Carbamazepine in Severe Liver Disease Due to Alpha-1 Antitrypsin Deficiency (CBZ)
This study is currently recruiting participants.
(see Contacts and Locations)
Verified June 2016 by Washington University School of Medicine
Sponsor:
Washington University School of Medicine
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
ClinicalTrials.gov Identifier:
NCT01379469
First received: June 15, 2011
Last updated: June 9, 2016
Last verified: June 2016
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Purpose
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 | Intervention | Phase |
|---|---|---|
|
Alpha-1-antitrypsin Deficiency Liver Cirrhosis |
Drug: Drug-Carbamazepine (Tegretol XR) Drug: Carbamazepine (Tegretol XR) Placebo |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, 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 |
Resource links provided by NLM:
Genetics Home Reference related topics:
North American Indian childhood cirrhosis
alpha-1 antitrypsin deficiency
U.S. FDA Resources
Further study details as provided by Washington University School of Medicine:
Primary Outcome Measures:
- The primary outcome will be to determine the effect of Carbamazepine on hepatic ATZ load. [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]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:
- For the secondary outcomes we will determine the effect of Carbamazepine treatment on hepatic fibrosis. [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]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.
- For the secondary outcome we will determine if Carbamazepine treatment reduces the MELD score. [ Time Frame: 52 weeks. ] [ Designated as safety issue: Yes ]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.
| Estimated Enrollment: | 30 |
| Study Start Date: | January 2012 |
| Estimated Study Completion Date: | January 2017 |
| Estimated Primary Completion Date: | January 2017 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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:
|
|
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.
|
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.
Eligibility| Ages Eligible for Study: | 14 Years to 80 Years (Child, Adult, Senior) |
| Genders Eligible for Study: | Both |
| 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01379469
Please refer to this study by its ClinicalTrials.gov identifier: 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 |
| St. 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
Additional Information:
Publications:
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 |
| Study First Received: | June 15, 2011 |
| Last Updated: | June 9, 2016 |
| Health Authority: | United States: Food and Drug Administration |
| Individual Participant Data | |
| 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 Trypsin Inhibitors Serine Proteinase Inhibitors |
Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action 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 |
ClinicalTrials.gov processed this record on September 30, 2016