Clinical Trials

The objective of this study is to compare the long-term efficacy of treatment with combination therapy with peginterferon plus tenofovir versus tenofovir monotherapy in the treatment of chronic hepatitis B. This is a randomized (1:1) parallel group design trial comparing (i) Tenofovir DF 300 mg daily for 192 weeks (4 years) and (ii) peginterferon alfa-2a 180 µg weekly for 24 weeks plus Tenofovir DF 300 mg daily for 192 weeks (4 years). Enrolled participants will be stratified by HBeAg status (positive/negative), genotype (A vs. all others) and cirrhosis (present vs. absent). After 192 weeks of treatment, participants meeting criteria for treatment discontinuation will stop treatment and be followed for 48 weeks (total duration of treatment and follow up is 240 weeks). A liver biopsy will be obtained at the end-of-treatment (week 192) to assess improvement in histology. Emtricitabine/tenofovir coformulated as Truvada, approved for treatment of HIV but not for treatment of HBV infection, will be offered to patients with primary nonresponse, partial virological response or confirmed virologic breakthrough.

Hepatorenal syndrome is a rare syndrome of marked renal dysfunction in patients with cirrhosis, decompensated liver disease, and portal hypertension. Hepatorenal syndrome type 1 is characterized by a rapid progressive renal impairment and has a very poor prognosis with > 80% mortality within 3 months. At present, there are no approved drug therapies for HRS type 1 in the US, Australia, or Canada. The only curative treatment for HRS type 1 and the underlying end-stage cirrhosis is liver transplantation. However, many patients will not survive long enough to receive a liver transplant and therapy, which may provide a bridge to transplantation, is badly needed. Increased understanding of the pathophysiology of HRS type 1 has demonstrated that vasoconstrictive drug therapy may reverse HRS type 1. Substantial data available from many published clinical investigations in the literature provide compelling evidence suggesting that administration of terlipressin improves renal function in patients with HRS.

The incidence of Non alcoholic fatty liver disease (NAFLD) continues to increase, and prevalence estimates for NAFLD range from 17-33%, making it is the most common cause of chronic liver disease in North America. It is associated with increased cardiovascular morbidity as well as progression to cirrhosis is a subset of patients. There is currently no approved treatment for NAFLD. A key barrier to the development of effective therapies is a lack of consensus on the criteria for diagnosis and endpoints for studies evaluating diagnostic markers, prognosis and therapeutic modalities. NAFLD encompasses an entire pathological spectrum of disease, from relatively benign accumulation of lipid (steatosis) to progressive non alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and necrosis. It has been estimated that 20-30% of patients with NAFLD will exhibit biochemical and histological changes characteristic of NASH, and 15-20% of those patients will progress to have cirrhosis. NASH remains an important phenotypic state, because this sub-group of patients is deemed at high-risk for developing progressive disease resulting in cirrhosis, liver failure requiring transplantation, or death. Although NAFLD has not to date been included as a component of the metabolic syndrome, there is increasing evidence that NAFLD frequently accompanies the development of insulin resistance and therefore may be an indicator or predictor of future cardiometabolic risk. Moreover, recent findings in skeletal muscle of experimental insulin resistance (lipid infusion) as well as naturally occurring obese and type 2 diabetic, insulin resistant patients show that skeletal muscle inflammation leads to a pattern of extracellular matrix, structural, and remodeling abnormalities that closely resemble the TGFb, connective tissue growth factor (CTGF) mediated fibrotic response that differentiates simple steatotic liver from NASH. This suggests there may be a common underlying mechanism. Given the ready availability of skeletal muscle tissue using percutaneous needle muscle biopsies, compared to the more invasive liver biopsy, it may be possible to use characteristics of skeletal muscle to distinguish the severity of liver fibrosis. Given the preponderance of patients being identified with NAFLD, the recognition of less and non invasive tests that help to discriminate the different phenotypic types of NAFLD would be highly practical and useful. This would help identify patients at risk of progression to cirrhosis, and thus make them the target of any available therapeutic interventions. The investigators hypothesize that 1. Insulin resistance measured through glucose tolerance test directly correlates with the extent of liver and muscle fibrosis, and 2. Inflammation and fibrosis in the skeletal muscles correlates with the histopathological changes seen in patients with NAFLD, and potentially skeletal muscle inflammation may be used as a diagnostic predictor to differentiate patients with NASH from patients with simple steatosis. The overall goal of this project is to determine the extent to which inflammation and fibrosis in skeletal muscle mirrors and is predictive of the level of liver inflammation and can distinguish NASH from simple steatosis. Specifically, the investigators propose the following Aims: 1. To use estimates of insulin sensitivity from modeling of oral glucose tolerance tests to test the hypothesis that the extent of liver and muscle fibrosis is directly related to insulin resistance. 2. To use liver and muscle biopsies to characterize the changes in abundance of mRNAs and proteins that characterize inflammation, extracellular matrix remodeling, and fibrosis. The investigators will use quantitative rt-PCR and immunoblot analysis to compare mRNA expression and protein abundance of collagens I and III, fibronectin, and connective tissue growth factor (CTGF) to test the hypothesis that there is a direct relationship between the levels of these proteins in muscle and liver and the degree of fibrosis. 3. To establish a biospecimen repository of serum, mRNA from circulating white blood cells, liver and muscle tissue, and DNA to serve as the substrate for future studies of the pathogenesis of NASH.

Ifetroban sodium (ifetroban) is an investigational drug that has been studied previously in healthy volunteers and patients with cardiovascular diseases. Cumberland Pharmaceuticals Inc. (CPI) is developing ifetroban for treatment of type 1 and type 2 hepatorenal syndrome (HRS) and proposed to conduct a study in hospitalized adult patients with HRS to assess the safety and pharmacokinetics of escalating doses of ifetroban. The primary objective of this study is as follows: - To determine the pharmacokinetic profile of multiple daily intravenous doses of ifetroban and its major metabolite ifetroban acylglucuronide. - To determine the tolerability and safety of ifetroban injection in patients with HRS. The secondary objective of this study is as follows: • To determine if ifetroban changes renal function, showing evidence of HRS reversal.

Patients with PSC often have ongoing inflammation and fibrosis (scars) along the length of their bile ducts, and eventually this involves the liver itself which can lead to cirrhosis (severe scarring), severe infections (cholangitis), bile duct cancer and death. Although many patients are treated with UDCA, and experience improvement in their liver tests and relief of symptoms, no medical treatment to date has been found to produce a long-term improvement of inflammation and scarring, or to improved survival. For this reason, there is a great need to identify new medications which are effective for the treatment of PSC. Recent work in animals by the research group at Yale University School of Medicine has shown that the combination of UDCA and ATRA produced a significant improvement in liver scarring and inflammation in animals with bile duct disease similar to that seen in PSC. This improvement included a lowering in the levels of bile acids, which are harmful to the liver, and a lowering of inflammation in the liver tissue of these animals. The benefits seen in this study were greater in animals receiving the combination of UDCA and ATRA compared to animals who received either medicine alone. The medication ATRA is related to vitamin A, and has been used for many years as a topical medication in the treatment of skin conditions such as acne and psoriasis. It has also been used for nearly 20 years as an oral medicine in the treatment of a form of blood cancer (acute promyelocytic leukemia), where it is given for 90 days at a time. ATRA has been shown to produce a remission from the leukemia and is currently a standard treatment for patients with that specific condition. ATRA is not used routinely in the care of patients with liver or bile duct disease. Based on the benefits observed by treatment with ATRA and UDCA in our animal studies, the investigators plan to study this combination in patients with PSC and believe that this may be an effective regimen for patients with this condition. The investigators will check blood tests of the liver and bile ducts before, during, and after the treatment in order to look for changes to liver tests which would be due to the medication combination. Therefore, the goal of this study is to study the changes to liver tests in patients with PSC who take a combination of UDCA and ATRA for 90 days, comparing levels at the beginning of the study to those at the end of the study.