Clinical Research Directory

RE and Probiotics in MAFLD/NAFLD

This project aims to evaluate the roles of the autonomic nervous system (ANS) and gut microbiota as correlates of clinical improvement in metabolic dysfunction-associated fatty liver disease (MAFLD) and non-alcoholic fatty liver disease (NAFLD) in response to a therapeutic regimen comprising resistance exercise and probiotic supplementation. The primary objective is to investigate the effects of these non-pharmacological interventions on MAFLD/NAFLD and to identify patient phenotypes based on baseline ANS profiles and gut microbiota composition that predict clinical responses.

Accurate Point of Care Liver Disease Diagnostics (Phase 2)

This research study is being conducted to find out more about techniques to non-invasively evaluate liver disease. This is the second phase of a project in which we are testing a new technology to evaluate the liver (LiverScope®). We will compare LiverScope® to other methods to evaluate the liver, including advanced conventional liver MR exams. MR exams are common exams used to monitor MASLD (also known as NAFLD). Conventional MR scanners use magnetic fields and radio waves to make pictures of the liver. LiverScope® is a small, portable MR-based device that uses similar, but simplified technology, and can be used on top of an exam table in an outpatient setting. LiverScope® currently is not approved for clinical use. In this second phase of the study, we took what we learned in the first phase to optimize the LiverScope® device and are now testing to see how LiverScope® measurements compare to MR after these optimizations. Study participants will be asked to complete a one-time visit which includes: * LiverScope exam * MR exam * FibroScan exam (optional) * Blood draw * Completion of study questionnaires

A Study to Evaluate DD01 in Overweight/Obese Subjects With MASLD/MASH

This is a Phase 2 Study to evaluate the effect of DD01 treatment in overweight/obese patients with metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH).

Semaglutide vs Sitagliptin

The effect of once daily dosing of oral Semaglutide versus once daily dosing Sitagliptin on glycemic control, body weight, and safety and tolerability will be compared in Liver Transplant Recipients with poorly-controlled Diabetes Mellitus.

Short and Long Term Clinical and Patient-Reported Outcomes Associated With Intragastric Balloon Placement in Patients With Nonalcoholic Fatty Liver Disease

This study aims to enroll a robust cohort of NAFLD patients who undergo Intragastric Balloon placement through a multidisciplinary program approach to evaluate clinical and patient-reported outcomes for at least one-year post-placement.

Target of Suv420h1/2 in Hepatocytes

Nonalcoholic fatty liver disease (NAFLD) is globally the leading cause of liver disease and frequently progresses to cirrhosis and liver cancer. The identification of effective drugs is the main unmet clinical need. Changes in liver histones methylation accompanies the development and progression of NAFLD. Our preliminary data demonstrate that inactivation of the methyltransferases SUV420H1/2 in hepatocytes protects mice against NAFLD. In this project we propose to examine the relevance of these findings by evaluating the impact of genetic deletion of hepatic SUV420H1/2 in mice fed a steatogenic diet. To further evaluate the potential for clinical translation of these results, we will next 1) evaluate the expression of SUV420H1/2 in human liver transcriptomic data and 2) analyze the impact of genetic variations on disease outcomes in population-based cohorts; 3) test an innovative therapeutic approach based on hepatocyte-targeted antisense oligonucleotides downregulating SUV420H1/2 in human liver organoids/assembloids.

Effects of Two Different Exercise Programs and Diet in Obese Subjects With NAFLD

The aim of the study is to estimate the effectiveness of two different exercise programs combined with the Mediterranean diet versus diet alone on inflammatory status in subjects aged 18-65 years with obesity (BMI\>30) and Non-Alcoholic Fatty Liver Disease (NAFLD) (CAP \>248 dB/m).

GLP-1 RA on Liver OMICS in MASLD

In patients with type II diabetes mellitus (T2DM) and obesity, an excess plasma-free fatty acid is found with an associated increased lipid accumulation in adipocytes and liver tissue. Lipid droplet accumulation in the hepatocytes is an initial step in the development of metabolic dysfunction associated steatotic liver disease (MASLD. Insulin resistance, which is associated with T2DM, mediates the inflammation of these lipids, resulting in the progression of MASLD to metabolic dysfunction associated steatotic hepatitis (MASH). Hence, in T2DM, obesity, and MASLD, changes in the lipid profile occur, and they are interrelated. In this study, we aim to assess improvement in the lipidomic, its associated metabolic changes and evaluate the co-regulated genes in the liver tissue among patients with MASLD with intervention with GLP-1 RA, which has shown to benefit T2DM and obesity.

