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

Liver Cirrhosis Clinical Trial

— CBZ  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01379469
• Other study ID #: 201510060-PRO09070279
• Secondary ID: 1R21DK092567-01
• Status: Terminated
• Phase: Phase 2
• Start date: January 2012
• Est. completion date: February 2017

Study information

• Verified date: October 2021
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 .

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: February 2017
• Est. primary completion date: February 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alpha 1-Antitrypsin Deficiency
• Alpha-1-antitrypsin Deficiency
• Liver Cirrhosis
• Liver Diseases

Intervention

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..
• 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.

Locations

Country	Name	City	State
United States	Children's Hospital of Pittsburgh, UPMC	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Medical Center, Presbyterian Hospital	Pittsburgh	Pennsylvania
United States	Washington University in St. Louis School of Medicine	Saint Louis	Missouri

Sponsors (5)

Lead Sponsor	Collaborator
Washington University School of Medicine	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Novartis, University of Pittsburgh

Country where clinical trial is conducted

United States, 

References & Publications (47)

Brent DA, Emslie GJ, Clarke GN, Asarnow J, Spirito A, Ritz L, Vitiello B, Iyengar S, Birmaher B, Ryan ND, Zelazny J, Onorato M, Kennard B, Mayes TL, Debar LL, McCracken JT, Strober M, Suddath R, Leonard H, Porta G, Keller MB. Predictors of spontaneous and systematically assessed suicidal adverse events in the treatment of SSRI-resistant depression in adolescents (TORDIA) study. Am J Psychiatry. 2009 Apr;166(4):418-26. doi: 10.1176/appi.ajp.2008.08070976. Epub 2009 Feb 17. Erratum in: Am J Psychiatry. 2019 Sep 1;176(9):764. — View Citation

Burroughs AK, Thalheimer U. Hepatic venous pressure gradient in 2010: optimal measurement is key. Hepatology. 2010 Jun;51(6):1894-6. doi: 10.1002/hep.23710. — View Citation

Chen P, Lin JJ, Lu CS, Ong CT, Hsieh PF, Yang CC, Tai CT, Wu SL, Lu CH, Hsu YC, Yu HY, Ro LS, Lu CT, Chu CC, Tsai JJ, Su YH, Lan SH, Sung SF, Lin SY, Chuang HP, Huang LC, Chen YJ, Tsai PJ, Liao HT, Lin YH, Chen CH, Chung WH, Hung SI, Wu JY, Chang CF, Chen L, Chen YT, Shen CY; Taiwan SJS Consortium. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. 2011 Mar 24;364(12):1126-33. doi: 10.1056/NEJMoa1009717. — View Citation

Cholongitas E, Senzolo M, Standish R, Marelli L, Quaglia A, Patch D, Dhillon AP, Burroughs AK. A systematic review of the quality of liver biopsy specimens. Am J Clin Pathol. 2006 May;125(5):710-21. Review. — View Citation

Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004 Apr 1;428(6982):486. — View Citation

Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003 May;98(5):960-7. — View Citation

Delcò F, Tchambaz L, Schlienger R, Drewe J, Krähenbühl S. Dose adjustment in patients with liver disease. Drug Saf. 2005;28(6):529-45. Review. — View Citation

Dodson W., Carbamazepine and oxycarbazepine, Pediatric Epilepsy: Diagnosis and Therapy, P.J. Dodson W.E., Editor. 1993; Demos Publications: New York. 303-314.

Emslie GJ, Mayes T, Porta G, Vitiello B, Clarke G, Wagner KD, Asarnow JR, Spirito A, Birmaher B, Ryan N, Kennard B, DeBar L, McCracken J, Strober M, Onorato M, Zelazny J, Keller M, Iyengar S, Brent D. Treatment of Resistant Depression in Adolescents (TORDIA): week 24 outcomes. Am J Psychiatry. 2010 Jul;167(7):782-91. doi: 10.1176/appi.ajp.2010.09040552. Epub 2010 May 17. — View Citation

Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N Engl J Med. 1986 Mar 20;314(12):736-9. — View Citation

Frey B, Schubiger G, Musy JP. Transient cholestatic hepatitis in a neonate associated with carbamazepine exposure during pregnancy and breast-feeding. Eur J Pediatr. 1990 Dec;150(2):136-8. — View Citation

George J, Liddle C, Murray M, Byth K, Farrell GC. Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis. Biochem Pharmacol. 1995 Mar 30;49(7):873-81. — View Citation

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.

Huband N, Ferriter M, Nathan R, Jones H. Antiepileptics for aggression and associated impulsivity. Cochrane Database Syst Rev. 2010 Feb 17;(2):CD003499. doi: 10.1002/14651858.CD003499.pub3. Review. — View Citation

Ishizu H, Shiomi S, Kawamura E, Iwata Y, Nishiguchi S, Kawabe J, Ochi H. Gastric emptying in patients with chronic liver diseases. Ann Nucl Med. 2002 May;16(3):177-82. — View Citation

Kalambokis G, Manousou P, Vibhakorn S, Marelli L, Cholongitas E, Senzolo M, Patch D, Burroughs AK. Transjugular liver biopsy--indications, adequacy, quality of specimens, and complications--a systematic review. J Hepatol. 2007 Aug;47(2):284-94. Epub 2007 May 24. Review. — View Citation

Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13. — View Citation

Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000 Apr;31(4):864-71. — View Citation

Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia. 2007 May;48(5):1015-8. Erratum in: Epilepsia. 2008 May;49(5):941. — View Citation

