Clinical trial NCT00226447: Different Regimens of Pegylated Interferon and Lamivudine Combination Therapy in Chronic Hepatitis B Patients
Official title: A Study on the Viral Kinetics of Different Regimens of Pegylated Interferon and Lamivudine Combination Therapy in HBeAg Positive Chronic Hepatitis B
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Hepatitis B
Keywords: Chronic Hepatitis B
Pegylated Interferon
Lamivudine
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
name: GlaxoSmithKline
First posted: 2005-09-27
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim is to investigate the best treatment regime of PEG-Intron A and lamivudine combination in terms of viral clearance in chronic hepatitis B patients.

Detailed description: Chronic hepatitis B is a major cause of mortality and morbidity in Hong Kong and most Southeast Asian countries. The efficacy interferon-alfa (IFN-alfa) or lamivudine monotherapy is far from satisfactory with approximately 20% sustained viral response. Extended use of lamivudine is associated with the emergence of drug resistance mutants. As interferon is an immune modulator and lamivudine directly suppresses viral replication, it is therefore logical to combine the 2 drugs for more efficient viral clearance.

Previous studies on IFN-alfa and lamivudine combination treatment of chronic hepatitis B showed marginal benefit over lamivudine monotherapy. In these studies, lamivudine was either started 8 weeks prior to IFN-alfa or simultaneous with IFN-alfa. Recently, we have performed a study comparing the efficacy of polyethylene glycol-interferon alfa-2b (PEG-Intron A) and lamivudine versus lamivudine monotherapy for 1 year in the treatment of chronic hepatitis B. In our protocol, PEG-Intron A is started 8 weeks before the commencement of lamivudine, and PEG-Intron A is given for 32 weeks while lamivudine is given for a total of 52 weeks. Our published results suggested PEG-Intron A and lamivudine combination treatment is far superior to lamivudine monotherapy (end of treatment virological response 92% vs 20%, p=0.0015). We are not certain whether the benefit of PEG-Intron A and lamivudine combination in our study is due to our staggered regime, the superiority of PEG-Intron A over IFN-alfa, or both. The aim of this study is to investigate the best treatment regime of PEG-Intron A and lamivudine combination in terms of viral clearance.

Eligibility criteria: Inclusion Criteria:

* HBsAg positive for at least 6 months prior to screening
* Serum HBV-DNA \> 10\^6 copies per ml at screening
* Serum HBeAg positive at screening
* Abnormal ALT (1.3-10x upper limit normal) within one month prior to entry
* Compensated liver disease with the following minimum criteria:

  1. Hemoglobin within range \& not less than 10% from lower normal limit
  2. WBC \>= 4,000/mm3
  3. Platelets \>= 100,000/mm3
  4. Bilirubin normal (except for Gilbert's disease).
  5. Albumin stable and normal
* Serum creatinine normal or not more than 10% above the upper normal limit
* Thyroid Stimulating Hormone (TSH) within normal limits (Patients requiring medication to maintain TSH levels in the normal range are eligible if all other inclusion/exclusion criteria are met.)
* Alfa-fetoprotein in normal range (obtained within the previous year, or if elevated and \< 500 ng/ml with a negative ultrasound for hepatocellular carcinoma at screening).
* Written informed consent

Exclusion Criteria:

* Co-infection with hepatitis C virus and/or HIV
* Evidence or history of decompensated liver disease

  1. Child's B cirrhosis
  2. Ascites, bleeding varices, spontaneous encephalopathy
  3. Hypersplenism (hemoglobin, white cell count, platelet outside inclusion criteria)
  4. Coagulopathy (PT \> 13 sec)
* Any known pre-existing medical condition that could interfere with the patient's participation in and completion of the treatment such as:
* Pre-existing psychiatric condition, especially severe depression, or a history of severe psychiatric disorder.
* Patients on anti-depressant therapy are excluded
* CNS trauma or active seizure disorders requiring medication
* Poorly controlled diabetes mellitus
* Immunologically mediated disease (e.g., inflammatory bowel disease (Crohn's disease, ulcerative colitis, idiopathic thrombocytopenic purpura, lupus erythematous, autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis).
* Clinical gout
* ANA \> 1:320
* documentation that women of childbearing potential are using contraception. A serum pregnancy test obtained within two weeks prior to initiation of treatment must be negative. Female patients must not be breast feeding.
* Any known history of hypersensitivity to nucleoside analogues or interferon
* Previous use of interferon, lamivudine, immunosuppressive drugs or corticosteroid
* Subjects with clinically significant retinal abnormality
* Substance abuse, such as alcohol (\>80 g/day), iv drugs and inhaled drugs. If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 2 years. Subjects receiving methadone within the past 2 years are also excluded.
* Subjects not willing to be counseled/abstain from the consumption of alcohol

Primary outcomes:
measure: HBV DNA reduction at week 52
Secondary outcomes:
measure: Normalization of ALT & negative HBV DNA at EOT, negative HBV DNA at EOT & 24 weeks after cessation of treatment, normalization of ALT at the end of treatment and 24 weeks after the cessation of treatment, Safety of treatment
Other outcomes:
Locations:
city: Hong Kong SAR
country: China
facility: Cheng Suen Man Shook Hepatitis Center, Institute of Digestive Disease, The Chinese University of Hong Kong, Prince of Wales Hospital
Study officials:
affiliation: Chinese University of Hong Kong
name: Henry LY Chan, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray DF. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998 Jul 9;339(2):61-8. doi: 10.1056/NEJM199807093390201.
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