Effect of VLCD on the Reduction of Liver Steatosis and Fibrosis in Subjects With Obesity and NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity which can progress to deadly complications like end-stage liver disease and hepatocellular carcinoma. In the wake of the obesity epidemic, NAFLD is becoming the main etiology of liver transplantation in the US. Currently, there are no FDA approved pharmacological treatments for NAFLD. Weight loss through lifestyle modifications, pharmacotherapy and bariatric surgery can be effective strategies for the management of NAFLD. Even though substantial weight loss and improvement in NAFLD can be achieved with bariatric surgery, only a small proportion of patients with obesity undergo surgery. Very-low calorie diets (VLCD) are replacement meals manufactured to substitute natural foods and limited total intake of 800-960 kcal in divided meals. Very low-calorie diets can produce substantial weight loss of 10% over 2 to 3 months. We hypothesize that VLCD reduce liver steatosis and, fibrosis measured non-invasively with transient elastography. Our main aim is #1 to assess the effect of VLCD on liver fatty infiltration and fibrosis. We also have three exploratory aims exploring novel pathogenic factors that mediate the improvement of NAFLD by VLCD: #2 assess the effect of VLCD on micro RNAs (miRs) associated with pathophysiology of NAFLD: #3 assess the effect of VLCD on changes of salivary and fecal microbiome in the setting of NAFLD: #4 to determine the effect of VLCD on platelet function. This pilot project will produce preliminary data for the development of a larger grant application to study the efficacy of VLCD in the management of NAFLD. Furthermore, it will potentially identify factors that mediate improvement of NAFLD after VLCD. We will treat 10 subjects with obesity and NAFLD for 8 weeks with VLCD or lower calorie diet (control group) and obtain transient elastography before and after the interventions along with other measurements of interest. Our project may have significant impact by establishing VLCD as a clinically effective option for the improvement of liver steatosis and fibrosis in patients with obesity and NAFLD ineligible or without access to bariatric surgery.

The Effects of Glucagon on Hepatic Metabolism

Whether impaired postprandial glucagon suppression in prediabetes and T2DM is an attempt to overcome resistance to glucagon's actions on hepatic AA catabolism, a defect in α-cell function, or a combination of both are important, unanswered questions. NAFLD is associated with T2DM risk and impaired insulin action. Unfortunately, it is unclear if glucagon resistance is caused by obesity, hepatic steatosis or both. The experiments outlined will determine if glucagon's actions on hepatic amino acid catabolism and EGP interact with hepatic lipid metabolism in lean and obese subjects with and without T2DM (and with varying degrees of hepatic steatosis).

A Clinical Study of Efinopegdutide in People With Compensated Cirrhosis Due to Steatohepatitis (MK-6024-017)

Researchers are looking for ways to treat a type of liver disease caused by elevated liver fat, called metabolic dysfunction-associated steatohepatitis (MASH). MASH was formerly called non-alcoholic steatohepatitis (NASH). Researchers want to learn if a study medicine called efinopegdutide can treat MASH.The goals of this study are to learn: * If efinopegdutide can lower the amount of fat, inflammation, and scarring (fibrosis) in the liver * About the safety of efinopegdutide and how well people tolerate it

Effects of Empagliflozin on Fibrosis and Cirrhosis in Chronic Hepatitis B Patients

