Adefovir Dipivoxil For The Treatment Of Patients With Chronic Hepatitis B Related Advanced Fibrosis Or Cirrhosis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00347009
First received: June 30, 2006
Last updated: May 31, 2012
Last verified: March 2011
  Purpose

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.


Condition Intervention Phase
Hepatitis B, Chronic
Cirrhosis
Fibrosis
Chronic Hepatitis B
Drug: adefovir dipivoxil
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Study of Adefovir Dipivoxil for the Treatment of Patients With Chronic Hepatitis B Related Advanced Fibrosis or Cirrhosis.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants With Histologic Improvement at Month 36 (Intent-to-Treat Population) [ Time Frame: Screening and Month 36 ] [ Designated as safety issue: No ]
    The Ishak fibrosis score is a scoring system (ranging from 0 to 6) that measures the degree of fibrosis (scarring) of the liver, which is caused by chronic necroinflammation (an inflammatory process in the liver including or leading to death of liver cells). A score of 0 represents no fibrosis, and a score of 6 represents established cirrhosis. Participants were classified as improved if the Ishak fibrosis score at Month 36 was 1 or more points less from the Screening score.

  • Number of Participants With Histologic Improvement at Month 36 (Per Protocol Population) [ Time Frame: Screening and Month 36 ] [ Designated as safety issue: No ]
    The Ishak fibrosis score is a scoring system (ranging from 0 to 6) that measures the degree of fibrosis (scarring) of the liver, which is caused by chronic necroinflammation (an inflammatory process in the liver including or leading to death of liver cells). A score of 0 represents no fibrosis, and a score of 6 represents established cirrhosis. Participants were classified as improved if the Ishak fibrosis score at Month 36 was 1 or more points less from the Screening score.


Secondary Outcome Measures:
  • Number of Participants With a Reduction From Baseline in the Child-Pugh Score by 2 Points or More at Months 12, 24, and 36 [ Time Frame: Baseline and Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    The Child-Pugh score (modified version for scoring prothrombin time against reference range) was used in the study to assess the prognosis of chronic liver disease, mainly cirrhosis. The score employs five clinical measures of liver disease: encephalopathy, ascites, albumin, prothrombin time, and bilirubin. Each measure is scored on a scale of 1-3, with 1 being normal and 3 indicating most severe derangement. The total score for the Child-Pugh assessment was calculated as the sum of the 5 contributing scores, with a score range of 5 (best prognosis) to 15 (worst prognosis).

  • Number of Participants With a Reduction From Screening of at Least 2 Points in the Knodell Necroinflammation Score at Month 36 [ Time Frame: Screening and Month 36 ] [ Designated as safety issue: No ]
    The Knodell scoring system, also called the Histologic Activity Index (HAI), classifies liver biopsy specimens according to scores into 4 categories of histologic features: (I) periportal and/or bridging necrosis (scores from 0 to 10); (II) intralobular degeneration and focal necrosis (scores from 0 to 4); (III) portal inflammation (scores from 0 to 4); (IV) fibrosis (scores from 0 to 4). The Knodell necroinflammation score is the sum of scores from Parts I-III, hence a range of 0 to 18, and measures the degree of acute necroinflammatory activity in the liver.

  • Change From Baseline in Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Level at Months 12, 24, and 36 [ Time Frame: Baseline and Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    The levels of HBV DNA in serum were measured using the Amplicor Cobas assay by Roche Diagnostics (detection limit 300 copies/milliliter [ml]). Changes from baseline in the serum HBV DNA level at Months 12, 24 and 36 were calculated as Month 12 minus baseline, Month 24 minus baseline, and Month 36 minus baseline respectively. Change is reported in log10 units.

  • Number of Participants Achieving Virological Response (HBV DNA Level <= 10^3 Copies/ml) at Months 12, 24, and 36 [ Time Frame: Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    Virological response was defined as an HBV DNA level <= 10^3 copies/ml.

  • Number of Participants Achieving Virological Response (HBV DNA Level <= 10^4 Copies/ml) at Months 12, 24, and 36 [ Time Frame: Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    Virological response was defined as an HBV DNA level <= 10^4 copies/ml.

  • Number of Participants With Undetectable HBV DNA at Months 12, 24, and 36 [ Time Frame: Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    Undetectable HBV DNA was defined as an HBV DNA level below the lower limit of detection (LLOD) of 300 copies/ml.

  • Number of Participants With Virological Breakthrough at Months 12, 24, and 36 [ Time Frame: Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    Virological breakthrough was defined as an increase in serum HBV DNA levels by more than 1 log10 copies/ml from treatment nadir, i.e., the lowest HBV DNA value during the study.

  • Number of Participants With Alanine Aminotransferase (ALT) Normalization at Months 12, 24, and 36 [ Time Frame: Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    ALT levels were measured as part of the liver function tests. Participants with ALT normalization at each visit were defined as those with a value below the upper limit of the normal (ULN) range for ALT provided by that site at the respective visit.

  • Number of Participants Who Were Hepatitis B Envelope Antigen (HBeAg) Positive at Baseline and Developed Undetectable Levels of HBeAg at Months 12, 24, and 36 [ Time Frame: Baseline and Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    HBeAg positive was defined as the presence of a detectable level of HBeAg.

  • Number of Participants Who Were HBeAg Positive at Baseline, With HBeAg Seroconversion at Months 12, 24, and 36 [ Time Frame: Baseline and Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    HBeAg seroconversion was defined as a decrease in HBeAg to undetectable levels and a gain of detectable levels of Hepatitis B envelope antibody (HBeAb).

  • Number of Participants Who Were Hepatitis B Surface Antigen (HBsAg) Positive at Baseline and Developed Undetectable Levels of HBsAg at Months 12, 24, and 36 [ Time Frame: Baseline and Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    HBsAg positive was defined as the presence of a detectable level of HBsAg.

  • Number of Participants Who Were HBsAg Positive at Baseline, With HBsAg Seroconversion at Months 12, 24, and 36 [ Time Frame: Baseline and Months 12, 24, and 36 ] [ Designated as safety issue: No ]
    HBsAg seroconversion was defined as a decrease in HBsAg to undetectable levels and a gain of detectable levels of Hepatitis B surface antibody (HBsAb).


Enrollment: 155
Study Start Date: May 2005
Study Completion Date: September 2009
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Adefovir Dipivoxil
10mg once daily in patients with CHB related advanced fibrosis/cirrhosis.
Drug: adefovir dipivoxil
10mg once daily
Other Name: adefovir dipivoxil

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00347009

Locations
Hong Kong
GSK Investigational Site
Pokfulam, Hong Kong
Korea, Republic of
GSK Investigational Site
Daegu, Korea, Republic of, 700-712
GSK Investigational Site
Pusan, Korea, Republic of, 602-739
GSK Investigational Site
Seoul, Korea, Republic of, 137-701
GSK Investigational Site
Seoul, Korea, Republic of, 135-710
GSK Investigational Site
Seoul, Korea, Republic of, 120-752
GSK Investigational Site
Sungnam-City, Korea, Republic of, 463-712
Singapore
GSK Investigational Site
Singapore, Singapore, 169608
Taiwan
GSK Investigational Site
Kaohsiung, Taiwan, 833
GSK Investigational Site
Taipei, Taiwan, 100
GSK Investigational Site
Taipei, Taiwan, 114
Vietnam
GSK Investigational Site
Ho Chi Minh City, Vietnam
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00347009     History of Changes
Other Study ID Numbers: ADF104070
Study First Received: June 30, 2006
Results First Received: September 20, 2010
Last Updated: May 31, 2012
Health Authority: Taiwan: Department of Health

Keywords provided by GlaxoSmithKline:
Cirrhosis
Advanced Fibrosis
Chronic Hepatitis B
Adefovir Dipivoxil

Additional relevant MeSH terms:
Hepatitis B
Hepatitis B, Chronic
Fibrosis
Hepatitis
Hepatitis A
Hepatitis, Chronic
Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Adefovir
Adefovir dipivoxil
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents

ClinicalTrials.gov processed this record on July 29, 2014