Clinical trial NCT06599918: Study of the Efficacy and Safety of Nicotinamide in Patients with Diabetes Mellitus Type 2 and Liver Fibrosis (NICOFIB)
Official title: Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Nicotinamide in Patients with Diabetes Mellitus Type 2 and Liver Fibrosis (NICOFIB)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Fatty Liver
Obesity
Diabete Type 2
Hepatic Fibrosis
NAFLD
Nicotinamide
Keywords: Nicotinamide
Fatty liver
Nafld
Diabetes Type 2
Lead sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
Sponsor class: OTHER
Collaborators: name: Germans Trias i Pujol Hospital
First posted: 2024-09-19
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A controlled, randomized, double-blind, and multicenter clinical trial has been designed to explore the proof-of-concept regarding the effects of nicotinamide (NAM) administration on hepatic inflammation and fibrosis in individuals with obesity and type 2 diabetes (DM2). The trial adopts a parallel design, incorporating a placebo control group.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.
* Liver ultrasound.
* Ultrasound of abdominal and preperitoneal fat.
* Musculoskeletal ultrasound.
* 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.
* Liver ultrasound.
* Ultrasound of abdominal and preperitoneal fat.
* Musculoskeletal ultrasound.
* 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

Eligibility criteria: 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 30-40 kg/m2.
* Type 2 diabetes mellitus (T2DM) diagnosed by their referring physicians.
* 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.

Primary outcomes:
measure: Effect of nicotinamide on hepatic fibrosis
timeFrame: Fibroscan at 0 and 12 months.
Secondary outcomes:
measure: Effect of nicotinamide on body fat and hepatic fat distribution
timeFrame: 0 and 12 months
measure: Effect of nicotinamide on the general health state (weight)
timeFrame: Blood test and strength test at 0, 3, 6, and 12 months
measure: Effect of nicotinamide on the general health state (strenght)
timeFrame: Blood test and strength test at 0, 3, 6, and 12 months
measure: Effect of nicotinamide on the Insulin resistance
timeFrame: Blood test and strength test at 0, 3, 6, and 12 months
measure: Effect of nicotinamide on gut microbiota
timeFrame: Test at 0, 3, 6, and 12 months
measure: Effect of nicotinamide on systemic inflammation
timeFrame: Blood test at 0, 3, 6, and 12 months
measure: Effect of nicotinamide on cellular inflammation
timeFrame: Blood test at 0, 3, 6, and 12 months
measure: Security evaluation LIVER
timeFrame: 0, 1, 3, 6, 9, and 12 months
measure: Security evaluation KIDNEY
timeFrame: 0, 1, 3, 6, 9, and 12 months
measure: Effect of nicotinamide on liver parameters
timeFrame: 0 and 12 months
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
Study officials:
References: