Safety and Tolerability of Novel Medical Nutrition Products for NAFLD Treatment

To the moment, only limited data are present on the efficacy of changes in diet composition of patients with non-alcoholic fatty liver disease (NAFLD). The national database search in the federal registry of specialized products revealed no registered products for medical nutrition for patients with NAFLD. We developed the composition of specialized food products, produced their experimental batches, and performed laboratory studies of their safety, including tests on toxicology and microbiology (which revealed no concerns). Organoleptic studies of the products showed acceptable results. The aim of the present study is to assess safety and tolerability of newly developed specialized products for medical nutrition of patients with non-alcoholic fatty liver diseases in a prospective randomized placebo-controlled trial.

Development of specialized medical products is actual due to the high prevalence of non-alcoholic fatty liver disease (NAFLD), which accounts for 20-30% of the world's population, while non-alcoholic steatohepatitis (NASH) accounts for about 20% of all cases of NAFLD and affects all age groups, including children. Currently, there are no generally accepted and efficient methods to treat the disease. Recommended measures include changes in lifestyle, i.e., weight loss and dietary modifications together with increased physical activity. Pragmatic approaches combining dietary restriction and a progressive increase in aerobic exercise / resistance training are preferable and should be individually tailored. Only general principles of diet modification are strongly recommended, though the evidence of their efficacy is far from excellent. According to EASL 2016 guidelines on NAFLD, there is a need for energy restriction, exclusion of NAFLD-promoting components (processed food, and food and beverages high in added fructose; the macronutrient composition should be adjusted according to the Mediterranean diet) and avoidance of excessive alcohol intake. Only limited data are available on the change of diet composition, including the intake of products with low glycaemic index, containing larger amounts of components with known antioxidant capacity (including vitamins and minerals) and dietary fibre. Still, the use of mentioned components is promising in the regard of their potential to trigger metabolic changes, decrease insulin resistance, inflammatory processes in the liver tissue and excessive lipid accumulation in the liver in patients with NAFLD. The database search in the federal registry of specialized products revealed no specialized products for medical nutrition for patients with NAFLD. Despite some similarities in the pathogenesis of the diseases, specialized medical products for patients with diabetes mellitus are not optimal for patients with fatty liver disease. Based on the published data, medical and biological requirements for specialized product of medical nutrition were formulated. According to them, at an earlier stage of the present work we developed the composition of specialized food products, produced their experimental batches, and performed laboratory studies of their safety, including tests on toxicology and microbiology (which revealed no concerns). Organoleptic studies of the products showed acceptable results. The aim of the present study is to assess safety and tolerability of newly developed specialized products for medical nutrition of patients with non-alcoholic fatty liver diseases in a prospective randomized placebo-controlled trial.

Eligibility Criteria:
Inclusion Criteria:

* Males or females aged from 18 to 75 years inclusive;
* Willingness to participate based on the written informed consent form;
* Documented evidence of non-alcoholic fatty liver disease presence, defined based on the following: steatohepatitis evaluated by liver biopsy taken within 12 months prior to enrolment (when liver biopsy is available, at least a score of 1 in each component of the NAS (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3), NAS ≥4, fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system should be present); or ultrasound markers of fatty liver in combination with persistent elevated alanine aminotransferase (ALT; absence of normal value of ALT within the past year), obesity defined by a body mass index (BMI) ≥30, metabolic syndrome (NCEP ATP III definition), type 2 diabetes, or homeostasis model assessment of insulin resistance (HOMA-IR) \>6;
* Patients in whom it is safe and practical to proceed with specialized medical food product treatment;
* If a patient is treated with 1 of the following drugs: vitamin E (\>400 IU/day), polyunsaturated fatty acids (\>2 g/day), or ursodeoxycholic acid; a stable dose from at least 6 months prior to the enrolment;
* For patients with type 2 diabetes, glycaemia must be controlled. If glycaemia is controlled by antidiabetic drugs, change in anti-diabetic therapy must follow these requirements:

  * no qualitative change 6 months prior to randomization (i.e., implementation of a new anti-diabetic therapy) for patients treated with metformin, gliptins, sulfonylureas, sodium/glucose cotransporter (SGLT) 2 inhibitors, glucagon-like peptide (GLP)-1 agonists, or insulin. Dose changes of these medications are allowed in the 6 months prior to randomization, except for GLP-1 agonists, which must remain on stable dose in the 12 months prior to enrolment.
  * no implementation of any antidiabetic drugs before the end of the treatment (day 14).

Exclusion Criteria:

* Pregnant or breast feeding females;
* Liver cirrhosis based on liver histology or liver stiffness measurements (\> or equal to 14 kPa), or APRI \>or equal to 1; or BARD score \> or equal to 2.
* Known chronic heart failure (Grade I to IV of New York Heart Association classification).
* History of efficient bariatric surgery within 5 years prior to enrollment.
* Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy.
* Type 1 diabetes patients.
* Patients with haemoglobin A1c \[HbA1c\] \>9.0%.
* Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening
* Weight loss of more than 5% within 6 months prior to Randomization.
* Current or recent history (\<5 years) of significant alcohol consumption. For men, significant consumption is defined as higher than 30 g pure alcohol per day. For women, it is typically defined as higher than 20 g pure alcohol per day
* Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not limited to:

  * positive hepatitis B surface antigen
  * positive hepatitis C Virus (HCV) RNA (tested for in case of known cured HCV infection or positive HCV Ab at Screening)
  * suspicion of drug-induced liver disease
  * alcoholic liver disease
  * autoimmune hepatitis
  * Wilson's disease
  * primary biliary cirrhosis, primary sclerosing cholangitis
  * genetic homozygous haemochromatosis
  * known or suspected hepatocellular carcinoma (HCC)
  * history or planned liver transplant, or current MELD score \>12
* Known hypersensitivity to the investigation product or any of its components.
* Patients who are currently participating in, plan to participate in, or have participated in an investigational drug trial or medical device trial containing active substance within 30 days or five half-lives, whichever is longer, prior to Screening.
* Use of the following concomitant medications:

  * Fibrates are not permitted from 2 months before Randomization. Patients that used statins, ezetimibe, or other nonfibrate lipid lowering drugs before Screening may participate if the dosage has been kept constant for at least 2 months prior to Screening.
  * Currently taking drugs that can induce steatosis/steatohepatitis including, but not restricted to: corticosteroids (parenteral \& oral chronic administration only), amiodarone (Cordarone), tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall), which are not permitted 30 days prior to Screening and up to end of treatment.
  * Currently taking any medication that could interfere with study medication absorption, distribution, metabolism, or excretion or could lead to induction or inhibition of microsomal enzymes, e.g., indomethacin, which are not permitted from Randomization until end of treatment.
* Patients who have the following associated illnesses or conditions:

  * Any medical conditions that may diminish life expectancy to less than 2 years including known cancers;
  * Evidence of any other unstable or, untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease;
  * Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain.
* patients should not present any of the following biological exclusion criteria:

  * Positive anti-human immunodeficiency virus antibody.
  * Aspartate aminotransferase (AST) and/or ALT \>10 x upper limit of normal (ULN).
  * Conjugated bilirubin \> 26 umol/l due to altered hepatic function (Gilbert Disease patients are allowed into the study.
  * International normalized ratio \>1.40 due to altered hepatic function.
  * Platelet count \<100,000/mm\^3 due to portal hypertension.
  * Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney damage or estimated glomerular filtration rate \[eGFR\] of less than 60 ml/min/1.73 m\^2).
* Patients for whom participation in the trial is not reasonable according to the opinion of Investigator or in cases when participation in the trial may put the patient at any kind of risk.

The data of patients with evidence or suspected compliance to the provided treatment lower than 80% will be excluded from the analysis