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

NCT01379469 | Terminated Phase 2 Results DMC

• 2 other identifiers: 201510060-PRO090702791R21DK092567-01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 3

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 .

Conditions

Alpha-1-antitrypsin Deficiency; Liver Cirrhosis

Keywords

Carbamazepine (Tegretol) use; severe liver disease; alpha-1-antitrypsin deficiency

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• For the Secondary Outcomes we Will Determine the Effect of Carbamazepine Treatment on Hepatic Fibrosis.

  52 weeks

Study Arms (2)

Drug-Carbamazepine (Tegretol XR)

ACTIVE COMPARATOR

One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency.

Drug: Drug-Carbamazepine (Tegretol XR)

Drug-Carbamazepine (Tegretol XR) Placebo

PLACEBO COMPARATOR

One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency.

Drug: Carbamazepine (Tegretol XR) Placebo

Interventions

Drug-Carbamazepine (Tegretol XR) DRUG

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..

Also known as: Tegretol-XR Carbamazepine extended release tablets., NDC 0078-0510-05.

Drug-Carbamazepine (Tegretol XR)

Carbamazepine (Tegretol XR) Placebo DRUG

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.

Also known as: Carbamazepine (Tegretol-XR) placebo.

Drug-Carbamazepine (Tegretol XR) Placebo

Eligibility Criteria

• Age: 14 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Child Pugh Score greater than or equal to 12. Serum total bilirubin \> 5 mg/dl. INR \> 2.2.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Novartis: collaborator
• National Institutes of Health (NIH): collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• University of Pittsburgh: collaborator

Study Sites (3)

Washington University in St. Louis School of Medicine

St Louis, Missouri, 63110, United States

Location

Children's Hospital of Pittsburgh, UPMC

Pittsburgh, Pennsylvania, 15201, United States

Location

University of Pittsburgh Medical Center, Presbyterian Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (48)

• 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.

  BACKGROUND

• Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res. 2006 Aug;60(2):233-8. doi: 10.1203/01.pdr.0000228350.61496.90.

  PMID: 16864711 BACKGROUND

• 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.

  PMID: 18617899 BACKGROUND

• 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. doi: 10.1002/hep.20815.

  PMID: 16044402 BACKGROUND

• 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. doi: 10.1378/chest.128.4.2076.

  PMID: 16236857 BACKGROUND

• 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. doi: 10.1056/NEJM197606102942404.

  PMID: 1083485 BACKGROUND

• 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. doi: 10.1056/NEJM198603203141202.

  PMID: 3485248 BACKGROUND

• 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. doi: 10.1002/bjs.1800600817. No abstract available.

  PMID: 4541913 BACKGROUND

• 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. doi: 10.1053/he.2000.5852.

  PMID: 10733541 BACKGROUND

• 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. No abstract available.

  PMID: 20512984 BACKGROUND

• 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. doi: 10.1016/s0168-8278(05)80521-5.

  PMID: 8445220 BACKGROUND

• 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.

  PMID: 19616339 BACKGROUND

• 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. doi: 10.1016/j.cgh.2007.02.022. Epub 2007 Jun 4.

  PMID: 17544878 BACKGROUND

• 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.

  BACKGROUND

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

  BACKGROUND

• 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. doi: 10.1038/417292a.

  PMID: 12015604 BACKGROUND

• 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. doi: 10.1083/jcb.200504035.

  PMID: 16186256 BACKGROUND

• 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.

  BACKGROUND

• 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. doi: 10.1111/j.1528-1157.1978.tb04487.x.

  PMID: 679894 BACKGROUND

• 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. doi: 10.1038/428486a.

  PMID: 15057820 BACKGROUND

• 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. doi: 10.1111/j.1528-1167.2007.01022.x. Erratum In: Epilepsia. 2008 May;49(5):941.

  PMID: 17509004 BACKGROUND

• 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.

  PMID: 21428769 BACKGROUND

• 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.

  PMID: 21428768 BACKGROUND

• 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.

  PMID: 19637072 BACKGROUND

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

  PMID: 20166067 BACKGROUND

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

  PMID: 20238337 BACKGROUND

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

  PMID: 20426709 BACKGROUND

• Wilkinson GR, Schenker S. Drug disposition and liver disease. Drug Metab Rev. 1975;4(2):139-75. doi: 10.3109/03602537508993754. No abstract available.

  PMID: 770104 BACKGROUND

• 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.

  PMID: 9046378 BACKGROUND

• 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. doi: 10.1111/j.1572-0241.2003.07486.x.

  PMID: 12809815 BACKGROUND

• Tandra S, Vuppalanchi R. Use of statins in patients with liver disease. Curr Treat Options Cardiovasc Med. 2009 Aug;11(4):272-8. doi: 10.1007/s11936-009-0028-2.

  PMID: 19627660 BACKGROUND

• 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. doi: 10.1007/BF02996298.

  PMID: 12126042 BACKGROUND

• Parlesak A, Schafer C, Schutz 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. doi: 10.1016/s0168-8278(00)80242-1.

  PMID: 10845660 BACKGROUND

• Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update. Clin Pharmacokinet. 1995 Nov;29(5):370-91. doi: 10.2165/00003088-199529050-00005.

  PMID: 8582120 BACKGROUND

• Verbeeck RK, Horsmans Y. Effect of hepatic insufficiency on pharmacokinetics and drug dosing. Pharm World Sci. 1998 Oct;20(5):183-92. doi: 10.1023/a:1008656930082.

  PMID: 9820880 BACKGROUND

• 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. doi: 10.1159/000016942.

  PMID: 10754364 BACKGROUND

• Delco F, Tchambaz L, Schlienger R, Drewe J, Krahenbuhl S. Dose adjustment in patients with liver disease. Drug Saf. 2005;28(6):529-45. doi: 10.2165/00002018-200528060-00005.

  PMID: 15924505 BACKGROUND

• 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. doi: 10.1016/0006-2952(94)00515-n.

  PMID: 7741759 BACKGROUND

• 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. doi: 10.1046/j.1525-1497.2001.016009606.x.

  PMID: 11556941 BACKGROUND

• 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. doi: 10.1309/W3XC-NT4H-KFBN-2G0B.

  PMID: 16707372 BACKGROUND

• 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. doi: 10.1016/j.jhep.2007.05.001. Epub 2007 May 24.

  PMID: 17561303 BACKGROUND

• 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.

  PMID: 18704569 BACKGROUND

• 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. doi: 10.1111/j.1600-0404.2004.00291.x.

  PMID: 15147458 BACKGROUND

• 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.

  PMID: 19223438 BACKGROUND

• 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.

  PMID: 20478877 BACKGROUND

• 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. doi: 10.1542/peds.113.4.825.

  PMID: 15060234 BACKGROUND

• 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. doi: 10.1007/BF02072057.

  PMID: 2279511 BACKGROUND

• Silverman GA, Pak SC, Perlmutter DH. Disorders of protein misfolding: alpha-1-antitrypsin deficiency as prototype. J Pediatr. 2013 Aug;163(2):320-6. doi: 10.1016/j.jpeds.2013.03.077. Epub 2013 May 8. No abstract available.

  PMID: 23664631 DERIVED

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency; Liver Cirrhosis; Liver Diseases

Interventions

Carbamazepine

Condition Hierarchy (Ancestors)

Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Fibrosis

Intervention Hierarchy (Ancestors)

Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

The primary \& secondary outcomes could not be assessed because the number of subjects with available pre \& post biopsies was insufficient in subject number and sample quality to conduct the analyses. As described in more detail in Outcome Measures. .

Results Point of Contact

• Title: David Rudnick MD, PhD- Associate Professor
• Organization: Washington University School of Medicine

rudnick_d@wustl.edu

314-286-2832

Study Officials

• David H. Perlmutter, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2011
• First Posted: June 23, 2011
• Study Start: January 1, 2012
• Primary Completion: February 1, 2017
• Study Completion: February 1, 2017
• Last Updated: October 12, 2021
• Results First Posted: October 12, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share

Locations

US (3)