Clinical trial of the efficacy and safety of nicotinamide in patients with diabetes mellitus type 2 and liver fibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

2 Jan 2024 → ongoing

Decision date (initial)

2023-06-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Carlos III Health Institute - Spain

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Prophylaxis, Safety

To determine the efficacy of NAM administration (1.2 g/m², up to a maximum of 3 g/day) on the development and progression of liver fibrosis, monitored through the use of FibroScan® along with the Enhanced Liver Fibrosis (ELF™) test over a 12-month period in overweight subjects with NAFLD (FibroScan® with CAP >250 dB/m) and early-stage liver fibrosis (FibroScan® >8 kPa).

Secondary objectives 2

1. To assess the safety of administering the intended dose of NAM throughout the study by collecting adverse reactions (clinically important, serious and unexpected) related to the use of NAM and serial analyses during follow-up.
2. To evaluate the favorable influence of NAM on: The amount of intrahepatic fat evaluated by ultrasound and CAP (Controlled Attenuation Parameter) measurement by Fibroscan®. The distribution and physiology of body fat by abdominal CT imaging technique. Obesity-related clinical variables (body weight, BMI, circumferences), biochemical (HOMA-IR, adipo-IR indices), and body adiposity (ultrasound, bioimpedance, and nuclear magnetic resonance). Muscle function and risk of sarcopenia by means of hand-pressure strength (MPF) and chair test. Thermogenic capacity of adipose tissue by body thermography monitoring. Systemic inflammation through peripheral blood monocyte counts (CD14+, CD16-) as well as their M1/M2 polarization using specific markers by flow cytometry. Circulating concentration of different pro- and anti-inflammatory cytokines (TNFa, IL-6, IL-1b, IL-10, IL-13), adipokines (adipoconectin, leptin, visfatin, resistin), sCD163, sCD206, and fatty acid profile by miliplex, ELISA, flow cytometry/lipidomics, as appropriate. Circulating concentration of different adipokines (S100A4 and FABP4) by ELISA. The composition of the microbiota by metagenomic analysis, and its relationship with concomitant changes in serum levels of different metabolites (organic acids and short chain fatty acids and NAM intermediates) whose serum levels are influenced by changes in the microbiota.

Conditions and MedDRA coding

Hepatic fibrosis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Patients aged between 18 and 85 years.
2. 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).
3. BMI between 27-40 kg/m2.
4. Fibroscan® value higher than 8kPa.
5. ELF test > 7.7

Exclusion criteria 28

1. 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.
2. 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).
3. Decreased renal function (estimated glomerular filtration rate <45 ml/min/1.73 m2, calculated using the CKD-EPI formula) at screening.
4. Alcohol consumption greater than 30 g/day in men or 20 g/day in women.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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).
11. History or evidence of an autoimmune disorder considered clinically significant by the investigator or requiring systemic, chronic use of systemic corticosteroids or other immunosuppressants.
12. Patients being treated with hepatotoxic drugs (amiodarone, immunosuppressants, ART, anti-tuberculosis drugs, corticosteroids, etc.).
13. Patients who consume narcotic and psychotropic substances with hepatotoxic effects.
14. Individuals with disabling illnesses or cognitive impairment.
15. Institutionalized patients or patients without a fixed address.
16. Principal investigator judgment in case there are indications of low adherence to the trial or follow-up visits.
17. People with a life expectancy of less than 12 months.
18. 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.
19. Previous use of vitamin B3 (NAM), abstinence must be at least 3 months before screening.
20. 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.
21. Breastfeeding women.
22. Patients who are receiving treatment/supplementation with vitamin E.
23. Patients receiving probiotics.
24. Patients on the waiting list to undergo bariatric surgery in the next 12 months.
25. Patients undergoing treatment with drugs that may have an effect on the progression of liver disease.
26. 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.
27. 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
28. Patients who do not sign the informed consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Changes in liver stiffness measured by Fibroscan® at 12 months after the start of treatment compared to baseline.
2. Changes in the quantification of intrahepatic fat measured by CAP at 12 months after the start of treatment compared to the initial value.
3. Changes in the value obtained through the ELFTM Test (metabolomics-based methodology) at 12 months after the start of treatment compared to the initial value.
4. Histological changes in case of final liver biopsy in patients with a biopsy prior to the start of the study.

Secondary endpoints 3

1. Changes in the distribution of body adiposity, measured by bioimpedance at 12 months after the start of treatment with respect to the initial value.
2. Cambios en la composición relativa de la microbiota intestinal analizada en heces mediante metabolómica y de las concentraciones séricas de metabolitos relacionados con su metabolismo, a lo largo del tratamiento (basal, 3, 6, y 12 meses).
3. Changes in circulating levels of cytokines/adipokines related to systemic inflammation throughout treatment (baseline, 3, 6, and 12 months). This point will be assessed at the end of the study, by means of a sample from the biobank.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Sponsor organisation

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Address

Calle De San Quintin 77-79

City

Barcelona

Postcode

08041

Country

Spain

Scientific contact point

Organisation

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Contact name

UICEC

Public contact point

Organisation

Fundacio Institut De Recerca De L Hospital De La Santa Creu I Sant Pau

Contact name

UICEC

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications