Clinical Research Directory

Liver-gut Axis Study Through Identification of Liver Disease-specific Microbiome

In this study, we aim to identify gut microbiomes specific to patients with chronic refractory liver disease and to conduct a gut-liver axis study on the pathogenesis and disease progression.

Belimumab in Autoimmune Hepatitis

Background: Autoimmune hepatitis (AIH) is a rare chronic and lifelong liver disease. Untreated, disease progresses to end-stage cirrhosis and the focus of therapy is with immunosuppression. Current therapies are limited, not targeted, and associated with side effects that patients report reduce quality of life. AIH is believed to arise as a consequence of genetic \& environmental risks. Disease is characterised by impaired immunoregulation, that favours a chronic and relapsing hepatitis. As well as recognising an important role for cytotoxic T cells and regulatory T cells, it has become apparent that in AIH, as well as other related autoimmune conditions, that B-cells are important. AIH is characterised by a plasma cell rich interface hepatitis and elevated IgG concentrations. Furthermore B-cell lineages interact with regulatory T-cells. Off-label use of Rituximab, an anti-CD20 agent, has been described for patients with AIH. A number of other ways of effectively targeting B-cells in the treatment of related autoimmune diseases have also been developed, but there have been limited studies in people living with autoimmune hepatitis. Belimumab is a human monoclonal antibody that inhibits B-cell activating factor (BAFF), also known as B-lymphocyte stimulator. It is approved in the Canada to treat systemic lupus erythematosus and lupus nephritis. It has not been studied before in AIH, but off-label reports are published. In an open-label clinical trial of people living with autoimmune hepatitis, the investigator will now formally study the effect of adding Belimumab to existing standard of care, with the goal being to evaluate treatment efficacy, the ability to reduce the burden of existing therapies whilst still controlling AIH disease, and to describe the tolerability \& safety of Belimumab in people with AIH. Study Design: Open label, multi-centre, Canadian clinical trial. Patient population: Patients with autoimmune hepatitis, excluding patients with decompensated liver disease, who either have active disease despite standard of care (Group A), or who are maintained with disease remission using standard of care therapy (Group B). 48 patients will be recruited. Intervention: Weekly sub-cutaneous Belimumab. Duration: 72 weeks with interim analysis after 24 patients have been treated for 24 weeks; target recruitment 48 patients. Evaluation: Safety, Serum liver tests, quality of life, exploratory immunologic biomarkers, optional liver biopsy or fine needle liver aspirate. Primary end-point: Group A: 50% or more of subjects have an ALT\<2x ULN \& corticosteroids at a dose of \</= 5mg of Prednisone (or equivalent); Group B: 50% or more of subjects able to maintain remission (normal ALT, normal IgG) on monotherapy with Belimumab. Conclusion: Using a combination of makers of treatment efficacy and safety the investigator will test the hypothesis that Belimumab should be further formally evaluated for people living with AIH.

Machine Learning for Prediction of Therapy Response in Autoimmune Hepatitis

The 5th International Autoimmune Hepatitis Group (IAIHG) research workshop emphasized the integration of large clinical cohorts with artificial intelligence (AI) for enhanced prediction of therapy responses and outcomes in Autoimmune Hepatitis (AIH). This project aims to develop and validate machine learning (ML) models using data from the R-Liver registry and other international cohorts. After rigorous preprocessing to ensure data uniformity and quality, the investigators will identify and characterize factors influencing therapy response. They will then implement ML models to predict complete biochemical response (CBR) at 6 and 12 months, using five-fold cross-validation, and validate these models in external cohorts from Spain, Canada, and the international AIH group, ensuring robustness and generalizability. Finally, the investigators will prospectively validate the models in newly registered cases, assessing both short-term and long-term outcomes. This project seeks to advance personalized treatment strategies in AIH, facilitating timely adjustments in therapy and improving patient prognosis through AI-driven decision support. This projects' interdisciplinary team, with expertise in clinical AI and hepatology, is well-equipped to address these challenges and enhance the clinical management of AIH.

Liver Cirrhosis Network Cohort Study

Liver Cirrhosis Network (LCN) Cohort Study is an observational study designed to identify risk factors and develop prediction models for risk of decompensation in adults with liver cirrhosis. LCN Cohort Study involves multiple institutions and an anticipated 1200 participants. Enrolled participants will have study visits every 6 months (180 days), with opportunities to complete specific visit components via telehealth or remotely. Visits will include collection of questionnaire data and the in-person visits will include questionnaires, physical exams, imaging, and sample collection.

A Study of SIPLIZUMAB in AILD and LT Patients

There is a significant unmet need for safe and effective therapeutic approaches to prevent immune-mediated graft injury and its complications in liver transplant (LT) recipients with autoimmune liver disease (AILD) including autoimmune hepatitis and primary sclerosing cholangitis. Siplizumab is an anti-cluster of differentiation 2 (CD2) monoclonal antibody that has demonstrated a favorable safety profile of siplizumab in over 779 human subjects and has been shown to target memory T cells-a key driver in the immune processes surrounding rejection and autoimmunity post LT in AILD. The purpose of this pilot, open-label phase 1 study is to determine the safety of siplizumab for induction in patients with AILD undergoing LT. Up to eight (8) subjects will receive siplizumab 0.6 mg/kg/dose on the day of transplant (Day 0) and Day 4 post-transplant, for a total of two doses. All subjects will be followed in the study for 12 months post-LT.

Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation

The main objective of this study is to generate diagnosis and therapeutic-decision tools through the identification of molecular causes of PIDs with autoimmunity/inflammation and the variability in disease outcome at the transcriptional level using a combination of omics signatures (transcriptomics, epigenomics, proteomics, metagenomics, metabolomics and lipidomics).

TruGraf Liver Gene Expression Serial Test

This is an Investigator Initiated, single center, non-randomized, single arm study utilizing TruGraf liver gene expression serial testing in patients with autoimmune liver diseases (AIH, PSC, PBC) monthly for the first 6 months after transplant to help inform immunosuppression (IS) optimization. Approximately 20 patients will be enrolled in the study. Study outcomes will include 1-year graft survival, 1 year BPAR and clinically treated rejection rates, number of changes to IS based on the results of Trugraf, eGFR and immune mediated issues. TruGraf®, (Transplant Genomics, Inc., a member of Eurofins Transplant Diagnostics) is a non-invasive blood-based test to assist the clinician in lowering immunosuppression in liver transplant patients. It is the first and only blood-based test that offers biomarker guidance to aid physicians in minimizing immunosuppression in transplant recipients. Unfortunately, achieving the tight control of therapeutic levels of immunosuppression that is required to maintain the balance between "too much" and "too little" can be difficult. TruGraf liver can help clinicians confirm immune "quiescence" prior to, as well as following, immunosuppression reduction in patients with stable graft function, minimizing the risk of overt graft injury due to rejection. The clinical context of use for TruGraf is to provide reassurance to the clinician who is contemplating a preemptive reduction in IS therapy that a patient's immune status is "quiescent" thus reducing the risk of triggering acute rejection with that IS reduction. Having the ability to assess whether the patient's immune status is "quiescent" or activated when considering an increase or decrease in IS therapy allows the clinician greater confidence in decision making.

Swiss Autoimmune Hepatitis Cohort Study

Research project in which biological material is sampled and health-related personal data is further used and collected. Coded data are used.

Host-Diet-Gut Interaction Post Vegan Diet in Pediatric Autoimmune Hepatitis.