Chronic hepatitis B (CHB) affects 257million individuals worldwide. In 2017, it caused around 39.7 million cases of cirrhosis and 0.4 million cirrhosis-related deaths in 2017. However, there is no specific treatment for liver fibrosis/cirrhosis. Although nucleos(t)ide analogues (NAs) profoundly suppress viral replication, fibrosis/cirrhosis progression can still occur in NA-treated patients. Sodium-glucose cotransporter type-2 (SGLT2) inhibitors are antidiabetic drugs that may prevent fibrosis/cirrhosis progression by reducing hepatic steatosis/inflammation, dampening renin-angiotensin aldosterone system (RAAS) activation, and reducing fluid retention, effects of which are independent of glycemic control. Clinical studies in diabetic patients show SGLT2 inhibitors reduce hepatis steatosis/inflammation, regress ascites (a cirrhotic complication), and improve liver function parameters and survival prognosis in terms of model for end-stage liver disease (MELD) score. There are currently no randomized controlled trials (RCTs) on role of SGLT2 inhibitors in preventing fibrosis/cirrhosis progression in CHB patients. Magnetic resonance elastography (MRE) and transient elastography (TE) are non-invasive techniques for liver stiffness measurement (LSM), although MRE is more accurate than TE. The investigators propose a double-blind, randomized, placebo-controlled trial to compare effect of empagliflozin (an SGLT2 inhibitor) with placebo (1:1 ratio) in preventing fibrosis progression in both diabetic and non-diabetic NA-treated CHB patients with significant/advanced fibrosis or compensated cirrhosis. 108 patients will be randomly sampled from our pre-existing TE database. Empagliflozin 10mg daily will be given to treatment arm. Placebo pills will be manufactured identical in appearance to empagliflozin. Subjects will receive active or placebo pills for three years, and undergo clinical, anthropometric and laboratory assessments (at baseline, weeks 8, 16, and every 4 months thereafter). They will undergo LSM by TE at baseline, end of first, second and third year, and by MRE at baseline and end of third year. Primary outcome is difference in change to liver stiffness (measured by MRE) from baseline between the two groups at the end of third year. The study results will determine whether SGLT2 inhibitors can prevent hepatic fibrosis/cirrhosis progression in NA-treated CHB patients.

Prevalence and Predictors of Hepatic Steatosis in Persons Living With HIV

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver conditions associated with fat accumulation that ranges from benign, non-progressive liver fat accumulation to severe liver injury, cirrhosis, and liver failure. NAFLD is the most common liver disease in US adults and the second leading cause for liver transplantation in the US. The natural history of NAFLD in the general population has been well described, with those with non-alcoholic fatty liver (NAFL, or simple steatosis) destined to have rare incidence of hepatic events compared to those with non-alcoholic steatohepatitis (NASH), who are at high risk for future development of cirrhosis, liver cancer and liver failure. The NASH Clinical Research Network (NASH CRN) was established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2002, through the mechanism of RFA-DK-01-025, to further the understanding of diagnosis, mechanisms, progression and therapies of NASH. The NASH CRN effort has resulted in numerous seminal studies in the field. However, NASH CRN studies have systematically excluded persons living with HIV (PLWH), as NAFLD in these persons was thought to be different from that in the general population due to HIV, ART, concomitant medications, and co-infections. This has resulted in major knowledge gaps regarding NAFLD in the setting of HIV. This ancillary study of NAFLD and NASH in Adults with HIV (HIV NASH CRN), HNC 001 goal is to examine the prevalence of hepatic steatosis and NAFLD in a large, multicenter, and multiethnic cohort of PLWH (Steatosis in HIV Study)

SGLT2 Inhibitors as a Novel Treatment for Pediatric Non-Alcoholic Fatty Liver Disease

This study is a randomized, double-blind, placebo-controlled trial specifically designed to evaluate the preliminary feasibility, initial efficacy and safety of SGLT2 inhibitors for treating NAFLD in adolescents with obesity.

Nonalcoholic Fatty Liver Disease in HIV Database

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver conditions associated with fat accumulation that ranges from benign, non-progressive liver fat accumulation to severe liver injury, cirrhosis, and liver failure. The spectrum of NAFLD encompasses simple nonalcoholic steatosis (nonalcoholic fatty liver \[NAFL\]) and nonalcoholic steatohepatitis (NASH) in which there is evidence of hepatocellular injury and/or fibrosis. NAFLD is the most common liver disease in adults and the second leading cause for liver transplantation in the U.S. The natural history of NAFLD in the general population has been well described. The NASH Clinical Research Network (NASH CRN) was established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2002 to further the understanding of the diagnosis, mechanisms, progression and therapies of NASH. This effort has resulted in numerous seminal studies in the field. However, NASH CRN studies have systematically excluded persons living with HIV (PLWH) , as NAFLD in PLWH was thought to be different from that in the general population due to HIV infection, antiretroviral therapy (ART), concomitant medications and co-infections. This resulted in major knowledge gaps regarding NAFLD in the setting of HIV infection. Thus, the natural history of NAFLD in PLWH is largely unknown. The goal of this ancillary study of NAFLD and NASH in Adults with HIV (HIV NASH CRN), is to conduct a prospective, observational, multicenter study of NAFLD in PLWH (HIV-associated NAFLD).

