Efficacy and Safety of Nicotinamide in Type 2 Diabetes Mellitus and Hepatic Fibrosis: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-504100-28-00
Protocol: IIBSP-NIC-2021-157
Sponsor: Fundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

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Diseases & Conditions

Hepatic fibrosis

Objectives

The primary objective of this randomized, double-blind, placebo-controlled study is to evaluate the **efficacy** and **safety** of nicotinamide in patients with type 2 diabetes mellitus and hepatic fibrosis. This is clinically relevant as it aims to determine the potential therapeutic benefits and risks of nicotinamide in managing these conditions, which are prevalent and often co-existing, thereby potentially improving patient outcomes and quality of life.

Secondary objectives include:

Assessing the safety of administering the intended dose of nicotinamide throughout the study by collecting adverse reactions, including clinically important, serious, and unexpected events related to its use.
Evaluating the favorable influence of nicotinamide on various parameters such as intrahepatic fat content, body fat distribution, obesity-related clinical variables, muscle function, thermogenic capacity of adipose tissue, systemic inflammation, circulating concentrations of cytokines and adipokines, and microbiota composition. These assessments are conducted using advanced imaging techniques, biochemical analyses, and metagenomic analysis, providing a comprehensive understanding of nicotinamide's impact on metabolic and inflammatory processes.

Participants

The clinical trial involves participants diagnosed with **type 2 diabetes mellitus** and **hepatic fibrosis**. The study population includes both male and female subjects aged between 18 and 85 years. Participants are required to have a body mass index (BMI) between 30-40 kg/m² and a Fibroscan® value higher than 8 kPa. Additionally, an ELF test result greater than 7.7 is necessary for inclusion. The trial excludes individuals with significant alcohol consumption and other liver diseases, focusing on those diagnosed with non-alcoholic steatohepatitis (NASH) by their referring physicians. The sponsor has not provided information regarding the total number of participants. The trial does not involve a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **nicotinamide** in patients with type 2 diabetes mellitus and **hepatic fibrosis**. The trial is set to run for a total duration of 12 months, with an estimated recruitment start date of June 1, 2023, and an anticipated end date of February 28, 2026. Participants will be randomly assigned to receive either nicotinamide or a placebo, administered orally, with a maximum daily dose of 3 units. The study is categorized as a Phase 4 trial, focusing on treatment and prevention in the specified patient population.

Study visits are structured to include an initial screening visit, where eligibility criteria are assessed. Key inclusion criteria include patients aged 18 to 85 years, a diagnosis of non-alcoholic steatohepatitis (NASH) with a Fibroscan® value higher than 8 kPa, and an ELF test score greater than 7.7. Follow-up visits are scheduled at baseline, 3, 6, and 12 months to monitor changes in liver stiffness, intrahepatic fat, and other metabolic parameters. The primary endpoints include changes in liver stiffness, intrahepatic fat quantification, and ELF test values at 12 months compared to baseline. Secondary endpoints involve changes in body adiposity distribution, gut microbiota composition, and circulating cytokine levels throughout the treatment period.

The expected length of participant involvement is 12 months, with conditions for early termination including significant adverse events or withdrawal of consent. The end-of-study visit will assess the final outcomes, including histological changes in patients who undergo a liver biopsy. The trial aims to provide robust data on the therapeutic potential of nicotinamide in this patient cohort, contributing to the understanding of its role in managing type 2 diabetes mellitus and hepatic fibrosis.

Treatment

The clinical trial involves the administration of **nicotinamide** as the experimental medication. Nicotinamide is presented in a pharmaceutical form identified as PHF00245MIG. The medication is administered orally, with a maximum daily dose of 3 units, and the same maximum total dose amount. The treatment period is set for a maximum of 12 weeks. Nicotinamide is classified under the ATC code A11HA01, indicating its categorization as a vitamin. The trial is designed to evaluate the efficacy and safety of nicotinamide in patients diagnosed with type 2 diabetes mellitus and liver fibrosis.

In addition to the experimental treatment, a placebo is utilized as a comparator in this randomized, double-blind, placebo-controlled study. The placebo is administered in a manner identical to the experimental treatment to ensure blinding and maintain the integrity of the study design. The placebo is also given orally, with the same dosing schedule as the nicotinamide, to ensure consistency across treatment groups. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol and to accurately assess the outcomes of the treatment.