Pediatric autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH) and overlap syndromes like sclerosing cholangitis, are among the most common chronic liver conditions in the pediatric population. Currently, the treatment for AIH often involves long-term use of immunosuppressive therapy, which carries risks of severe side effects both in the short and long term. Due to these potential adverse effects, there is a critical need to explore alternative therapies that can modulate autoimmunity and potentially reduce or eliminate the dependence on immunosuppressive drugs. Autoimmune diseases, including AIH, typically arise in genetically predisposed individuals after exposure to certain environmental factors, leading to a breakdown in self-tolerance.The gut microbiome plays a crucial role in modulating the immune system through both anti-inflammatory and pro-inflammatory pathways. In advanced liver diseases, factors such as intestinal dysmotility, small intestinal bacterial overgrowth (SIBO), and increased intestinal permeability contribute to enhanced bacterial translocation, consistent with the "leaky gut" hypothesis. This phenomenon allows the passage of toxins, antigens, and bacteria into the systemic circulation, potentially exacerbating autoimmune responses. Consequently, altering the gut microbiome through dietary changes, probiotics, prebiotics, or fecal microbiota transplantation presents a promising therapeutic approach for autoimmune diseases.This study aims to investigate the gut microbiome and its modification following dietary intervention (specifically, a plant-based vegan diet) in pediatric AIH. Additionally, investigator will explore the potential role of such interventions in managing intestinal dysfunction in patients with advanced liver disease. In Aim 1, investigator will compare the baseline gut microbiome profiles of treatment-naïve pediatric AIH patients with those of healthy, age- and sex-matched controls to provide foundational insights. In Aim 2, investigator will evaluate the proportion of patients achieving biochemical remission after 180 days of a vegan versus standard diet in AIH patients. Investigator will also assess changes in stool metagenomics, metabolomics, cytokine profiles, gut epithelial barrier function, and liver disease severity scores between the two dietary groups. This study aims to demonstrate the potential benefits of a vegan diet in managing autoimmune hepatitis. It seeks to provide evidence supporting dietary modifications as a complementary approach to standard medical treatments for a wide range of autoimmune or autoimmune-like disorders, potentially paving the way for future therapeutic strategies.

A-LiNK: Improving Outcomes in Autoimmune Liver Disease

The Autoimmune Liver disease Network for Kids (A-LiNK) is a multi-institutional group with the mission to deliver the best care to kids with pediatric autoimmune liver disease (AILD). This study will establish a shared clinical registry and a learning health network for the participating sites focusing on collecting and transmitting clinical measurement data, information about processes, and participation in an improvement collaborative. Pediatric Autoimmune Hepatitis (AIH) and Primary Sclerosing Cholangitis (PSC), represent a spectrum of AILD which present unique diagnostic and therapeutic challenges.A lack of accepted guidelines for disease monitoring or symptom management results in wide treatment variation with liver transplants indicated in refractory, progressive disease. The aims of A-LiNK are to: 1.) Create a learning health network focused on patient-centered outcomes research characterized by transparent sharing among centers, common priorities, and feasible plans for implementing new practices; 2) shift from traditional investigator-driven study to a patient and family-centered approach, and 3.) improve clinical outcomes and quality of life for pediatric AILD patients.

Mediterranean Diet Versus Western Diet on Fatigue in Autoimmune Hepatitis Patients

This is a single-center, proof-of-concept pilot study which uses a cross-over design to compare two dietary interventions/treatments: Western Diet (WD) vs Mediterranean (MD) and impact on quality-of-life parameters in AIH. Participants will receive both treatments through two phases and will be divided into two groups.

Role of USP35 in the Detection of Ferroptosis in Juvenile Autoimmune Hepatitis

1. To evaluate the immunohistochemical expression of USP35 in cases of juvenile autoimmune hepatitis and control cases. 2. To correlate this with the level of necro-inflammation and extent of fibrosis using Massion's trichrome stain in cases of juvenile autoimmune hepatitis.

Efficacy and Safety of Therapeutic Plasma Exchange vs Standard Medical Therapy in Severe Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that can lead to cirrhosis and liver failure. AIH can present in all ages, races, and ethnicities, but it mostly affects women. As a heterogeneous disease, AIH presents variably in different patients, making diagnosis and treatment a challenge.It is associated with varied clinical presentations and natural history and somewhat unpredictable treatment responses. Steroids and immunosupressants are main stay of treatment.In acute severe presentations corticosteroid response rates are more variable.According to treatment guidelines if patients fail to respond to corticosteroids, Liver transplant is the only option. But Liver transplant is not feasible in all situations such as limited donor availability.Plasma exchange is associated with a reduction in levels of pro-inflammatory cytokines,DAMPs, and bacterial endotoxins and increase in the levels of anti-inflammatory cytokines.Plasma exchange has reportedly been used for acute presentations of AIH but there are few trials which prove its independent benefit and role in influencing transplant free survival.The study aims at proving the efficacy of Plasma exchange as a bridge between steroid therapy and Liver transplant.It includes the patients with acute severe autoimmune hepatitis .One group of patients are taken up for plasma exchange sessions and compared with the other group started on high dose of steroids and they will be observed for 28 days and are assessed for transplant free survival and efficacy of plasma exchange in reducing transaminitis and Bilirubin levels.

