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Using Entecavir to Reduce Hepatitis in Highly Viremic HBV Patients During Anti-tuberculous Treatment

NCT ID: NCT01724723

Last Updated: 2012-11-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

50 participants

Study Classification

INTERVENTIONAL

Study Start Date

2012-12-31

Study Completion Date

2014-06-30

Brief Summary

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Hepatitis during anti-tuberculous treatment (HATT) has been an obstacle in managing TB patients, especially in those with viral hepatitis. A previous study revealed the risk of HATT is significantly higher in TB patients with high serum hepatitis B virus (HBV) DNA level than those with low HBV DNA level. Based on these findings, we thus hypothesize that the risk of HATT in TB patients with high baseline serum HBV DNA level can be reduced by concomitant use of anti-HBV agent. In this proposal, we will conduct a prospective randomized clinical study to assess the reduction of HATT risk by using entecavir in TB patients with high baseline serum HBV DNA level, and to evaluate the risk of other treatment-related adverse events in two hospitals.

Detailed Description

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Tuberculosis (TB) remains one of the important infectious diseases worldwide. Timely implementation of optimized anti-tuberculous therapy is still the mainstay to prevent further transmission of TB. However, hepatitis during anti-tuberculous treatment (HATT) has been an obstacle in managing TB patients, especially in those with viral hepatitis. A previous study revealed the risk of HATT is significantly higher in TB patients with high serum hepatitis B virus (HBV) DNA level than those with low HBV DNA level (39% vs. 11%), the latter cases have a similar risk of HATT as those without viral hepatitis (14%). Based on these findings, we thus hypothesize that the risk of HATT in TB patients with high baseline serum HBV DNA level can be reduced by concomitant use of anti-HBV agent. In this proposal, we will conduct a prospective randomized clinical study to assess the reduction of HATT risk by using entecavir in TB patients with high baseline serum HBV DNA level, and to evaluate the risk of other treatment-related adverse events in two hospitals. From January 2012 to June 2014, subjects with culture-confirmed TB and aged from 18 to 80 with high serum HBV viral load prior to anti-tuberculous treatment will be enrolled and randomized into either study or control group. High serum HBV viral load is defined as \>20,000 and \>2,000 IU/mL for HBeAg-positive and HBeAg-negative subjects, respectively. In addition to standard anti-tuberculous treatment, subjects in the study group will receive entecavir (BARACLUDE®) 0.5 mg per day during anti-tuberculous treatment and for 6 months after stopping anti-tuberculous treatment. Hemogram, liver function, renal function, and serum HBV viral load will be regularly monitored to detect the development of HATT and other adverse events. In this study, HATT is defined as fulfilling anyone of the following conditions: (1) increase in serum AST and/or ALT level of \>3 times upper limit of normal (ULN) with symptoms if baseline liver function is normal; (2) increase in serum AST and/or ALT level of \>5 times ULN without symptoms if baseline liver function is normal; (3) increase in serum AST and/or ALT level of \>2 times baseline if baseline liver function is abnormal; and (4) increase in serum total bilirubin level of \> 2.5 mg/dL.

Conditions

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Hepatitis Tuberculosis hepatitisB

Keywords

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hepatitis during anti-tuberculous treatment tuberculosis hepatitis B virus viral load entecavir

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

NONE

Study Groups

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Entecavir group

Study treatment for only treatment group: entecavir (BARACLUDE®) 0.5 mg per day during and within 6 months after anti-tuberculous treatment.

Group Type EXPERIMENTAL

entecavir (BARACLUDE®)

Intervention Type DRUG

entecavir 0.5 mg per day during and within 6 months after anti-tuberculous treatment

Control group

Not receiving entecavir (BARACLUDE®)

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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entecavir (BARACLUDE®)

entecavir 0.5 mg per day during and within 6 months after anti-tuberculous treatment

Intervention Type DRUG

Other Intervention Names

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BARACLUDE®

Eligibility Criteria

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Inclusion Criteria

* culture-confirmed tuberculosis
* serology-confirmed chronic HBV infection without flare-up at present (IgM Anti-HBc-negative and either HBsAg-positive or Anti-HBc-positive)
* high serum HBV viral load, defined as \>20,000 and \>2,000 IU/mL for HBeAg positive and HBeAg negative patients, respectively
* serum AST and/or ALT level \<2 times ULN
* serum level of total bilirubin \<2.0 mg/dL
* willing to receive directly observed therapy, short course (DOTs)

Exclusion Criteria

* Target Disease Exceptions: human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV) co-infection, multidrug-resistant tuberculosis (defined as simultaneous resistant to isoniazid and rifampin)
* Medical History and Concurrent Diseases

1. . ever receiving anti-viral therapy for HBV
2. . alcoholism or presence of hepatic disease other than hepatitis B
3. . life expectancy less than 1 year
* Sex and Reproductive Status

1. . Pregnancy
2. . Breast-feeding
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Taiwan University Hospital

OTHER

Sponsor Role lead

Responsible Party

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National Taiwan University Hospital

Physician

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Jann-Yuan Wang, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

National Taiwan University Hospital

Locations

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National Taiwan University Hospital

Taipei, , Taiwan

Site Status

Countries

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Taiwan

Central Contacts

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Jann-Yuan Wang, Ph.D

Role: CONTACT

Phone: 886-2-23123456

Email: [email protected]

Chin-Chugn Shu, M.D

Role: CONTACT

Phone: 886-2-23123456

Email: [email protected]

Facility Contacts

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Jann-Yuan Wang, Ph.D.

Role: primary

Chin-Chung Shu, M.D.

Role: backup

References

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Albert RK, Iseman M, Sbarbaro JA, Stage A, Pierson DJ. Monitoring patients with tuberculosis for failure during and after treatment. Am Rev Respir Dis. 1976 Dec;114(6):1051-60. doi: 10.1164/arrd.1976.114.6.1051.

Reference Type BACKGROUND
PMID: 827221 (View on PubMed)

American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: controlling tuberculosis in the United States. Am J Respir Crit Care Med. 2005 Nov 1;172(9):1169-227. doi: 10.1164/rccm.2508001.

Reference Type BACKGROUND
PMID: 16249321 (View on PubMed)

Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR; ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006 Oct 15;174(8):935-52. doi: 10.1164/rccm.200510-1666ST.

Reference Type BACKGROUND
PMID: 17021358 (View on PubMed)

American Thoracic Society; CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep. 2003 Jun 20;52(RR-11):1-77. No abstract available.

Reference Type BACKGROUND
PMID: 12836625 (View on PubMed)

Lee BH, Koh WJ, Choi MS, Suh GY, Chung MP, Kim H, Kwon OJ. Inactive hepatitis B surface antigen carrier state and hepatotoxicity during antituberculosis chemotherapy. Chest. 2005 Apr;127(4):1304-11. doi: 10.1378/chest.127.4.1304.

Reference Type BACKGROUND
PMID: 15821209 (View on PubMed)

Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, Tam CM, Leung CC, Lai CL. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology. 2000 Jan;31(1):201-6. doi: 10.1002/hep.510310129.

Reference Type BACKGROUND
PMID: 10613746 (View on PubMed)

Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, Pitchenik AE. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1871-6. doi: 10.1164/ajrccm.157.6.9711039.

Reference Type BACKGROUND
PMID: 9620920 (View on PubMed)

Ozick LA, Jacob L, Comer GM, Lee TP, Ben-Zvi J, Donelson SS, Felton CP. Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients. Am J Gastroenterol. 1995 Nov;90(11):1978-80.

Reference Type BACKGROUND
PMID: 7485004 (View on PubMed)

Wang JY, Lee LN, Yu CJ, Chien YJ, Yang PC; Tami Group. Factors influencing time to smear conversion in patients with smear-positive pulmonary tuberculosis. Respirology. 2009 Sep;14(7):1012-9. doi: 10.1111/j.1440-1843.2009.01598.x. Epub 2009 Jul 30.

Reference Type BACKGROUND
PMID: 19659516 (View on PubMed)

Shakya R, Rao BS, Shrestha B. Incidence of hepatotoxicity due to antitubercular medicines and assessment of risk factors. Ann Pharmacother. 2004 Jun;38(6):1074-9. doi: 10.1345/aph.1D525. Epub 2004 Apr 30.

Reference Type BACKGROUND
PMID: 15122004 (View on PubMed)

Chen CJ, Yang HI. Natural history of chronic hepatitis B REVEALed. J Gastroenterol Hepatol. 2011 Apr;26(4):628-38. doi: 10.1111/j.1440-1746.2011.06695.x.

Reference Type BACKGROUND
PMID: 21323729 (View on PubMed)

Lee MH, Yang HI, Jen CL, Lu SN, Yeh SH, Liu CJ, You SL, Sun CA, Wang LY, Chen WJ, Chen CJ; R.E.V.E.A.L.-HCV Study Group. Community and personal risk factors for hepatitis C virus infection: a survey of 23,820 residents in Taiwan in 1991-2. Gut. 2011 May;60(5):688-94. doi: 10.1136/gut.2010.220889. Epub 2010 Nov 10.

Reference Type BACKGROUND
PMID: 21068131 (View on PubMed)

Wang JY, Liu CH, Hu FC, Chang HC, Liu JL, Chen JM, Yu CJ, Lee LN, Kao JH, Yang PC. Risk factors of hepatitis during anti-tuberculous treatment and implications of hepatitis virus load. J Infect. 2011 Jun;62(6):448-55. doi: 10.1016/j.jinf.2011.04.005. Epub 2011 Apr 28.

Reference Type BACKGROUND
PMID: 21570123 (View on PubMed)

Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology. 2003 Apr;37(4):924-30. doi: 10.1053/jhep.2003.50144.

Reference Type BACKGROUND
PMID: 12668988 (View on PubMed)

Lee HC, Suh DJ, Ryu SH, Kim H, Shin JW, Lim YS, Chung YH, Lee YS. Quantitative polymerase chain reaction assay for serum hepatitis B virus DNA as a predictive factor for post-treatment relapse after lamivudine induced hepatitis B e antigen loss or seroconversion. Gut. 2003 Dec;52(12):1779-83. doi: 10.1136/gut.52.12.1779.

Reference Type BACKGROUND
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Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epler GR. Isoniazid-associated hepatitis in 114 patients. Gastroenterology. 1975 Aug;69(2):289-302.

Reference Type BACKGROUND
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Other Identifiers

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NTUH-IRB-201109046MB

Identifier Type: -

Identifier Source: org_study_id