Trial of Lamivudine Treatment in HBeAg Negative Chronic Hepatitis B Patients (in Asia)

Chronic Hepatitis B Clinical Trial

Official title:

A Randomised, Double-Blinded, Placebo-Controlled Trial of Lamivudine Treatment in HBeAg Negative Chronic Hepatitis B Patients (in Asia)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00338780
• Other study ID #: NUC30934
• Status: Completed
• Phase: Phase 4
• First received: June 19, 2006
• Last updated: October 27, 2006
• Start date: November 2000
• Est. completion date: January 2005

Study information

• Verified date: October 2006
• Source: Chinese University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Health authority: Hong Kong: Department of Health
• Study type: Interventional

Clinical Trial Summary

The aim is to investigate whether Lamivudine 100mg daily is effective in the long term treatment of HBeAg negative chronic HBV infected patients with active liver disease in Asia

Description:

Recent studies have proved lamivudine a very potent antiviral drug in suppressing viral replication and improving hepatic necro-inflammation with minimal adverse effects in HBeAg positive chronic hepatitis B patients. The efficacy of lamivudine in HBeAg positivce Asian patients has been weel established. However, the evidence in HBeAg negative patients is limited.

In the absence of HBeAg seroconversion, guidance on the clinical management of HBeAg negative hepatitis B patitents treated with lamivudine and data on the efficacy of lamivudine in controlling pre-core HBV disease long-term is still needed. Existing data in HBeAg negative/ HBV DNA positive HBV demonstrate clear and statisticallysignificant serological benefit of lamivudine over placebo during treatment. Limited sustained response was observed post-treatment following a one year treatment period. Whether these results can be applied to patients in Asia is uncertain. This study is therefore intended to further assess te efficacy profile over an extended treatment period in the Asian population.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 0
• Est. completion date: January 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age=>18 years

• HBsAg positive and HBeAg negative for at least 6 months prior to screening

• Serum HBV-DNA postiviet, HBeAg negative and HBeAb positive at the same timepoint on at least one occasion during the last 6 months

• ALT >1.5 to 10 x upper limit of normal for at least two occasions within the previous 6 months and at screening, or ALT > upper limit normal and with at least one biochemical flare-up (ALT > 200IU/l) in the last 12 months.

• Informed writted consent

• Liver biopsy material/ slides taken within the previous 12 months, and at least 5 months after any previous antiviral treatment which show evidence of active liver disease (ie. evidence of necroinflammatory activity)

• Written informed consent

Exclusion Criteria:

• Hepatocellular carcinoma

• ALT > 10xULN at screening or history of acute exacerbation leading to transient decompensation

• Serum hepatitis C, hepatitis D or HIV

• Decompensated liver desease as indicated by any of the following: serum bilirubin >3mg/dL, prothrombin time >=2 seconds prolonged above upper limit of reference range, serum albumin <28g/L, history of variceal haemorrhage, presence of intractable ascites at the screening assessment.

• Encepalopathy

• Planned for liver transplantation or previous liver transplantation

• Evidence of autoimmune hepatitis

• Amylase and/ or lipase > 2 times upper limit of reference range

• Serum creatinine >1.5 times upper limit of reference range

• Haemoglobin < 11g/dL

• WBC count <3x10^9/L

• Platelets <100x10^9

• Serious concurrent medical illness other than hepatitis B

• Use of immunosuppressive therapy, immunomodylatory therapy or chronic antiviral thgerpay with other agents within the previous 6 months or during the study

• Previous treatment with lamivudine or famciclovir within the last 6 months

• History of hypersensitivity to nucleoside analogues

• Women of childbearing potential not practising adequate contraception

• Pregnancy or lactation

• Receipt of any investigational drug within 30 days of the first dose of study drug

• Child-Pugh class B or C cirrhosis

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Lamivudine/ Placebo 100mg daily

Locations

Country	Name	City	State
China	Cheng Suen Man Shook Hepatitis Center, Institute of Digestive Disease, The Chinese University of Hong Kong, Prince of Wales Hospital	Hong Kong SAR

Sponsors (2)

Lead Sponsor	Collaborator
Chinese University of Hong Kong	GlaxoSmithKline

Country where clinical trial is conducted

China, 

References & Publications (15)