MRI Biomarkers in as Predictor of Clinical Endpoints in Pediatric Autoimmune Liver Disease

Autoimmune liver diseases (AILD), which include Primary Sclerosing Cholangitis (PSC) and Autoimmune Hepatitis (AIH) are a common etiological factor for chronic liver disease among adolescents. This is a longitudinal study to identify surrogate endpoints with an accurate predictive value for the progression of hepatobiliary damage in subjects with pediatric onset AILD. This study will involve collection of MRI-based data at the time of enrollment and at year 1 and 2 of follow up, and collection of clinical data for 10 years following enrollment. There is a strong possibility that MRI quantitative techniques may be more sensitive to disease progression than standard clinical and laboratory tests. To investigate predictivity of MRI based biomarkers, summary measures of MRCP/MREL from baseline, Year 1 and Year 2, e.g. change rate, maximum, and average will be calculated as predictors for Year 10 clinical outcomes. The same predictors will also be used to model native liver survival in a proportional hazard regression. Findings from this study may be used to assess disease progression and to predict complications and survival of liver disease patients.

MRI Based Biomarkers in Pediatric Autoimmune Liver Disease

Autoimmune liver diseases (AILD), which include Primary Sclerosing Cholangitis (PSC) and Autoimmune Hepatitis (AIH) are a common etiological factors for chronic liver disease among adolescents. In all these conditions, autoimmune lymphocyte responses are thought to orchestrate inflammatory injury against hepatocytes (primarily in AIH) or cholangiocytes (in PSC). In this proposal we aim to evaluate the Magnetic Resonance Imaging (MRI) modalities; MR cholangiopancreatography (MRCP) and MR elastography (MREL), as non-invasive biomarkers to assess two primary pathophysiological processes of AILD: bile duct damage and liver fibrosis. In this cross-sectional study MRI based findings of bile duct injury and liver fibrosis will be correlated with both liver histology and circulating biomarkers of these disease processes.

Induction of Remission in Autoimmune Hepatitis With Azathioprine vs. MMF

The goal of this clinical trial is to determine the effectiveness of azathioprine (AZA) versus mycophenolate mofetil (MMF) in inducing remission in treatment-naive patients with autoimmune hepatitis (AIH). The main questions it aims to answer are: Does MMF combined with prednisolone lead to higher remission rates compared to AZA with prednisolone after 24 weeks? Is MMF associated with fewer adverse events than AZA in these patients? Researchers will compare two treatment arms (MMF vs. AZA) to see if MMF leads to improved remission rates and safety outcomes. Primary Outcome Measure: Biochemical remission: The primary outcome is the normalization of liver enzymes (AST, ALT) and IgG levels at 24 weeks. Secondary Outcome Measures: Safety and adverse events: Monitoring and comparing the incidence and severity of side effects between the two groups. Treatment adherence: Evaluating how well patients stick to their assigned treatment regimens. Improvement in quality of life: Assessing changes in the patient's quality of life using validated questionnaires. Reversal of fibrosis: Measured by liver stiffness using Fibroscan, aiming for no progression of fibrosis. Participants will: Receive either MMF or AZA, alongside a tapering dose of prednisolone. Be monitored regularly through clinic visits, laboratory tests, and safety assessments to track remission and any adverse events.

