Study of the Efficacy and Safety of Nicotinamide in Patients With Liver Fibrosis (NICOFIB)

Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Nicotinamide in Patients With and Liver Fibrosis (NICOFIB)

The objective of this clinical trial, a pilot study, is to assess the impact of nicotinamide (NAM) on individuals with hepatic fibrosis.

The main question it aims to answer is:

- To determine if the treatment with NAM is able to arrest, or even reduce, the hepatic fibrosis.

In addition, we also want to study the effect of NAM on:

• General parameters (weight, HOMA-IR, etc).
• Adiposity distribution (liver and body).
• Systemic inflammation.
• Thermogenic capacity of adipose tissue.
• Microbiota composition.

Researchers will compare NAM to a placebo, to see if NAM can arrest or revert hepatic fibrosis and its associated effects.

Participants will take either NAM or placebo. The dosage will be 1.2g/m2 NAM per day, for one year.

Patients with a Fibroscan > 8 kPa will be offered to participate in this study. Participants will receive either placebo or a NAM dose adjusted to body weight. The duration of the treatment is 12 months.

Participants will be subjected to a total of 5 follow-up and/or control visits:

Visit 1

• Physical examination(weight, height, BMI, waist circumference, neck circumference, blood pressure, and heart rate).
• Assessment of muscle status and risk of sarcopenia: grip strength, chair test.
• Basal electrocardiogram.
• Blood analysis.
• Bioelectrical impedance analysis.
• Nuclear magnetic resonance.
• Thermographic image.
• Food questionnaire (PREDIMED).
• International Physical Activity Questionnaire (IPAQ).
• Collection of blood, urine, and feces samples for storage in the biobank.

Visit 2. Control visit (time month 1)

• Monitoring of adverse events (AE) and adverse reactions (AR).
• Electrocardiogram.
• Control blood analysis: sodium, potassium, liver biochemistry (AST, ALT, bilirubin, GGT, FA), renal function (urea, creatinine, estimated glomerular filtration), and coagulation tests.
• Physical examination and measurement of vital signs.

Visit 3. Follow-up visit (time month 3)

• Monitoring of AE and AR.
• Drug adherence questionnaire.
• Electrocardiogram.
• Blood analysis.
• Physical examination (weight, BMI, waist circumference, neck circumference, blood pressure, and heart rate).
• Collection of blood, urine, and feces samples for biobank.
• Collection of concomitant medication.
• Adherence to study treatment and dietary recommendations.

Visit 4. Follow-up visit (time month 6)

• Monitoring of AE and AR.
• Drug adherence questionnaire.
• Electrocardiogram.
• Blood analysis.
• Physical examination (weight, BMI, waist circumference, neck circumference, blood pressure, and heart rate).
• Collection of blood, urine, and feces samples for biobank.
• Collection of concomitant medication.
• Adherence to study treatment and dietary recommendations.

Visit 5. Control visit (time month 9).

• Monitoring of AE and AR.
• Drug adherence questionnaire.
• Electrocardiogram.
• Control blood analysis.
• Physical examination.
• Collection of concomitant medication.

Visit 6. Final exploration (time month 12)

• Monitoring of AE and AR.
• Drug adherence questionnaire.
• Food questionnaire (PREDIMED).
• Physical Activity Questionnaire (IPAQ).
• Physical examination and measurement of vital signs (weight, BMI, waist circumference, neck circumference, blood pressure, and heart rate).
• Assessment of muscle status and risk of sarcopenia: FPM, chair test.
• Electrocardiogram.
• Blood analysis.
• Measurement of NAM and derived metabolites in serum and urine.
• Nuclear magnetic resonance.
• Bioimpedance.
• Thermographic image.
• Fibroscan® with CAP.
• Collection of blood, urine, and feces samples for biobank

The safety of the participants will be assessed using a record of the AEs and ARs that could arise and their annotation in the EDC, as well as a regular evaluation of liver, kidney, and heart function at baseline, 1, 3, 6, 9 and 12 months

Inclusion Criteria:

• Patients aged between 18 and 85 years.
• Diagnosis of non-alcoholic fatty liver disease (NAFLD) by their referring physicians (NAFLD defined as the presence of hepatic steatosis and in the absence of significant alcohol consumption, having excluded other liver diseases).
• BMI between 27-40 kg/m2.
• Fibroscan® value greater than 9.2 kPa, obtained within the last 6 months prior to the start of the study.

