Intrahepatic Cholestasis Associated With Alcoholic Liver Disease
Conditions
Keywords
Intrahepatic Cholestasis
Brief summary
A research study of an approved drug called Heptral®, ademetionine, to treat adults with intrahepatic cholestasis (a condition where bile cannot flow from the liver to the duodenum) in pre-cirrhotic and cirrhotic states. Experience from clinical studies in subjects with liver disease has shown that ademetionine is effective.
Interventions
DRUGAdemetionine IV+tablet
IV ademetionine (500 mg/vial) for 2 weeks followed by oral ademetionine (500 mg/tablet, 2 in the morning and 1 before dinner) for 6 weeks
DRUGAdemetionine tablet
oral ademetionine (500 mg/tablet, 2 in the morning and 1 before dinner) for 8 weeks
Sponsors
Ascent
Datamap
ClinIntel
Catalent
Abbott
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent given by the subject * Age ≥ 18 years to 75 years * Chronic liver disease due to alcoholic liver disease * Compensated alcoholic liver disease, defined as having a Maddrey Score \< 32 and not being treated with pentoxifylline or prednisolone within 6 months prior to the study * History of chronic alcohol use, defined as, history of consumption of \> 40 g of alcohol per day for females and \> 80 g alcohol per day for males for more than 5 years prior to enrolment * Subjects who abstain from alcohol for more than 2 weeks and will not consume alcohol during the study * Subjects with Intrahepatic Cholestasis (IHC): * ALP: more than 1.5 x upper normal limit and * γGT: more than 3 x upper normal limit * Subjects with additional serum conjugated bilirubin (SCB) \> Upper Limit of Normal (ULN) will be selected for initial IV treatment
Exclusion criteria
* Subjects with a known hypersensitivity to the active substance of ademetionine or to any of the inactive ingredients * Subjects with extrahepatic cause of cholestasis (proven by ultrasound or described in medical history) * Diagnosis of human immunodeficiency virus (HIV) in medical history * Subjects with chronic liver disease Child-Pugh class C * Subjects in the decompensation stage of ALD (such as Maddrey Score \>32) * Subjects with primary sclerosing cholangitis (PSC) * Subjects with primary biliary cirrhosis (PBC) * Any form of malignancy within the past 5 years and/or basal cell carcinoma and squamous cell carcinoma of the skin within the past two years * Subjects with drug-induced liver disease * History of active substance abuse (oral, inhaled or injected) within one year prior to the study * Subjects with renal impairment (creatinine level of \>2.0 mg/dL or \> 150 µmol/l) * Subjects with known genetic defects affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia (e.g., cystathionine beta-synthase deficiency, Vitamin B12 metabolism defect) or known folate, Vitamin B6 or B12 deficiency * Subjects on total parenteral nutrition in the year prior to screening * Subjects after or planned for bariatric surgery (jejunoileal bypass or gastric weight loss surgery) * Subjects after liver transplantation and subjects on the waiting list for liver transplantation * Subjects with any of the following disease in medical history: * Viral hepatitis (serum positive HBcAb or Hepatitis C Virus (HCV) RNA) * Evidence of autoimmune liver disease * Wilson´s disease * Hemochromatosis * Alpha-1-antitrypsin deficiency * Subjects with history of biliary diversion * History of major depression or bipolar disease * Women of childbearing potential: positive urine pregnancy test during screening or unwillingness to use an effective form of birth control during the study. * Breastfeeding women * Any condition that, in the opinion of the investigator, does not justify the patient's inclusion into the study * Investigational drug intake within one month prior to the study * Active, serious medical disease other than ALD with likely life-expectancy less than five years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentrations (Units per liter) of Alkaline phosphatase (ALP) or gamma-glutamyltransferase (γGT) | from baseline up to the end of treatment visit (56-60 days) | Improvement of ALP or γGT after 8 weeks of treatment with ademetionine compared to baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concentrations of ALP, γGT, Alanine Transaminase (ALT) and Aspartate aminotransferase (AST) (Units per liter) and of serum total and conjugated bilirubin (µmol per liter) | At baseline and after 2 weeks intravenously (IV) treatment or after 4 weeks oral treatment and after 2 months treatment | Improvement of ALP, γGT and serum total and conjugated bilirubin, ALT and AST compared to baseline |
| The intensity of clinical symptoms (jaundice, pruritus, fatigue and depressed mood) will be recorded for each symptom separately using six categories: No symptoms (0), minimum (1) to maximum (5). | At baseline and after 2 weeks IV treatment or after 4 weeks oral treatment and after 2 months treatment | Record of intensity of jaundice, pruritus, fatigue and depressed mood compared to baseline |
| Evaluation of the responder rate by comparing concentrations at certain time points (units per liter) to baseline concentrations | At baseline and after 2 weeks IV treatment or after 4 weeks oral treatment and after 2 months treatment | \>20% reduction of ALP or γGT or normalization of ALP or γGT compared to baseline |
Countries
Russia
Outcome results
None listed