PredIcting SterOid DepeNdEnt LivEr InjuRy with Polyreactive Immunoglobulin G

The investigators identified polyreactive immunoglobulin G (pIgG) in adults (published in Hepatology: https://doi.org/10.1002/hep.32134) and children (in preparation). Quantification of these pIgG using a "home-made" ELISA facilitates the diagnosis of autoimmune hepatitis (AIH) as compared to non-AIH liver diseases and healthy controls. Positivity for pIgG was independent from ANA/SMA positivity and equally diagnostic for AIH even when conventional autoantibodies (ANA/SMA/SLA/LKM) were negative. Additionally, the frequency of pIgG was lower than conventional autoantibodies (ANA, SMA) in vaccinia/drug associated severe liver injury in a retrospective multicenter study after Covid-19 vaccination (https://doi.org/10.1016/j.jhepr.2022.100605). Aims of the study The study aims to evaluate the diagnostic capacity of pIgG to predict AIH in comparison to other liver diseases prospectively. To avoid diagnostic inaccuracy between AIH with long-term need for an immunosuppression and drug induced liver injury with autoimmune features, which can be indistinguishable from AIH at baseline and which has a very low relapse rate after a short steroid course, a follow-up after six months is obligatory for inclusion. Therefore, the investigators will collect one serum sample from every patient (without immunosuppressive treatment) that presents to the respective hospital for evaluation of liver disease by liver biopsy within one year after initiation of the study and that provided written informed consent. Follow-up for evaluation of steroid dependency at six months after diagnosis is obligatory.

Tissue Repository Providing Annotated Biospecimens for Approved Investigator-directed Biomedical Research Initiatives

To collect, preserve, and/or distribute annotated biospecimens and associated medical data to institutionally approved, investigator-directed biomedical research to discover and develop new treatments, diagnostics, and preventative methods for specific and complex conditions.

A Study on Factors of Biochemical Response in Autoimmune Hepatitis

The goal of this observational study is to clarify the clinical characteristics of autoimmune hepatitis (AIH) in China. The main questions it aims to answer are: Human leukocyte antigen (HLA) gene susceptibility in Chinese AIH patients prognostic factors associated with AIH Participants will provide liver tests results and details of treatment during follow-up.

Vaccine Response to COVID-19 Vaccines in Patients Using Immunosuppressive Medication

The purpose of this study is to assess the strength and duration of the immunological response to COVID-19 vaccines in patients treated with immunosuppressive and/or immunomodulating medication for immune-mediated inflammatory diseases in rheumatology and gastroenterology and after a liver transplantation.

Development of a Autoimmune Hepatitis Patient's Database Linked to a Biological Sample Storage

Autoimmune Hepatitis (AIH) is chronic fibroinflammatory disease of the liver characterized by chronic, relapsing liver inflammation, and a risk for progression to liver failure and need for liver transplantation. No AIH-specific registry does exist in Italy, so that the actual epidemiology of the disease in the country is unknown. This is an observational, retrospective and prospective, multicenter study evaluating incidence, prevalence and disease course of AIH in subjects \> 1 years old in Italy.

Autoimmune Hepatitis Cohort in China

The goal of this observational study is to describe the clinical features and long-term prognosis in patients diagnosed with autoimmune hepatitis (AIH) in China and assess the effectiveness and safety of AIH treatment options in a real-world setting.

Canadian Network for Autoimmune Liver Disease

CaNAL is a longitudinal observational cohort study of patients diagnosed with Primary Biliary Cholangitis (PBC), Autoimmune Hepatitis (AIH), or overlap syndrome. This study creates a nationwide registry and network focusing on high quality long-term follow-up of individual patient data from major Canadian centers. Primary Biliary Cholangitis (PBC) and Autoimmune Hepatitis (AIH) are rare and slowly progressive liver diseases associated with development of cirrhosis, liver cancer (HCC) and liver failure requiring liver transplantation or leading to premature death. The rarity and slowly progressive nature of these autoimmune liver diseases make them difficult to study and only a large scale approach combining patient data from multiple centers across Canada will allow new insights. The primary aim of the Canadian Network for Autoimmune Liver Disease is to build a Canadian registry of patients with PBC, AIH, and overlap syndrome. We capture patient characteristics, laboratory assessments and natural history, patient-reported outcomes including quality of life measures and environmental exposures, response to treatment, and pre- and post-transplant outcomes. We will then identify risk factors associated with critical outcomes for the patient, including response to treatment, progression to transplant, risk of liver cancer, and recurrent disease after transplant. We can identify biomarkers (biochemical indicators of progression of disease) to help diagnose autoimmune liver disease at its earliest stages, ensuring timely treatment and preventing disease progression. CaNAL will provide a better understanding of autoimmune liver diseases, biomarkers predictive of disease progression or non-response to therapy as well as better knowledge of the etiology and pathogenesis. CaNAL will also help to serve as a platform for conducting clinical trials or targeted lab-studies to answer important questions that are unlikely to be evaluated by the pharmaceutical industry.