Rutin and Vitamin C in Patients With Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD)

evaluate the combined effects of Rutin and Vitamin C versus Vitamin C alone on selected oxidative stress markers, inflammation, hepatic steatosis regression, and associated metabolic parameters in patients with MASLD

An Imaging-based Quantitative Biomarker Assay for NAFLD in Children

This study will validate recently developed Magnetic Resonance Imaging (MRI) and Ultrasound (US) based methods for liver fat quantification in children with obesity and healthy range of body mass index (BMI).

Prevalence of NAFLD in T2DM Patients

To determine the prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM).

Human Liver ORganoids as a Model to Study the Development of Non-Alcoholic SteatOhepatitis (NASH)

The primary objective of the study is to generate and characterize three-dimensional models, called "assembloids", composed of the main liver cell populations (in particular from the co-culture of organoids with stellate cells, responsible for fibrogenesis, deriving from clinical samples). These models will be used in order to imitate the first phases of the onset of steatohepatitis, in conditions of altered lipid metabolism (induced through exposure to the main environmental determinants of this condition: excess fatty acids, fructose, cholesterol) in the presence or absence of the mutation I148M of PNPLA3. Other genetic variants will also be analyzed, such as TM6SF2, MBOAT7 and GCKR, which have previously been correlated with the development of non-alcoholic steatohepatitis. Further objectives will be: 1) identify new biomarkers of pathological activation of human stellate cells and progression of liver damage, to be subsequently validated in clinical case series for future use in clinical management for individual risk stratification; 2) study the epigenetic factors that underlie the onset of non-alcoholic steatohepatitis and its progression to fibrosis, cirrhosis and HCC; 3) evaluate the impact of antisense oligonucleotides directed against PNPLA3 on the severity of the "steatohepatitic" phenotype (lipid accumulation, lipotoxicity and inflammation and fibrogenesis) in assembloids

Chrononutrition/ Chronotoxicity Intervention in People With Metabolic-associated Steatotic Liver Disease.

The goal of this clinical trial is to study the effect of a time-restricted eating (TRE) dietary pattern combined with a time of consumption restriction about the daily portions of fruits and vegetables in people diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD). The protocol of the study is an intention to treat protocol. The main research questions are: 1. Does compliance in a TRE dietary scheme (positively) affect changes in body weight and body fat mass in people diagnosed with MASLD? 2. Does an additional time restriction on the consumption of fruits and vegetables within the "light-window" of the day affects the metabolism of food contaminants? Participants will be asked to: 1. Adhere to a TRE dietary pattern for 3 months. TRE consists of an 8-hour eating vs 16 hours fasting within the day. First meal of the day should not occur at least an hour after wake-up time and last meal of the day should occur not later than 2 hours before bed-time. 2. Adhere to a further time restricted consumption of a "5-a-day" portions of fruits and vegetables between the "light-window hours" between 9am to 4pm. 3. Visit the Nutrition \& Dietetics Clinic once every month for anthropometric measurements (on 4 time points). 4. Collect and deliver first morning urine samples (on 7 time points). 5. Collect and deliver saliva samples at baseline and at the end of the trial (Saliva collection should occur every 4-hours for 48-hours including fasting collection at baseline and at the end of three months) 5\) Complete a compliance and lifestyle questionnaire questionnaire via telephone interview to the research team every 2 weeks. 6\) Share photos to the research team with the use of an application on time of actual fruit and vegetables consumption, 3-4 times per week throughout the study protocol. Researchers will compare the designed intervention package of this TRE with the Standard of Care (SoC) protocol (based on the international guidelines) that is currently used in daily practice for the management of MASLD.

