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

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ClinicalTrials.gov Identifier: NCT01379469
Recruitment Status : Recruiting
First Posted : June 23, 2011
Last Update Posted : May 11, 2017
Sponsor:
Collaborators:
Novartis
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Pittsburgh
Information provided by (Responsible Party):
Washington University School of Medicine

Study Description
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Brief Summary:
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 .

Condition or disease Intervention/treatment Phase
Alpha-1-antitrypsin Deficiency Liver Cirrhosis Drug: Drug-Carbamazepine (Tegretol XR) Drug: Carbamazepine (Tegretol XR) Placebo Phase 2

Detailed Description:

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Preliminary Study of the Efficacy and Safety of Carbamazepine in Severe Liver Disease Due to Alpha-1 Antitrypsin Deficiency
Study Start Date : January 2012
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2019

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Drug-Carbamazepine (Tegretol XR)
One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency.
 Drug: Drug-Carbamazepine (Tegretol XR)
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, and the placebo group will receive encapsulated tablets without CBZ.
Other Names:
  • Tegretol-XR Carbamazepine extended release tablets.
  • NDC 0078-0510-05.
Placebo Comparator: Drug-Carbamazepine (Tegretol XR) Placebo
One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency.
 Drug: Carbamazepine (Tegretol XR) Placebo
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.
Other Name: Carbamazepine (Tegretol-XR) placebo.


Outcome Measures
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Primary Outcome Measures :
  1. The primary outcome will be to determine the effect of Carbamazepine on hepatic ATZ load. [ Time Frame: 52 weeks ]
    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.


Secondary Outcome Measures :
  1. For the secondary outcomes we will determine the effect of Carbamazepine treatment on hepatic fibrosis. [ Time Frame: 52 weeks ]
    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.

  2. For the secondary outcome we will determine if Carbamazepine treatment reduces the MELD score. [ Time Frame: 52 weeks. ]
    This will be determined by monitoring the MELD score at the beginning and end of the 12-month treatment period, including measuring at seven follow-up visits while on active medication or placebo. The change in MELD score for subjects on active medication will be compared to that in subjects on placebo.Safety and tolerability will be investigated by close observation and routine laboratory testing of the 30 subjects.


Eligibility Criteria
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Ages Eligible for Study:   14 Years to 80 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01379469


Contacts
Contact: Adam D Kufen, RN, BS, CCRC 412-692-6558 adam.kufen@chp.edu
Contact: Terri Radake, RN, BSN, CCRC 314-747-5366 radaket@wustl.edu

Locations
United States, Missouri
Washington University in St. Louis School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Terri Radake, RN, BSN, CCRC    314-747-5366    radaket@wustl.edu   
Principal Investigator: David A Rudnick, MD, PhD         
Sub-Investigator: Kevin M. Korenblat, MD         
United States, Pennsylvania
Children's Hospital of Pittsburgh, UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15201
Contact: Robert H Squires, M.D.    412-692-7506    squiresr@upmc.edu   
Contact: Adam D Kufen, RN    412-692-8929    adam.kufen@chp.edu   
Principal Investigator: Robert H. Squires, JR., M.D.         
Sub-Investigator: Alejandro Hoberman, M.D.         
Sub-Investigator: Ira Bergman, M.D., PhD.         
Sub-Investigator: Andrew Chu, MD         
University of Pittsburgh Medical Center, Presbyterian Hospital Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: David H. Perlmutter, M.D.    412-692-8071    David.perlmutter@chp.edu   
Principal Investigator: Robert H. Squires, M.D.         
Sub-Investigator: George Michalopoulos, M.D., PhD.         
Sub-Investigator: Shahid Malik, M.D.         
Sub-Investigator: Kapil Chopra, M.D.         
Sub-Investigator: Michael Dunn, M.D.         
Sub-Investigator: Philip Orons, M.D.         
Sub-Investigator: Mitchell Tublin, M.D.         
Sub-Investigator: Allesandro Furlan, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Novartis
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Pittsburgh
Investigators
Principal Investigator: David H. Perlmutter, M.D. Washington University School of Medicine
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:
Carbamazepine in Severe Liver Disease Due to Alpha-1 Antitrypsin Deficiency  This link exits the ClinicalTrials.gov site

Publications of Results:
Perlmutter D.H., Alpha-1-Antitrypsin Deficiency, in Schiff's Disease of Liver, Schiff E.R., Maddrey W.C., Editor. 2007; Lippincott-Raven: Philadelphia. 1063-1084.
Hidvegi T., Perlmutter D.H., Watkins S., and Michalopoulos G., Carbamazepine ameliorates liver disease in mouse models of alpha-1-antitrypsin deficiency by enhancing intracellular disposal of the pathogenic aggregation-prone protein. Science; 2010; 329: 229-232.
Dodson W., Carbamazepine and oxycarbazepine, Pediatric Epilepsy: Diagnosis and Therapy, P.J. Dodson W.E., Editor. 1993; Demos Publications: New York. 303-314.
McNamara J., Drugs effective in the therapy of epilepsies, Goodman and Gillman's: The Pharmacological Basis of Therapeutics, J. Hardman, L. Limbird, and A. Cillman, Editors. 2001; McGraw-Hill: New York. 533-535.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01379469     History of Changes
Other Study ID Numbers: 201510060-PRO09070279
1R21DK092567-01 ( U.S. NIH Grant/Contract )
First Posted: June 23, 2011    Key Record Dates
Last Update Posted: May 11, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: We will share data and liver tissue with other researchers. They may be doing research in areas similar to this research or in other unrelated areas. These researchers may be at Washington University, at other research centers and institutions, or industry sponsors of research. We may also share research data with large data repositories (a repository is a database of information) for broad sharing with the research community. If individual research data is placed in one of these repositories only qualified researchers, who have received prior approval from individuals that monitor the use of the data, will be able to look at the information.

Keywords provided by Washington University School of Medicine:
Carbamazepine (Tegretol) use
severe liver disease
alpha-1-antitrypsin deficiency

Additional relevant MeSH terms:
Alpha 1-Antitrypsin Deficiency
Alpha 1-Antitrypsin
Protein C Inhibitor
Liver Diseases
Liver Cirrhosis
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Pathologic Processes
Carbamazepine
Anticonvulsants
Antimanic Agents
 Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers
Molecular Mechanisms of Pharmacological Action
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors