a diary of their symptoms, diet, activity

Conditions

MASLD/MASH (Metabolic Dysfunction-Associated Steatotic Liver Disease / Metabolic Dysfunction-Associated Steatohepatitis); Diabetes Mellitus; Hypertension; Hyperlipidaemia

Keywords

elastography; human LRG1, liver enzymes, metabolic- dysfuncion steatotic liver disease, metabolic syndrome; probiotics, treatment

Outcome Measures

Primary Outcomes (2)

• change in the controlled attenuated coefficient CAP (dB/m/MHZ) for steatosis

  at baseline and after 270 days of intervention*

• change in liver stiffness measurement (LSM) (kPa) measured by transient elastography for fibrosis

  (1st and 2nd measured on FibroScan device, manufacturer Echosens, Paris, France)

  at baseline and after 270 days of intervention

Secondary Outcomes (12)

• change in serum levels of aspartate aminotransferase AST (U/L), alanine transferase ALT (U/L), gamma-glutamyl transferase GGT (U/L), ferritin (ng/ml)

  at baseline and after 270 days

• change in serum levels of glucose (mmol/l) and fasting insulin (pmol/L), calculation of insulin resistance using the Homeostatic Model Assessment for Insulin Resistance formula HOMA-IR (glucose (mmol/l) x insulin (pmol/L)/22.5)

  at baseline and after 270 days

• change in serum levels of cholesterol (mmol/L), triglycerides (mmol/L), HDL-cholesterol (mmol/L) and LDL-cholesterol (mmol/L)

  at baseline and after 270 days

• change in waist circumference (cm) and body mass index (BMI=body weight (kg)/body height2(m)), kg/m2)

  at baseline and after 270 days

• change in blood pressure (mmHg) measured by standard method

  at baseline and after 270 days

Study Arms (2)

test group

EXPERIMENTAL

Test group (n 57) The test product is a ready-to-use preparation PROBalansHepatocare, manufactured by PharmaS d.o.o., which contains 8 strains of live cultures of microorganisms (Bifidobacteriumbreve BBR8, Bifidobacteriuminfantis SP37, Bifidobacteriumlongum SP54, Lactobacillus acidophilus LA1, Lactobacillus bulgaricus LB2, Lactobacillus paracasei IMC502®, Lactobacillus plantarum BG 112, Streptococcusthermophilus SP4) with about 100 billion bacteria (50x109 CFU/capsule) in two capsules per day. In addition, the test product contains 100 mg of fructooligosaccharides, 210 mg of Ca-butyrate, and 10 ug (400 IU) of vitamin D in each capsule.

Dietary Supplement: The test product is a ready-to-use sinbiotic preparation of multispecies probiotics, ca-butyrate and FOS

Placebo

PLACEBO COMPARATOR

Placebo group (n 57)The placebo is identical to the test product in all aspects (organoleptic), but contains only excipients (cellulose; hydroxypropyl-methyl cellulose) and 10 ug (400 IU) of vitamin D.

Dietary Supplement: Placebo Drug

Interventions

The test product is a ready-to-use sinbiotic preparation of multispecies probiotics, ca-butyrate and FOS DIETARY_SUPPLEMENT

The test product is a ready-to-use preparation PROBalansHepatocare, manufactured by PharmaS d.o.o., which contains 8 strains of live cultures of microorganisms (Bifidobacteriumbreve BBR8, Bifidobacteriuminfantis SP37, Bifidobacteriumlongum SP54, Lactobacillus acidophilus LA1, Lactobacillus bulgaricus LB2, Lactobacillus paracasei IMC502®, Lactobacillus plantarum BG 112, Streptococcusthermophilus SP4) with about 100 billion bacteria (50x109 CFU/capsule) in two capsules per day. In addition, the test product contains 100 mg of fructooligosaccharides, 210 mg of Ca-butyrate, and 10 ug (400 IU) of vitamin D in each capsule.

test group

Placebo Drug DIETARY_SUPPLEMENT

Contains only excipients (cellulose; hydroxypropyl-methyl cellulose) and 10 ug (400 IU) of vitamin D. They do not contain dyes, flavors or preservatives, and contain traces of soy and milk, the levels of which do not affect people who are lactose intolerant.

Placebo

Eligibility Criteria

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

You may qualify if:

• MASLD confirmed by ultrasound and elastography with CAP \> 260 dB/m/MHz;
• other causes of chronic liver disease excluded and/or diagnosis confirmed by liver biopsy,
• signed informed consent.

You may not qualify if:

• pregnancy,
• significant alcohol intake (\>30g/day in men, \>20g/day in women),
• presence of autoimmune, viral, cholestatic (primary biliary cholangitis, primary sclerosing cholangitis, obstructive biliary tree diseases) or metabolic (hemochromatosis, Wilson) causes of chronic liver disease, transplant patients, malignant diseases, free fluid in the abdomen, significant small bowel resections,
• signs of liver cirrhosis or LSM\>13 kPa measured TE,
• use of medications that can promote the development of steatosis (e.g. corticosteroids, high doses of estrogen, methotrexate, amiodarone, valproate), and medications that can affect the composition of the microbiota for at least 3 months before the start of the study (antibiotics and probiotics),
• inability to reliably measure CAP and LSM (IQR/median\>30%),
• severe psychiatric patients in whom cooperation and consent are questionable.

Sponsors & Collaborators

• Eva Cubric: lead
• General Hospital Šibenik, Croatia: collaborator
• General Hospital Zadar: collaborator
• University Hospital Dubrava: collaborator
• University Hospital Rijeka: collaborator
• Clinical Hospital Merkur: collaborator
• University Hospital Sestre Milosrdnice: collaborator
• University Hospital of Split: collaborator

Study Sites (1)

General Hospital Sibenik-Knin County

Šibenik, Croatia, 22000, Croatia

Location

Related Publications (12)

• Lukenda Zanko V, Domislovic V, Trkulja V, Krznaric-Zrnic I, Turk-Wensveen T, Krznaric Z, Filipec Kanizaj T, Radic-Kristo D, Bilic-Zulle L, Orlic L, Dinjar-Kujundzic P, Poropat G, Stimac D, Hauser G, Mikolasevic I. Vitamin D for treatment of non-alcoholic fatty liver disease detected by transient elastography: A randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2020 Nov;22(11):2097-2106. doi: 10.1111/dom.14129. Epub 2020 Aug 5.

  PMID: 32613718 BACKGROUND

• Fogacci F, Giovannini M, Di Micoli V, Grandi E, Borghi C, Cicero AFG. Effect of Supplementation of a Butyrate-Based Formula in Individuals with Liver Steatosis and Metabolic Syndrome: A Randomized Double-Blind Placebo-Controlled Clinical Trial. Nutrients. 2024 Jul 28;16(15):2454. doi: 10.3390/nu16152454.

  PMID: 39125336 BACKGROUND

• Silva RSD, Mendonca IP, Paiva IHR, Souza JRB, Peixoto CA. Fructooligosaccharides and galactooligosaccharides improve hepatic steatosis via gut microbiota-brain axis modulation. Int J Food Sci Nutr. 2023 Nov;74(7):760-780. doi: 10.1080/09637486.2023.2262779. Epub 2023 Nov 15.

  PMID: 37771001 BACKGROUND

• Duseja A, Acharya SK, Mehta M, Chhabra S; Shalimar; Rana S, Das A, Dattagupta S, Dhiman RK, Chawla YK. High potency multistrain probiotic improves liver histology in non-alcoholic fatty liver disease (NAFLD): a randomised, double-blind, proof of concept study. BMJ Open Gastroenterol. 2019 Aug 7;6(1):e000315. doi: 10.1136/bmjgast-2019-000315. eCollection 2019.

