Study With Heptral in Subjects With Liver Disease Due to Alcohol Consumption

Study Overview
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Brief Summary
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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.

Official Title
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Open-Label Study With Ademetionine (Heptral®) in Subjects With Intrahepatic Cholestasis (IHC) Associated With Alcoholic Liver Disease (ALD)

Conditions
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Intrahepatic Cholestasis Associated With Alcoholic Liver Disease

Intervention / Treatment
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* Drug: Ademetionine IV+tablet
* Drug: Ademetionine tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ademetionine IV<br> | Drug: Ademetionine IV+tablet<br>* 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<br>|
| Experimental: Ademetionine oral<br> | Drug: Ademetionine tablet<br>* oral ademetionine (500 mg/tablet, 2 in the morning and 1 before dinner) for 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations (Units per liter) of Alkaline phosphatase (ALP) or gamma-glutamyltransferase (γGT) | Improvement of ALP or γGT after 8 weeks of treatment with ademetionine compared to baseline | from baseline up to the end of treatment visit (56-60 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of ALP, γGT, Alanine Transaminase (ALT) and Aspartate aminotransferase (AST) (Units per liter) and of serum total and conjugated bilirubin (µmol per liter) | Improvement of ALP, γGT and serum total and conjugated bilirubin, ALT and AST compared to baseline | At baseline and after 2 weeks intravenously (IV) treatment or after 4 weeks oral treatment and after 2 months treatment | 
| 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). | Record of intensity of jaundice, pruritus, fatigue and depressed mood compared to baseline | At baseline and after 2 weeks IV treatment or after 4 weeks oral treatment and after 2 months treatment | 
| Evaluation of the responder rate by comparing concentrations at certain time points (units per liter) to baseline concentrations | >20% reduction of ALP or γGT or normalization of ALP or γGT compared to baseline | At baseline and after 2 weeks IV treatment or after 4 weeks oral treatment and after 2 months treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intrahepatic Cholestasis