Exclusion Criteria:

• Patients with any medical condition or illness that, in the opinion of the investigator, could interfere with the study results and/or affect the patients' ability to participate or complete the study.
• History of clinically significant heart disease (ejection fraction <40% [normal range 50-70%], heart failure defined as New York Heart Association [NYHA] Class > 2; clinically significant congenital or acquired valvular disease; symptomatic coronary artery disease such as myocardial infarction or angina, history of unstable arrhythmias, history of atrial fibrillation).
• Decreased renal function (estimated glomerular filtration rate <45 mL/min/1.73 m2, calculated using the CKD-EPI formula) at screening.
• Alcohol consumption exceeding 30 g/day in men or 20 g/day in women.
• Patients with significant impairment of liver function in the selection analysis defined as repeated values of AST, ALT, and bilirubin > 3 times the upper limit of normal.
• Positive for hepatitis B surface antigen or hepatitis C antibodies.
• Patients with hepatocellular carcinoma.
• Patients with liver cirrhosis (Fibroscan® > 18, compatible biopsy, or those who have experienced decompensations of cirrhosis).
• Patients diagnosed with human immunodeficiency virus (HIV).
• Patients with hypersensitivity or a history of severe allergies to NAM or excipients used in the preparation of capsules (NAM and placebo).
• Patients with iodinated contrast allergy.
• History or evidence of an autoimmune disorder considered clinically significant by the investigator or requiring systemic, chronic use of systemic corticosteroids or other immunosuppressants.
• Patients on treatment with hepatotoxic drugs (amiodarone, immunosuppressants, ART, antituberculosis drugs, corticosteroids, etc.).
• Patients consuming narcotic and psychotropic substances with hepatotoxic effects.
• Individuals with incapacitating diseases or cognitive impairment.
• Institutionalized patients or those without a fixed address.
• Principal investigator's discretion in case of indications of low adherence to the trial or follow-up visits.
• Individuals with a life expectancy of less than 12 months.
• Patients participating in another interventional clinical trial, excluding observational/natural history studies, at the start of the study or within the last 30 days before the start of the study.
• Previous use of vitamin B3 (NAM), with abstinence required for at least 3 months before screening.
• Pregnant women as determined by a positive high-sensitivity serum or urine pregnancy test (minimum sensitivity of 25 IU/L or equivalent units of hCG) within 24 hours prior to screening, dosing, or completion of the study. Women of childbearing potential (WOCBP) will undergo a pregnancy test (serum or urine) 24 hours prior to screening, dosing, or completion of the study. Such participants must use a highly effective contraceptive method, such as combined hormonal contraceptives or intrauterine device (IUD), in accordance with the Clinical Trial Facilitation Group, throughout the entire study.
• Breastfeeding women.
• Patients undergoing treatment/supplementation with vitamin E.
• Patients receiving probiotics.
• Patients on the waiting list for bariatric surgery in the next 12 months.
• Patients undergoing treatment with drugs that may have an effect on the progression of liver disease.
• Drugs for the treatment of T2DM with effects on NAFLD (GLP-1 analogs, thiazolidinediones such as pioglitazone) initiated within 6 months before the study start.
• Drugs for the treatment of T2DM with effects on intestinal microbiota (metformin, α-GI inhibitors, DPP-4 inhibitors, and SGLT-2 inhibitors) initiated within 6 months before the study start.
• Patients who do not sign the informed consent.
• Patients with contraindications to the contrast agent to be used in imaging tests.