CBZ: Carbamazepine in Severe Liver Disease Due to Alpha-1 Antitrypsin Deficiency
Sponsor
Washington University School of Medicine (Other)
Overall Status
Terminated
CT.gov ID
NCT01379469
Collaborator
Novartis (Industry), National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), University of Pittsburgh (Other)
20
3
2
61
6.7
0.1
Study Details
Study Description
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 |
|---|---|---|
|
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
Study Type:
Interventional
Actual Enrollment
:
20 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
:
Jan 1, 2012
Actual Primary Completion Date
:
Feb 1, 2017
Actual Study Completion Date
:
Feb 1, 2017
Arms and Interventions
| 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..
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 Names:
|
Outcome Measures
Primary Outcome Measures
- The Primary Outcome Will be to Determine the Effect of Carbamazepine on Hepatic ATZ Load. [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
- For the Secondary Outcomes we Will Determine the Effect of Carbamazepine Treatment on Hepatic Fibrosis. [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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
14 Years
to 80 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Washington University in St. Louis School of Medicine | Saint Louis | Missouri | United States | 63110 |
| 2 | Children's Hospital of Pittsburgh, UPMC | Pittsburgh | Pennsylvania | United States | 15201 |
| 3 | University of Pittsburgh Medical Center, Presbyterian Hospital | Pittsburgh | Pennsylvania | United States | 15213 |
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
Study Documents (Full-Text)
More Information
Additional Information:
Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, Maurice N, Mukherjee A, Goldbach C, Watkins S, Michalopoulos G, Perlmutter DH. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science. 2010 Jul 9;329(5988):229-32. doi: 10.1126/science.1190354. Epub 2010 Jun 3.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res. 2006 Aug;60(2):233-8. Review.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Tandra S, Vuppalanchi R. Use of statins in patients with liver disease. Curr Treat Options Cardiovasc Med. 2009 Aug;11(4):272-8.
- Verbeeck RK, Horsmans Y. Effect of hepatic insufficiency on pharmacokinetics and drug dosing. Pharm World Sci. 1998 Oct;20(5):183-92. Review.
- 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.
- 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.
- 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.
- Wilkinson GR, Schenker S. Drug disposition and liver disease. Drug Metab Rev. 1975;4(2):139-75. Review.
- 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.
- Zakrzewska JM. Medical management of trigeminal neuropathic pains. Expert Opin Pharmacother. 2010 Jun;11(8):1239-54. doi: 10.1517/14656561003767449. Review.
- 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.
Responsible Party:
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01379469
Other Study ID Numbers:
- 201510060-PRO09070279
- 1R21DK092567-01
First Posted:
Jun 23, 2011
Last Update Posted:
Oct 12, 2021
Last Verified:
Oct 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Washington University School of Medicine
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Drug-Carbamazepine (Tegretol XR) | Drug-Carbamazepine (Tegretol XR) Placebo |
|---|---|---|
| Arm/Group Description | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. |
| Period Title: Overall Study | ||
| STARTED | 13 | 7 |
| COMPLETED | 1 | 3 |
| NOT COMPLETED | 12 | 4 |
Baseline Characteristics
| Arm/Group Title | Drug-Carbamazepine (Tegretol XR) | Drug-Carbamazepine (Tegretol XR) Placebo | Total |
|---|---|---|---|
| Arm/Group Description | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. | Total of all reporting groups |
| Overall Participants | 13 | 7 | 20 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
1
14.3%
|
1
5%
|
| Between 18 and 65 years |
13
100%
|
3
42.9%
|
16
80%
|
| >=65 years |
0
0%
|
3
42.9%
|
3
15%
|
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
50.7
(9.4)
|
53.7
(19.6)
|
51.75
(13.38)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
5
38.5%
|
3
42.9%
|
8
40%
|
| Male |
8
61.5%
|
4
57.1%
|
12
60%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| White |
13
100%
|
7
100%
|
20
100%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
13
100%
|
7
100%
|
20
100%
|
Outcome Measures
| Title | The Primary Outcome Will be to Determine the Effect of Carbamazepine on Hepatic ATZ Load. |
|---|---|
| Description | 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. |
| Time Frame | 52 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| The primary outcome was not assessable because the number of subjects with available pre & post PAS+/diastase stained liver biopsies & tissue for immunoblot was insufficient in subject number and sample quality. To elaborate only 3 subjects had both pre & post biopsies stained for PAS, 2 from the placebo & 1 from the Carbamazepine arms & the available histology quality was insufficient for histomorphormetry. Frozen liver samples were also of insufficient number & mass for immunoblot. |
| Arm/Group Title | Drug-Carbamazepine (Tegretol XR) | Drug-Carbamazepine (Tegretol XR) Placebo |
|---|---|---|
| Arm/Group Description | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. |
| Measure Participants | 0 | 0 |
| Title | For the Secondary Outcomes we Will Determine the Effect of Carbamazepine Treatment on Hepatic Fibrosis. |
|---|---|
| Description | 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. |
| Time Frame | 52 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| The secondary outcome was also not assessable because the number of subjects with available pre & post trichrome stained liver biopsies & tissue for hydroxyproline was also insufficient in subject number and sample quality. Again only 3 subjects had both pre & post biopsies stained for trichrome, 2 placebo- & 1 Carbamazepine treated. Available histology quality was also insufficient here for histomorphormetry &.frozen liver samples insufficient for hydroxyproline determination. |
| Arm/Group Title | Drug-Carbamazepine (Tegretol XR) | Drug-Carbamazepine (Tegretol XR) Placebo |
|---|---|---|
| Arm/Group Description | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | Serious Adverse Events and Adverse Events were collected for 52 weeks. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Drug-Carbamazepine (Tegretol XR) | Drug-Carbamazepine (Tegretol XR) Placebo | ||
| Arm/Group Description | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. 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. | ||
All Cause Mortality |
||||
| Drug-Carbamazepine (Tegretol XR) | Drug-Carbamazepine (Tegretol XR) Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/13 (0%) | 2/7 (28.6%) | ||
Serious Adverse Events |
||||
| Drug-Carbamazepine (Tegretol XR) | Drug-Carbamazepine (Tegretol XR) Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/13 (46.2%) | 4/7 (57.1%) | ||
| Blood and lymphatic system disorders | ||||
| Hematologic | 1/13 (7.7%) | 1 | 0/7 (0%) | 0 |
| Cardiac disorders | ||||
| Cardiac | 1/13 (7.7%) | 1 | 1/7 (14.3%) | 2 |
| Gastrointestinal disorders | ||||
| Gastrointestinal | 2/13 (15.4%) | 3 | 2/7 (28.6%) | 2 |
| General disorders | ||||
| Pain | 2/13 (15.4%) | 3 | 1/7 (14.3%) | 1 |
| Constitutional | 4/13 (30.8%) | 6 | 0/7 (0%) | 0 |
| Infections and infestations | ||||
| Infection | 2/13 (15.4%) | 4 | 2/7 (28.6%) | 2 |
| Metabolism and nutrition disorders | ||||
| Metabolic/Laboratory | 1/13 (7.7%) | 1 | 0/7 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Pulmonary | 1/13 (7.7%) | 2 | 1/7 (14.3%) | 2 |
| Vascular disorders | ||||
| Vascular | 2/13 (15.4%) | 2 | 0/7 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| Drug-Carbamazepine (Tegretol XR) | Drug-Carbamazepine (Tegretol XR) Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 13/13 (100%) | 7/7 (100%) | ||
| Blood and lymphatic system disorders | ||||
| Hematologic | 3/13 (23.1%) | 4 | 1/7 (14.3%) | 1 |
| Cardiac disorders | ||||
| Cardiac | 1/13 (7.7%) | 2 | 3/7 (42.9%) | 4 |
| Endocrine disorders | ||||
| Endocrine | 3/13 (23.1%) | 3 | 1/7 (14.3%) | 1 |
| Gastrointestinal disorders | ||||
| Gastrointestinal | 9/13 (69.2%) | 35 | 5/7 (71.4%) | 13 |
| General disorders | ||||
| Constitutional | 12/13 (92.3%) | 63 | 7/7 (100%) | 17 |
| Pain | 8/13 (61.5%) | 15 | 5/7 (71.4%) | 8 |
| Hepatobiliary disorders | ||||
| Child-Pugh Score Increase | 1/13 (7.7%) | 1 | 1/7 (14.3%) | 2 |
| Infections and infestations | ||||
| Infection | 7/13 (53.8%) | 16 | 3/7 (42.9%) | 5 |
| Metabolism and nutrition disorders | ||||
| Metabolic/Laboratory | 3/13 (23.1%) | 3 | 2/7 (28.6%) | 3 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal | 7/13 (53.8%) | 12 | 3/7 (42.9%) | 5 |
| Nervous system disorders | ||||
| Neurologic | 10/13 (76.9%) | 31 | 3/7 (42.9%) | 5 |
| Renal and urinary disorders | ||||
| Genitourological | 3/13 (23.1%) | 3 | 2/7 (28.6%) | 2 |
| Reproductive system and breast disorders | ||||
| Gynecological | 2/13 (15.4%) | 2 | 1/7 (14.3%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Pulmonary | 4/13 (30.8%) | 9 | 4/7 (57.1%) | 5 |
| Skin and subcutaneous tissue disorders | ||||
| Dermatologic | 2/13 (15.4%) | 2 | 2/7 (28.6%) | 4 |
| Vascular disorders | ||||
| Vascular | 5/13 (38.5%) | 5 | 1/7 (14.3%) | 1 |
Limitations/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.
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More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | David Rudnick MD, PhD- Associate Professor |
|---|---|
| Organization | Washington University School of Medicine |
| Phone | 314-286-2832 |
| rudnick_d@wustl.edu |
Responsible Party:
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01379469
Other Study ID Numbers:
- 201510060-PRO09070279
- 1R21DK092567-01
First Posted:
Jun 23, 2011
Last Update Posted:
Oct 12, 2021
Last Verified:
Oct 1, 2021