Carbamazepine in Severe Liver Disease Due to Alpha-1 Antitrypsin Deficiency

Study Overview
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Brief Summary
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The primary objective is to determine if the medication Carbamazepine, can be used as a therapy for patients with severe liver disease due to Alpha-1-Antitrypsin Deficiency .

Detailed Description
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The primary objective is to determine if Carbamazepine therapy in patients with severe liver disease due to Alpha-1-Antitrypsin Deficiency leads to a significant reduction in the hepatic accumulation of ATZ. The other objectives are: To determine whether Carbamazepine treatment reduces hepatic fibrosis in alpha-1-antitrypsin deficient patients with severe liver disease. To determine whether Carbamazepine treatment reduces portal pressure in alpha-1-antitrypsin deficient patients with severe liver disease. To determine whether Carbamazepine treatment is safe and tolerated by patients with severe liver disease caused by alpha-1-deficiency. To determine whether Carbamazepine treatment leads to stabilization in disease severity as measured by the MELD scores.

Official Title
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A Preliminary Study of the Efficacy and Safety of Carbamazepine in Severe Liver Disease Due to Alpha-1 Antitrypsin Deficiency

Conditions
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Alpha-1-antitrypsin Deficiency, Liver Cirrhosis

Intervention / Treatment
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* Drug: Drug-Carbamazepine (Tegretol XR)
* Drug: Carbamazepine (Tegretol XR) Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 14 years to less than or equal to 80 years of age. Alpha-1-Antitrypsin deficiency confirmed by ZZ or SZ phenotype & serum level < 83mg/dl. HVPG greater than or equal to 10 mmHg unless collateral vessels are visualized via transvenous biopsy. Exclusion Criteria: Child Pugh Score greater than or equal to 12. Serum total bilirubin > 5 mg/dl. INR > 2.2.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Drug-Carbamazepine (Tegretol XR)<br>One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. | Drug: Drug-Carbamazepine (Tegretol XR)<br>* To reduce the likelihood of hypersensitivity reactions the subjects will be started on 400 mg/day in 2 doses and the dose will be increased weekly by 200mg/day until reaching a stable therapeutic concentration with a dose not exceeding 1200mg/day(or 1000mg/day in subjects less than 15 years of age). The CBZ tablets will be encapsulated..<br>* Other names: NDC 0078-0510-05.;|
| Placebo Comparator: Drug-Carbamazepine (Tegretol XR) Placebo<br>One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. | Drug: Carbamazepine (Tegretol XR) Placebo<br>* Carbamazepine (Tegretol XR)Placebo-the subjects will be started on 400mg/day in 2 doses and the dose will be increased weekly by 200 mg/day until reaching a dose not exceeding 1200 mg/day (or 1000 mg/day in subjects less than 15 years of age). The placebo group will receive encapsulated tables without Carbamazepine.<br>* Other names: Carbamazepine (Tegretol-XR) placebo.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Outcome Will be to Determine the Effect of Carbamazepine on Hepatic ATZ Load. | The effect of Carbamazepine on hepatic ATZ load will be measured by the number of hepatocytes with PAS+/diastase-resistant globules and/or steady state levels of ATZ by immunoblot analysis. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For the Secondary Outcomes we Will Determine the Effect of Carbamazepine Treatment on Hepatic Fibrosis. | For the secondary outcomes we will determine the effect of Carbamazepine treatment on hepatic fibrosis on the basis of sirius red staining and hydroxyproline concentration and whether Carbamazepine treatment changes portal pressure as determined by Hepatic Venous Pressure Gradient. | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carbamazepine (Tegretol) use, severe liver disease, alpha-1-antitrypsin deficiency