Adefovir Dipivoxil For The Treatment Of Patients With Chronic Hepatitis B Related Advanced Fibrosis Or Cirrhosis
Condition: Hepatitis B, Chronic; Cirrhosis; Fibrosis; Chronic Hepatitis B
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic; Liver Cirrhosis; Fibrosis
Intervention: adefovir dipivoxil
Intervention description: 10mg once daily
Intervention MeSH terms: Adefovir; Adefovir dipivoxil
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 155.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cirrhosis; Advanced Fibrosis; Chronic Hepatitis B; Adefovir Dipivoxil

Summary:

      This 36-month open-label study of adefovir dipivoxil investigates the clinical benefits of
      the therapy in chronic hepatitis B patients with advanced fibrosis or cirrhosis confirmed
      with biopsy. Primary endpoint is histological improvement defined as a decrease of Ishak
      Fibrosis Score by one point or more from baseline at Month 36 of adefovir dipivoxil
      treatment. Approximately 150 patients will be recruited in study centres in the Asia Pacific
      area. The patients are offered 36 months of open label adefovir dipivoxil treatment, with
      assessments every three months, after which there is a 6-month post study treatment follow-up
      prior to study completion. After the 36 months of study treatment, it is likely that the
      patient will benefit from continued treatment with adefovir dipivoxil. If this is the case in
      the investigators clinical judgement, the investigator should ensure that a routine
      prescription is available in a timely manner, and that no unnecessary interruption in
      treatment occurs.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female patients ≥ 18 years of age

          -  A female is eligible to enter and participate in this study if she is of: a)
             non-childbearing potential (ie. Physiologically incapable of becoming pregnant,
             including any female who is pre-menarchal or post-menopausal); b) child-bearing
             potential with a negative serum pregnancy test at screen, and agrees to one of the
             following: -complete abstinence from intercourse from 2 weeks prior to administration
             of the study drug, throughout the study, and for a time interval after completion or
             premature discontinuation from the study to account for elimination of the
             investigational drug, (a minimum of 5 half-lives or longer if the pharmacodynamic
             profile of the investigational drug warrants a longer time period); or, -Female
             sterilization; or -Sterilization of male partner; or -Implants of levonorgestrel; or,
             -Injectable progestogen; or -Oral contraceptive (combined or progestogen only); or,
             -Any intrauterine device (IUD) with published data showing that the lowest expected
             failure rate is less that 1% per year (not all IUDs meet this criterion); or, -Any
             other methods with published data showing that the lowest expected failure rate for
             that method is less than 1% per year; or, -Barrier method only if used in combination
             with any of the above acceptable methods.

          -  Documented chronic hepatitis B infection determined by presence of serum HBsAg for at
             least 6 months (positive once at least 6 months before screening and at time of
             screening visit.)

          -  Positive HBV DNA plasma assay with screening value ≥ 1 x 10^5 copies /mL. (Roche COBAS
             AMPLICOR TM HBV Monitor Test, LLOD <300 copies/mL )

          -  Adequate renal function defined as serum creatinine ≤1.5 mg/dL (≤130 µmol/L).

          -  Willing and able to undergo two liver biopsies (prior to dosing, and after 36 months
             of therapy). The study baseline liver biopsy can be the most recent liver biopsy taken
             within 6 months of enrollment, as long as the biopsy was taken 6 months or more after
             the completion of any interferon or 3 months or more after completion of any antiviral
             treatment (eg. famciclovir, lamivudine etc.), and the patient has not had interferon
             therapy or any antiviral therapy between the biopsy and screening.

          -  Liver biopsy showing advance fibrosis/cirrhosis (Ishak fibrosis score ≥4). The slides
             must be available for review by an independent histopathologist.

          -  Availability and willingness of the subject to provide written informed consent per
             ICH/GCP and local Guidelines.

        Exclusion Criteria:

          1. ALT >10XULN at screening

          2. Child-Pugh Score ≥ 7

          3. History of acute exacerbation leading to transient decompensation

          4. Co-infections with HIV, HCV or HDV. Note: Patients who are anti-HCV seropositive and
             in whom HCV RNA is undetectable are considered to be HCV seropositive and will not be
             eligible for enrollment.

          5. Any of the following laboratory parameter within 4 weeks prior to study entry:
             -Haemoglobin <8.0 g/dL, -Absolute neutrophil count (ANC) < 1.5 x 10^9/L, -Platelet
             count ≤50 x 10^9/L, -Pancreatic amylase and/or lipase >2 x ULN

               -  Screening alpha-fetoprotein (AFP) value >50 ng/mL

               -  Clinical, ultrasonographic or radiologic evidence of hepatic mass suggestive of
                  hepatocellular carcinoma.

               -  Significant concurrent medical and/or psychiatric conditions other than hepatitis
                  B that in the opinion of the investigators might interfere with patient's
                  treatment, assessment or compliance according to study requirement, such as
                  malignancy, congestive heart failure, renal failure, chronic pancreatitis,
                  diabetes mellitus with poor control and alcoholism.

               -  Any of the following medications with 2 months prior to study entry (or the
                  expectation that subject will receive these during the course of the study):
                  -Nephrotoxic medication (eg aminoglycosides, amphotericin B, vancomycin,
                  cidofovir, foscarnet, cisplatin, pentamidine) or competitors or renal excretion
                  (eg probenecid, sulfinpyrazone), -Hepatotoxic medication (eg anabolic
                  steroids,ketoconazole, itraconazole, isoniazid, rifampin, rifabutin).

               -  Treatment with immunosuppressive/immunomodulatory agents (including interferon
                  and corticosteroids) within 6 months prior to study entry.

               -  Presence of other causes of liver disease (ie. hemochromatosis, Wilson's disease,
                  alcoholic liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis,
                  alpha-1 antitrypsin deficiency).

               -  A history of liver transplantation /planned for liver transplantation.

               -  Pregnancy (or lactation) or , in subjects capable of bearing children,
                  inability/unwillingness to practice adequate contraception.

               -  Females of child-bearing potential (post-puberty) willing or unable to have
                  pregnancy testing at any study visit.

               -  History of hypersensitivity to nucleoside and/or nucleotide analogues.

               -  Concurrent participation in another clinical trial in which the subject is or
                  will be exposed to another investigational or a non-investigational drug or
                  device within 30 days of the screening visit.