Manolakopoulos S, Triantos C, Theodoropoulos J, Vlachogiannakos J, Kougioumtzan A, Papatheodoridis G, Tzourmakliotis D, Karamanolis D, Burroughs AK, Archimandritis A, Raptis S, Avgerinos A. Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension. J Hepatol. 2009 Sep;51(3):468-74. doi: 10.1016/j.jhep.2009.05.031. Epub 2009 Jul 3. — View Citation

McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperaviciute D, Carrington M, Sills GJ, Marson T, Jia X, de Bakker PI, Chinthapalli K, Molokhia M, Johnson MR, O'Connor GD, Chaila E, Alhusaini S, Shianna KV, Radtke RA, Heinzen EL, Walley N, Pandolfo M, Pichler W, Park BK, Depondt C, Sisodiya SM, Goldstein DB, Deloukas P, Delanty N, Cavalleri GL, Pirmohamed M. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011 Mar 24;364(12):1134-43. doi: 10.1056/NEJMoa1013297. — View Citation

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.

Miller AD, Krauss GL, Hamzeh FM. Improved CNS tolerability following conversion from immediate- to extended-release carbamazepine. Acta Neurol Scand. 2004 Jun;109(6):374-7. — View Citation

Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD005064. doi: 10.1002/14651858.CD005064.pub3. Review. — View Citation

Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update. Clin Pharmacokinet. 1995 Nov;29(5):370-91. Review. — View Citation

Mueller TI, Stout RL, Rudden S, Brown RA, Gordon A, Solomon DA, Recupero PR. A double-blind, placebo-controlled pilot study of carbamazepine for the treatment of alcohol dependence. Alcohol Clin Exp Res. 1997 Feb;21(1):86-92. — View Citation

Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol. 2000 May;32(5):742-7. — View Citation

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.

Perlmutter DH. Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in alpha-1-antitrypsin deficiency. Cell Death Differ. 2009 Jan;16(1):39-45. doi: 10.1038/cdd.2008.103. Epub 2008 Jul 11. Review. — View Citation

Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res. 2006 Aug;60(2):233-8. Review. — View Citation

Piitulainen E, Carlson J, Ohlsson K, Sveger T. Alpha1-antitrypsin deficiency in 26-year-old subjects: lung, liver, and protease/protease inhibitor studies. Chest. 2005 Oct;128(4):2076-81. — View Citation

Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646-9. — View Citation

Roberts S, Gordon A, McLean C, Pedersen J, Bowden S, Thomson K, Angus P. Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis. Clin Gastroenterol Hepatol. 2007 Aug;5(8):932-7. Epub 2007 Jun 4. — View Citation

Rodriquez A, Martin A, Oterino JA, Blanco I, Jimenez M, Perez A, Novoa JM. Renal function in compensated hepatic cirrhosis: effects of an amino acid infusion and relationship with nitric acid. Dig Dis. 1999;17(4):235-40. — View Citation

Rudnick DA, Perlmutter DH. Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology. 2005 Sep;42(3):514-21. Review. — View Citation

Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, Pasco M, Cook LJ, Rubinsztein DC. Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol. 2005 Sep 26;170(7):1101-11. — View Citation

Shemesh E, Shneider BL, Savitzky JK, Arnott L, Gondolesi GE, Krieger NR, Kerkar N, Magid MS, Stuber ML, Schmeidler J, Yehuda R, Emre S. Medication adherence in pediatric and adolescent liver transplant recipients. Pediatrics. 2004 Apr;113(4):825-32. — View Citation

Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med. 1976 Jun 10;294(24):1316-21. — View Citation

Tandra S, Vuppalanchi R. Use of statins in patients with liver disease. Curr Treat Options Cardiovasc Med. 2009 Aug;11(4):272-8. — View Citation

Verbeeck RK, Horsmans Y. Effect of hepatic insufficiency on pharmacokinetics and drug dosing. Pharm World Sci. 1998 Oct;20(5):183-92. Review. — View Citation

Vibhakorn S, Cholongitas E, Kalambokis G, Manousou P, Quaglia A, Marelli L, Senzolo M, Patch D, Dhillon A, Burroughs AK. A comparison of four- versus three-pass transjugular biopsy using a 19-G Tru-Cut needle and a randomized study using a cassette to prevent biopsy fragmentation. Cardiovasc Intervent Radiol. 2009 May;32(3):508-13. doi: 10.1007/s00270-008-9412-7. Epub 2008 Aug 13. — View Citation

Vigo DV, Baldessarini RJ. Anticonvulsants in the treatment of major depressive disorder: an overview. Harv Rev Psychiatry. 2009;17(4):231-41. doi: 10.1080/10673220903129814. Review. — View Citation

Wada JA, Troupin AS, Friel P, Remick R, Leal K, Pearmain J. Pharmacokinetic comparison of tablet and suspension dosage forms of carbamazepine. Epilepsia. 1978 Jun;19(3):251-5. — View Citation

Wilkinson GR, Schenker S. Drug disposition and liver disease. Drug Metab Rev. 1975;4(2):139-75. Review. — View Citation

Williams RS, Cheng L, Mudge AW, Harwood AJ. A common mechanism of action for three mood-stabilizing drugs. Nature. 2002 May 16;417(6886):292-5. — View Citation

Zakrzewska JM. Medical management of trigeminal neuropathic pains. Expert Opin Pharmacother. 2010 Jun;11(8):1239-54. doi: 10.1517/14656561003767449. Review. — View Citation

Zoli M, Iervese T, Merkel C, Bianchi G, Magalotti D, Marchesini G, Gatta A, Pisi E. Prognostic significance of portal hemodynamics in patients with compensated cirrhosis. J Hepatol. 1993 Jan;17(1):56-61. — View Citation

* Note: There are 47 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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

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