Comparison of Two sTRAtegies For the Non-Invasive Diagnosis of advanCed Liver Fibrosis in NAFLD

NAFLD, closely linked to overweight and insulin resistance, has reached 25% prevalence worldwide. Advanced liver fibrosis(ALF) must be accurately diagnosed in NAFLD because it defines a subgroup of patients with impaired prognosis, and these patients need a specific management to prevent the occurrence of liver-related complication. Relatively few NAFLD patients develop ALF and it is a challenge for physicians to identify them. Liver biopsy is the reference for liver fibrosis evaluation but this invasive procedure cannot be first-line used in NAFLD. Non-invasive diagnosis of liver fibrosis is now available, especially liver stiffness measurement (LSM) with Fibroscan and blood fibrosis tests. However, Fibroscan is a costly device available only in few specialized centres with thus poor accessibility in face of the large NAFLD population. Blood fibrosis tests can be performed by every physician and are distinguished as "complex" or "simple". Because they include specialized biomarkers, complex blood fibrosis tests are accurate for the diagnosis of ALF but they are quite expensive and not reimbursed, with therefore limited use in clinical practice. Simple blood fibrosis tests have the advantage to include cheap and easy-to-obtain biomarkers with simple calculation thanks to free websites or smartphone applications. Simple blood fibrosis tests are globally less accurate than complex blood fibrosis tests or Fibroscan but, used with a high-sensitivity cut-off, they have the high interest of being able to accurately rule out advanced fibrosis in a significant proportion of NAFLD patients. Recently, two sequential diagnostic procedures have been developed for the diagnosis of ALF with the idea to combine the advantages of the different kind of fibrosis tests: the FIB4-Fibroscan (FIB4-FS) and the eLIFT-FibroMeterVCTE (eLIFT-FMVCTE) algorithms. These algorithms include as first-line procedure a simple blood fibrosis test (FIB4 or eLIFT) which identifies the patients who require a further second-line evaluation with a more accurate non-invasive test (Fibroscan or FibroMeterVCTE). Liver biopsy is finally used as third-line procedure in patients for whom the diagnosis remains undetermined. Such algorithms have the advantage to limit the use of complex fibrosis tests only to a subset of at risk-patients. The TRAFIC study compare two strategies for the diagnosis of ALF in NAFLD patients: the FIB4-Fibroscan algorithm and the eLIFT-FibroMeterVCTE algorithm

Study of the Efficacy and Safety of Nicotinamide in Patients With 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.

The Liver BIoBank Lombardia of Fatty Liver

NAFLD is most frequently linked to excess adiposity, insulin resistance and cardiometabolic risk factors, it has become the leading cause of liver disease worldwide, and is associated with increased mortality due to multiple causes. HFC has a strong genetic component and the investigators recently showed that it plays a causal role in determining progressive liver disease and insulin resistance. The genetic risk score predicting liver fat content (HFC-GRS) improves the stratification of liver related events, and the investigators have preliminary data on new common and rare variants that contribute to NAFLD susceptibility, and on a new non-invasive circulating biomarker associated with hepatic fat and lipotoxicity (Interleukin-32). However, no data are yet available on the causal role of hepatic fat on the procoagulant state associated with NAFLD, which could participate to liver damage and is a causal factor in atherothrombotic complications. The aim of the study is to examine the potential application of a precision medicine approach to the improvement of stratification of the risk of liver-related and cardiovascular thrombotic complications of hepatic fat accumulation (HFC) and non-alcoholic fatty liver disease (NAFLD), with a special focus on the role of procoagulant imbalance in mediating the at-risk phenotypes.

NAFLD Clinical Care Pathway

Non-alcoholic fatty liver disease (NAFLD) is a new condition that has become the most common chronic liver disease in the world and a main cause of liver cirrhosis, liver failure and liver cancer. Obesity and diabetes, conditions that are very common among Veterans are the main risk factors for NAFLD. Therefore, the burden of NAFLD and its complications among Veterans is substantial. However, most VA patients with NAFLD are undiagnosed and untreated, and their care is not consistent with practice guidelines. The NAFLD Clinical Care Pathway (NCCP) intervention seeks to close this major gap in the care of Veterans by automatically identifying patients at risk of NAFLD, calculating their risk scores of having severe NAFLD, and educating the primary care providers on the diagnosis and treatment of NAFLD. This clinical trial will test the benefit of this NCCP intervention against usual care in increasing the rates of NAFLD diagnosis as well as referral to and enrollment in appropriate treatment. The study will also identify barriers and promotors of future NCCP implementation.