Brunetto MR, Giarin MM, Oliveri F, Chiaberge E, Baldi M, Alfarano A, Serra A, Saracco G, Verme G, Will H, et al. Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4186-90. — View Citation

Chan HL, Hussain M, Lok AS. Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology. 1999 Mar;29(3):976-84. — View Citation

Chan HLY, Hui Y, Ching JYL, Leung NWY, Chan FKL, Sung JJY. Can we predict disease activity in chronic hepatitis B virus (CHB) infected patients with negative HBeAg. Gastroenterology 1999; 116: A1195

Chan HLY, Leung NY, Lau TCM, Wong ML, Sung JJY. Comparison of three different hepatitis B virus (HBV) DNA assays in monitoring of anti-viral therapy. Hepatology 1999 (in press)

Chan HLY,Ghany MC, Lok ASF. Hepatitis B. In Schiff ER, Sorrell MF, Madrey WC, Eds. Schiff's Deseases of the LIver, 8th ed. Lippincott-Raven Publishers, New York, 1998:757-92

Chu CM, Yeh CT, Chiu CT, Sheen IS, Liaw YF. Precore mutant of hepatitis B virus prevails in acute and chronic infections in an area in which hepatitis B is endemic. J Clin Microbiol. 1996 Jul;34(7):1815-8. — View Citation

Krajden M, Minor J, Cork L, Comanor L. Multi-measurement method comparison of three commercial hepatitis B virus DNA quantification assays. J Viral Hepat. 1998 Nov;5(6):415-22. — View Citation

Lai VC, Guan R, Wood ML, Lo SK, Yuen MF, Lai CL. Nucleic acid-based cross-linking assay for detection and quantification of hepatitis B virus DNA. J Clin Microbiol. 1999 Jan;37(1):161-4. — View Citation

Laras A, Koskinas J, Avgidis K, Hadziyannis SJ. Incidence and clinical significance of hepatitis B virus precore gene translation initiation mutations in e antigen-negative patients. J Viral Hepat. 1998 Jul;5(4):241-8. — View Citation

Maynard JE. Hepatitis B: global importance and need for control. Vaccine. 1990 Mar;8 Suppl:S18-20; discussion S21-3. Review. — View Citation

Tassopoulos NC, Volpes R, Pastore G, Heathcote J, Buti M, Goldin RD, Hawley S, Barber J, Condreay L, Gray DF. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology. 1999 Mar;29(3):889-96. — View Citation

ter Borg F, ten Kate FJ, Cuypers HT, Leentvaar-Kuijpers A, Oosting J, Wertheim-van Dillen PM, Honkoop P, Rasch MC, de Man RA, van Hattum J, Chamuleau RA, Reesink HW, Jones EA. Relation between laboratory test results and histological hepatitis activity in individuals positive for hepatitis B surface antigen and antibodies to hepatitis B e antigen. Lancet. 1998 Jun 27;351(9120):1914-8. Erratum in: Lancet 1999 Jul 17;354(9174):258. Lancet 1998 Jul 25;352(9124):328. — View Citation

Tu H, Li PY, Wen YM. Anti-HBe titre in patients infected with wild-type and e-minus variant of hepatitis B virus. Res Virol. 1996 Jan-Feb;147(1):39-43. — View Citation

Tu H, Xiong SD, Trepo C, Wen YM. Frequency of hepatitis B virus e-minus mutants varies among patients from different areas of China. J Med Virol. 1997 Feb;51(2):85-9. — View Citation

Zaaijer HL, ter Borg F, Cuypers HT, Hermus MC, Lelie PN. Comparison of methods for detection of hepatitis B virus DNA. J Clin Microbiol. 1994 Sep;32(9):2088-91. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients with complete response (normalisation of LAT, ie. <1xULN and disappearance of HBV DNA, lower limit of detection), at MOnth 24
Secondary	Proportion of patients with partial response
Secondary	Histological improvement at month 24
Secondary	Proportion of patients with complete response post-treatment (at Month 30)
Secondary	Proportion of patinets with partial response post-treatment (at Month 30)
Secondary	Progression of fibrosis
Secondary	Progression of fibrosis to cirrhosis
Secondary	HBsAg seroconversion
Secondary	Safety of treatment