Efficacy

The efficacy of nicotinamide in patients with type 2 diabetes mellitus and **hepatic fibrosis** will be assessed through a series of primary and secondary endpoints. Primary endpoints include changes in liver stiffness measured by Fibroscan® at 12 months compared to baseline, changes in intrahepatic fat quantification measured by Controlled Attenuation Parameter (CAP) at 12 months compared to the initial value, changes in the value obtained through the ELFTM Test (a metabolomics-based methodology) at 12 months compared to the initial value, and histological changes in patients undergoing a final liver biopsy who had a biopsy prior to the study.

Secondary endpoints will evaluate changes in body adiposity distribution measured by bioimpedance at 12 months compared to the initial value, changes in the relative composition of the intestinal microbiota analyzed in feces through metabolomics, and serum concentrations of metabolites related to its metabolism throughout the treatment at baseline, 3, 6, and 12 months. Additionally, changes in circulating levels of cytokines/adipokines related to systemic inflammation will be assessed at baseline, 3, 6, and 12 months, with a final assessment at the end of the study using samples from the biobank.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients aged between 18 and 85 years.
Diagnosis of NASH by their referring physicians (NASH defined as presence of hepatic steatosis and in the absence of significant alcohol consumption and having excluded other liver diseases).
BMI between 27-40 kg/m2.
Fibroscan® value higher than 8kPa.
ELF test > 7.7

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Exclusion Criteria

Patients with any medical condition or disease that, in the opinion of the investigator, could interfere with the results of the study and/or affect the patients' ability to participate in 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 pectoris, 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 greater than 30 g/day in men or 20 g/day in women.
Patients with significant alteration of liver function in the screening workup 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 hepatocarcinoma. Patients with liver cirrhosis (Fibroscan® > 18, compatible biopsy or who have suffered decompensation of cirrhosis). Patients diagnosed with human immunodeficiency virus (HIV). Patients with hypersensitivity or history of severe allergy to NAM or excipients used in the preparation of the capsules (NAM and placebo). 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 under 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 patients with no fixed abode. Principal investigator criteria in the case of indications of low adherence to the trial or follow-up visits. People with a life expectancy of less than 12 months. Patients participating in another interventional clinical trial, excluding observational/natural history studies, at baseline or in the last 30 days before the start of the study. Prior use of vitamin B3 (NAM), abstinence must be at least 3 months prior to screening.
Pregnant women as determined by a positive hCG test (serum or urine) at screening or prior to dosing. Participants of childbearing age should use adequate contraception. Nursing women.
Patients undergoing treatment/supplementation with vitamin E. 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 evolution of liver disease.
Patients with hypersensitivity or a history of severe allergies to NAM or excipients used in the preparation of the capsules (NAM and placebohard gelatin, microcrystalline cellulose, and colloidal silica).
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 being treated with hepatotoxic drugs (amiodarone, immunosuppressants, ART, anti-tuberculosis drugs, corticosteroids, etc.).
Patients who consume narcotic and psychotropic substances with hepatotoxic effects.
Individuals with disabling illnesses or cognitive impairment.
Institutionalized patients or patients without a fixed address.
Principal investigator judgment in case there are indications of low adherence to the trial or follow-up visits.
People with a life expectancy of less than 12 months.
Patients participating in another interventional clinical trial, excluding observational/natural history studies, at baseline or within the last 30 days before the start of the study.
Previous use of vitamin B3 (NAM), abstinence must be 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 hCG equivalent units) within 24 hours prior to screening, or dosing or completion of the study. Participating women of childbearing potential (WOCBP) will have a pregnancy test (serum or urine) performed 24 hours prior to screening, dosing, or completion of the study. These participants must use a highly effective contraceptive method such as combined hormonal contraceptives or intrauterine device (IUD), according to the Clinical Trial Facilitation Group, throughout the entire study.
Breastfeeding women.
Patients who are receiving treatment/supplementation with vitamin E.
Patients receiving probiotics.
Patients on the waiting list to undergo 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 (GLP1 analogues, thiazolidinediones, such as pioglitazone) started within 6 months before the start of the study.
Drugs for the treatment of T2DM with effects on the intestinal microbiota (metformin, α-GI inhibitors, DPP-4 and SGLT-2 inhibitors) initiated within 6 months before the start of the study
Patients who do not sign the informed consent.