5 Study Matches
Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients
Lipodystrophies are rare disorders characterized by selective loss of adipose tissue and predisposition to insulin resistance and its metabolic complications. Hepatic steatosis is a common complication in patients with partial and generalized lipodystrophies.Despite aggressive management of diabetes and hyperlipidemia, hepatic steatosis and its complications present a therapeutic challenge in many patients. Due to this large disease burden, it is important to assess the efficacy and safety of novel therapies for hepatic steatosis in patients with lipodystrophies.There are, however, no systematic studies evaluating various therapeutic interventions for reducing hepatic steatosis in patients with lipodystrophies. A variety of drugs have been investigated in nonlipodystrophic patients with non-alcoholic hepatic steatosis and steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). Recent data support the activation of the farnesoid X receptor (FXR, NR1H4), a nuclear hormone receptor regulated by bile acids, for treatment of NASH and NAFLD. FXR activates transcription of several genes particularly the atypical nuclear receptor small heterodimer partner (SHP, NR0B2) and thus can influence triglyceride metabolism within hepatocytes.Both cholic acid (CA) and chenodeoxycholic acid (CDCA) are ligands for FXR, however, UDCA which is the 7 hydroxy β-epimer of CDCA, does not activate FXR. Obeticholic acid (OCA) is a first-in-class selective FXR agonist which has approximately 100 fold greater FXR-agonistic activity in the nanomolar range, as compared to CDCA .It therefore appears that FXR modulation offers interesting therapeutic possibilities in treating hepatic steatosis. This study is primarily designed to study efficacy of OCA, a strong FXR ligand, in reducing hepatic triglyceride levels in patients with hepatic steatosis and Familial Partial Lipodystrophy (FPLD). If proven to be effective, it may reduce morbidity and mortality as a result of sequelae of hepatic steatosis in patients with lipodystrophies.
18 Years to 70 Years old
Inclusion Criteria:1. Patients with familial partial lipodystrophy of the Dunnigan variety with heterozygous disease-causing missense mutation in lamin A/C (LMNA) gene. 2. Hepatic steatosis (>5.6% hepatic triglyceride content) as demonstrated by 1H magnetic resonance spectroscopy. 3. Age 18-70 years. 4. Alcohol intake of less than 20 g per day in females and 30 g per day in males. 5. Participants and their partners with whom they are having sex, must use medically-acceptable birth control (contraceptives) during the study. Medically-acceptable methods of contraception include: (1) surgical sterilization, such as hysterectomy, tubal ligation or vasectomy. (2) approved hormonal contraceptives, such as birth control pills, patch or ring; Depo-Provera, Implanon. (3) barrier methods, such as condom, cervical cap or diaphragm used with a spermicide. (4) an intrauterine device (IUD).
Exclusion Criteria:1. Laboratory or other histologic findings highly suggestive of liver disease due to causes other than non-alcoholic steatohepatitis, such as chronic viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, biliary obstruction or genetic liver diseases such as Wilson's disease, hemochromatosis or alpha-1-antitrypsin deficiency. 2. Treatment with drugs associated with steatohepatitis, e.g., corticosteroids, high dose estrogens, methotrexate, amiodarone, tamoxifen, valproic acid, sulfasalazine, or oxacillin for more than 2 weeks in the 6 months prior to the study. 3. Decompensated liver disease as evidenced by clinical features of hepatic failure (variceal bleeding, ascites, hepatic encephalopathy etc.) and laboratory investigations (prolonged prothrombin time with INR > 1.3, hypoalbuminemia with serum albumin less than 3.0 g/dL, direct bilirubin > 1.3 mg/dL, or presence of esophageal varices etc.) 4. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging study suggestive of liver cancer. 5. Use of drugs which can potentially decrease hepatic steatosis during previous 3 months; ursodeoxycholic acid, thiazolidinediones, high-dose vitamin E, betaine, acetylcysteine and choline. 6. Significant systemic or major illnesses other than liver disease, such as congestive heart failure, cerebrovascular disease, respiratory failure, renal failure (serum creatinine >2 mg/dL), acute pancreatitis, organ transplantation, serious psychiatric disease, and malignancy, that could interfere with the trial and adequate follow up. 7. Acute medical illnesses precluding participation in the studies. 8. Known HIV-infected patient. 9. Current substance abuse. 10. Pregnant or lactating woman. 11. Hematocrit of less than 30%. 12. History of weight loss during past 3 months. 13. Patients on bile acid binding resins, cholestyramine, colestipol or colesevelam. 14. Hypersensitivity or intolerance to OCA or any components of its formulation. 15. Failure to give informed consent 16 .Previous clinical diagnosis of diabetes mellitus or fasting blood glucose ≥ 126 mg/dL or hemoglobin A1c ≥ 6.5%.
Drug: Obeticholic Acid, Drug: Placebo
Familial Partial Lipodystrophy
Emricasan, an Oral Caspase Inhibitor, in Subjects With Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension (ENCORE-PH)
This is a multicenter, randomized, double-blind, placebo-controlled trial involving subjects with NASH cirrhosis and severe portal hypertension (defined as HVPG ≥12 mmHg as determined by the central reader assigned to this study). Upon successful screening, subjects will be randomized to receive either emricasan 50 mg BID, 25 mg BID, or 5 mg BID or matching placebo BID.
18 Years and over
• Male or female subjects 18 years or older, able to provide written informed consent and able to understand and willing to comply with the requirements of the study.
• Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.)
• Compensated cirrhosis OR Decompensated cirrhosis with no more than 1 prior significant decompensating event
• Severe portal hypertension defined as HVPG ≥12 mmHg
• Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a stable dose for at least 3 months prior to Day 1
• Willingness to utilize effective contraception (for both males and females of childbearing potential) from Screening to 4 weeks after the last dose of study drug
• Evidence of severe decompensation
• Severe hepatic impairment defined as a Child-Pugh score ≥10
• ALT > 3 times upper limit of normal (ULN) or AST >5 times ULN during screening
• Estimated creatinine clearance <30 mL/min
• Prior transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure
• Known portal vein thrombosis
• Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy
• Current use of medications that are considered inhibitors of OATP1B1 and OATP1B3 transporters
• Alpha-fetoprotein >50 ng/mL
• History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of >500 msec
• History of or active malignancies, other than those successfully treated with curative intent and believed to be cured
• Prior liver transplant
• Change in diabetes medications or vitamin E within 3 months of screening
• Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening
• Significant systemic or major illness other than liver disease
• HIV infection
• Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening
• If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding
• Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1
Drug: Emricasan, Drug: Placebo
Non-alcoholic Steatohepatitis, Cirrhosis, Portal Hypertension
cirrhosis, Portal Hypertension, Non-alcoholic Steatohepatitis, Liver cirrhosis
Alcoholic Hepatitis Network Observational Study
The purpose of this research study is to create a clinical database and bio-repository. To do this, we will obtain blood, urine, and stool samples (e.g., biological samples) and personal health information from you to use in future research studies related to alcoholic hepatitis or other diseases. Part of your blood sample will be used to extract your DNA. DNA is the genetic material that gives us unique characteristics. We are doing this research study because we are trying to find out more about how and why illnesses related to alcoholic hepatitis or other diseases occur in people. To do this, we will study the biological samples and personal health information from healthy and sick people. A "biological sample" is usually blood, but can be any body fluid. "Personal Health Information" includes such items as your name, age, gender, race, and/or your medical information. It can also include data from measurements and tests that you had while participating in another research study or that were done during the course of your regular medical care or doctor visits.
21 Years and over
CASES: Heavy drinkers with alcoholic hepatitis Inclusion criteria 1. A clinical diagnosis of alcoholic hepatitis 2. Serum total bilirubin >3 mg/dL 3. Subject or guardian ability to understand and willingness to provide written consent 4. Age greater or equal to 21 years 5. Re-enrolment of an alcoholic hepatitis donor is permissible up to 4 times if the donor presents with a new episode of alcoholic hepatitis 24 weeks or longer after the most recent enrolment in the study Exclusion criteria 1. Liver disease significantly caused by hemochromatosis, autoimmune liver disease, Wilson disease, NAFLD, and acute viral hepatitis 2. (NOTE: The presence of chronic hepatitis C, hepatitis B, or HIV is not exclusion to participation.)Pregnant or breast feeding Based on the judgment of the investigator, subject is not capable of understanding or complying with the study requirements. CONTROLS: Heavy drinkers without significant liver disease Inclusion criteria 1. History of chronic alcohol consumption sufficient to cause liver damage. Generally, this is considered to be >40 g/day or >280g/week on average for women and >60 g/day or >420 g/week on average for men, for many years (usually decades). Judgement about chronic alcohol consumption will be made by the site investigator. 2. Subject or guardian ability to understand and willingness to provide written consent 3. Age greater or equal to 21 years Exclusion criteria 1. Past evidence of alcoholic liver disease, defined as a bilirubin > 2.0 mg/dL, an AST > 1.5 ULN, and any hospital admission for liver disease, or the presence of esophageal varices or ascites (at any time in the past). 2. Liver disease significantly caused by hemochromatosis, autoimmune liver disease, Wilson disease, NAFLD, and acute viral hepatitis (NOTE: The presence of chronic hepatitis C, hepatitis B, or HIV is not exclusion to participation.) 3. Alcohol intake at less than 40 g/day or 280g/week on average for women and 60 g/day or 420 g/week on average for men for longer than the past 28 days 4. If liver stiffness has been assessed within the prior 90 days, then stiffness suggesting fibrosis of F1 or greater is excluded. For Fibroscan, this is a fibrosis score >7.0 kPa. 5. Pregnant or breast feeding 6. Any of the following laboratory abnormalities within 90 days prior to signing the consent. 1. Total bilirubin: >ULN* 2. INR: > 1.4 5 *Individuals with a diagnosis of Gilbert's can have total bilirubin up to 3.0 mg/dL and still be eligible for participation. Healthy Controls Inclusion criteria 1. AUDIT-C scores of <4 for men and <3 for women (signifying no alcohol misuse) 2. Abstinent (consumption of less than one standard drink/week) during the 6 months prior to enrolment 3. Ability to understand and willingness to provide written consent. Exclusion criteria 1. Clinical history or laboratory evidence of liver disease including alcoholic liver disease, NAFLD, hemochromatosis, alcoholic hepatitis, autoimmune liver disease, Wilson disease, hepatitis C, or hepatitis B. 2. Presence of diabetes (requiring treatment with oral agents or insulin). 3. Significant heart disease (prior history of heart disease, other than hypertension) 4. Chronic lung disease (requiring chronic treatment) 5. Immune related conditions (such as Crohn's disease, rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, severe psoriasis, etc.) 6. Known infection with HIV 7. Presumed infection, or use of antibiotics or other medications (e.g., corticosteroids) that would affect immune function, within the past 14 days 8. BMI>35 9. Current or known history of cancer (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment 10. Pregnant or breast feeding 11. Any of the following laboratory abnormalities within 90 days prior to signing the consent. 1. Hemoglobin: <10 g/dL 2. Conjugated bilirubin: > ULN 3. INR: > 1.4 4. AST: >40 IU/mL 5. ALT: >40 IU/mL 12. Based on the judgment of the investigator, subject is not capable of complying with the study requirements
Novel Therapies in Moderately Severe Acute Alcoholic Hepatitis (NTAH-Mod)
This study is being done to find out whether a diet supplemented with a probiotic nutrient can improve alcoholic hepatitis and gut complications compared to routine standard care.
21 Years to 70 Years old
Inclusion Criteria:1. Ability to provide informed consent by subject or appropriate family member 2. Age between 21-70 years 3. Recent alcohol consumption > 50 g/d for > 6 months, continuing within two months before enrollment 4. At least 2 of the following symptoms or signs of acute alcoholic hepatitis: Anorexia, nausea, RUQ pain, jaundice, leukocytosis, hepatomegaly AND 5. Elevation of AST > 80 U/L, but < 500 U/L at the time of admission or within 3 days of baseline visit; AST > ALT and ALT < 200 U/L; total bilirubin > 3 mg/dL AND 6. Liver biopsy showing alcoholic hepatitis (steatohepatitis) OR ultrasound of liver showing increased echogenicity OR CT scan showing decreased attenuation of liver compared to spleen OR MRI showing fatty liver (decreased signaling intensity on T1 weighted images). If the liver biopsy (done within 60 days of inclusion) confirms diagnosis of AAH then inclusion e will be waived. 7. Model for End-Stage Liver Disease (MELD) <20 8. Willingness to utilize two reliable forms of contraception (both males and females of childbearing potential) from screening through the first six weeks of study.
Exclusion Criteria:1. Hypotension with BP < 80/50 after volume repletion 2. Pregnancy; incarceration; inability to provide consent or lack of appropriate family member 3. Signs of systemic infection: Fever > 38o C and positive blood or ascites cultures on appropriate antibiotic therapy for > 3 days within 3 days of inclusion 4. Acute gastrointestinal bleeding requiring > 2 units blood transfusion within the previous 4 days 5. Undue risk from immunosuppression: Positive HBsAg; a positive skin PPD skin test or history of treatment for tuberculosis; history of any malignancy including hepatocellular carcinoma; known HIV infection 6. Treatment with corticosteroids or other immunosuppressive medications including specific anti-TNF therapy (not including pentoxifylline), calcineurin inhibitors for > 3 days within the previous 3 months. 7. Evidence of acute pancreatitis: CT evidence and/or amylase or lipase > 5 X upper limit of normal 8. Serious cardiac, respiratory or neurologic disease or evidence of autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilsons disease, hemochromatosis, secondary iron overload due to chronic hemolysis, alpha-1-antitrypsin deficiency 9. Acute or chronic kidney injury with serum creatinine > 3.0 mg/dl
Dietary Supplement: Lactobacillus Rhamnosus GG, Drug: Placebo for Probiotic
Acute Alcoholic Hepatitis
Alcoholic Hepatitis, MELD < 20, Probiotic, Nutritional Supplement, Lactobacillus Rhamnosus GG
Efficacy Study of Anakinra, Pentoxifylline, and Zinc Compared to Methylprednisolone in Severe Acute Alcoholic Hepatitis
This study will compare two different treatments of acute alcoholic hepatitis. The current standard of care is treatment with corticosteroids (methylprednisolone). This will be compared to treatment with anakinra, pentoxifylline, plus zinc sulfate. The participants will be treated and followed for 6 months and the two treatment groups will be compared for differences in death rates and laboratory tests that measure liver and gut function.
21 Years to 70 Years old
Phase 2/Phase 3
Inclusion Criteria:1. Ability to provide informed consent by subject or appropriate family member 2. Age between 21-70 years 3. Recent alcohol consumption > 50 g/d for > 6 months, continuing within two months before enrollment 4. d. At least 2 of the following symptoms of acute alcoholic hepatitis: Anorexia, nausea, RUQ pain 5. Liver biopsy showing alcoholic hepatitis (steatohepatitis) OR ultrasound of liver showing increased echogenicity OR CT scan showing decreased attenuation of liver compared to spleen OR MRI showing fatty liver (decreased signaling intensity on T1 weighted images) If liver biopsy confirms diagnosis of alcoholic hepatitis then requirement for AST elevation > 50 is waived. The liver biopsy must be done within 60 days of study enrollment. 6. AST levels:
• AST> Or equal to 50 IU/mL but less than 500 IU/mL
• AST> ALT, ratio AST/ALT> 1.5; ALT < 200 IU/mL
• or biopsy proven alcoholic hepatitis. 7. Model for End-Stage Liver Disease (MELD) ≥ 20 and Maddrey DF ≥ 32. 8. Willingness to utilize two reliable forms of contraception (both males and females of childbearing potential) from screening through the first 6 weeks of the study.
Exclusion Criteria:1. Hypotension with BP < 80/50 after volume repletion 2. Pregnancy; incarceration; inability to provide consent or lack of appropriate family member 3. Signs of uncontrolled systemic infection: Fever > 38°C and positive blood or ascites cultures and on appropriate antibiotic therapy for ≥ 3 days within 3 days of inclusion 4. Acute gastrointestinal bleeding requiring >2 units blood transfusion within the previous 4 days 5. Undue risk from immunosuppression: Positive HBsAg; a positive skin PPD skin test, a positive quantiferon, or history of treatment for tuberculosis; history of any malignancy except skin cancer but including hepatocellular carcinoma within the last five years; HIV infection 6. Recent previous treatment with corticosteroids or other immunosuppressive medications including specific anti-TNF therapy (not including pentoxifylline), calcineurin inhibitors within the previous 3 months. Treatment with corticosteroids for ≤3 days prior to baseline is acceptable. 7. Evidence of acute pancreatitis: CT evidence or amylase or lipase > 5 X upper limit of normal (ULN). 8. Serious cardiac, respiratory or neurologic disease or evidence of other liver diseases such as autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, hemochromatosis, secondary iron overload due to chronic hemolysis, alpha-1-antitrypsin deficiency 9. Acute or chronic kidney injury with serum creatinine > 3.0 mg/dl.
Drug: Anakinra, Drug: Pentoxifylline, Drug: Zinc Sulfate, Drug: Methylprednisolone
Acute Alcoholic Hepatitis
Hepatitis, alcoholic, pentoxifylline, zinc, anakinra, glucocorticoids, MELD score, Intestinal mucosa