  PMID: 31423319 BACKGROUND

• Dong TS, Jacobs JP. Nonalcoholic fatty liver disease and the gut microbiome: Are bacteria responsible for fatty liver? Exp Biol Med (Maywood). 2019 Apr;244(6):408-418. doi: 10.1177/1535370219836739. Epub 2019 Mar 14.

  PMID: 30871368 BACKGROUND

• Khan A, Ding Z, Ishaq M, Bacha AS, Khan I, Hanif A, Li W, Guo X. Understanding the Effects of Gut Microbiota Dysbiosis on Nonalcoholic Fatty Liver Disease and the Possible Probiotics Role: Recent Updates. Int J Biol Sci. 2021 Feb 8;17(3):818-833. doi: 10.7150/ijbs.56214. eCollection 2021.

  PMID: 33767591 BACKGROUND

• Bozic D, Podrug K, Mikolasevic I, Grgurevic I. Ultrasound Methods for the Assessment of Liver Steatosis: A Critical Appraisal. Diagnostics (Basel). 2022 Sep 22;12(10):2287. doi: 10.3390/diagnostics12102287.

  PMID: 36291976 BACKGROUND

• Merriman RB, Ferrell LD, Patti MG, Weston SR, Pabst MS, Aouizerat BE, Bass NM. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology. 2006 Oct;44(4):874-80. doi: 10.1002/hep.21346.

  PMID: 17006934 BACKGROUND

• Sanyal AJ, Williams SA, Lavine JE, Neuschwander-Tetri BA, Alexander L, Ostroff R, Biegel H, Kowdley KV, Chalasani N, Dasarathy S, Diehl AM, Loomba R, Hameed B, Behling C, Kleiner DE, Karpen SJ, Williams J, Jia Y, Yates KP, Tonascia J. Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2023 Apr;78(4):693-703. doi: 10.1016/j.jhep.2022.11.029. Epub 2022 Dec 14.

  PMID: 36528237 BACKGROUND

• Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016 Aug;65(8):1038-48. doi: 10.1016/j.metabol.2015.12.012. Epub 2016 Jan 4.

  PMID: 26823198 BACKGROUND

• Kobyliak N, Abenavoli L, Mykhalchyshyn G, Kononenko L, Boccuto L, Kyriienko D, Dynnyk O. A Multi-strain Probiotic Reduces the Fatty Liver Index, Cytokines and Aminotransferase levels in NAFLD Patients: Evidence from a Randomized Clinical Trial. J Gastrointestin Liver Dis. 2018 Mar;27(1):41-49. doi: 10.15403/jgld.2014.1121.271.kby.

  PMID: 29557414 BACKGROUND

• Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, Kleiner DE, Loomba R. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-1835. doi: 10.1097/HEP.0000000000000323. Epub 2023 Mar 17. No abstract available.

  PMID: 36727674 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus; Hypertension; Hyperlipidemias; Metabolic Syndrome

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Dyslipidemias; Lipid Metabolism Disorders; Insulin Resistance; Hyperinsulinism

Study Officials

• Marko Skelin, ass.prof.dr.sc, mag.pharm.

  GH Sibenik-Knin County, Medical Faculty University of Rijeka, Croatia

  STUDY CHAIR

Central Study Contacts

Eva Cubric, doctor of medicine

CONTACT

+38522641465; gastroenterologija@bolnica-sibenik.hr

Marko Skelin, doctor of science, magh.pharm

CONTACT

+38522641641; marko.skelin@uniri.hr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: doctor medicine

Model Details: This is a randomized, multicenter, double-blind clinical trial. If they meet the inclusion criteria at the next medical examination (study start-randomization period) upon entering the study, patients will be randomized into two groups in a 1:1 ratio, where one group will receive the test product (n=57) and the other/control group placebo (n=57).

Study Record Dates

• First Submitted: June 10, 2025
• First Posted: June 18, 2025
• Study Start: July 1, 2025
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2029
• Last Updated: June 18, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

CR (1)