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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00347009
• Collaborator: (none)
• Enrollment: 155
• Locations: 12
• Arm: 1
• Duration (Months): 52
• Patients Per Site: 12.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis B, Chronic; Cirrhosis; Fibrosis; Chronic Hepatitis B	Drug: adefovir dipivoxil	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 155 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (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.
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Other: Adefovir Dipivoxil 10mg once daily in patients with CHB related advanced fibrosis/cirrhosis.	Drug: adefovir dipivoxil; 10mg once daily

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Histologic Improvement at Month 36 (Intent-to-Treat Population) [Screening and Month 36]

   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.

2. Number of Participants With Histologic Improvement at Month 36 (Per Protocol Population) [Screening and Month 36]

   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

1. Number of Participants With a Reduction From Baseline in the Child-Pugh Score by 2 Points or More at Months 12, 24, and 36 [Baseline and Months 12, 24, and 36]

   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).

2. Number of Participants With a Reduction From Screening of at Least 2 Points in the Knodell Necroinflammation Score at Month 36 [Screening and Month 36]

   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.

3. Change From Baseline in Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Level at Months 12, 24, and 36 [Baseline and Months 12, 24, and 36]

   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.

4. Number of Participants Achieving Virological Response (HBV DNA Level <= 10^3 Copies/ml) at Months 12, 24, and 36 [Months 12, 24, and 36]

   Virological response was defined as an HBV DNA level <= 10^3 copies/ml.

5. Number of Participants Achieving Virological Response (HBV DNA Level <= 10^4 Copies/ml) at Months 12, 24, and 36 [Months 12, 24, and 36]

   Virological response was defined as an HBV DNA level <= 10^4 copies/ml.

6. Number of Participants With Undetectable HBV DNA at Months 12, 24, and 36 [Months 12, 24, and 36]

   Undetectable HBV DNA was defined as an HBV DNA level below the lower limit of detection (LLOD) of 300 copies/ml.

7. Number of Participants With Virological Breakthrough at Months 12, 24, and 36 [Months 12, 24, and 36]

   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.

8. Number of Participants With Alanine Aminotransferase (ALT) Normalization at Months 12, 24, and 36 [Months 12, 24, and 36]

   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.

9. 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 [Baseline and Months 12, 24, and 36]

   HBeAg positive was defined as the presence of a detectable level of HBeAg.

10. Number of Participants Who Were HBeAg Positive at Baseline, With HBeAg Seroconversion at Months 12, 24, and 36 [Baseline and Months 12, 24, and 36]

    HBeAg seroconversion was defined as a decrease in HBeAg to undetectable levels and a gain of detectable levels of Hepatitis B envelope antibody (HBeAb).

11. 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 [Baseline and Months 12, 24, and 36]

    HBsAg positive was defined as the presence of a detectable level of HBsAg.

12. Number of Participants Who Were HBsAg Positive at Baseline, With HBsAg Seroconversion at Months 12, 24, and 36 [Baseline and Months 12, 24, and 36]

    HBsAg seroconversion was defined as a decrease in HBsAg to undetectable levels and a gain of detectable levels of Hepatitis B surface antibody (HBsAb).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Pokfulam		Hong Kong
2	GSK Investigational Site	Daegu		Korea, Republic of	700-712
3	GSK Investigational Site	Pusan		Korea, Republic of	602-739
4	GSK Investigational Site	Seoul		Korea, Republic of	120-752
5	GSK Investigational Site	Seoul		Korea, Republic of	135-710
6	GSK Investigational Site	Seoul		Korea, Republic of	137-701
7	GSK Investigational Site	Sungnam-City		Korea, Republic of	463-712
8	GSK Investigational Site	Singapore		Singapore	169608
9	GSK Investigational Site	Kaohsiung		Taiwan	833
10	GSK Investigational Site	Taipei		Taiwan	100
11	GSK Investigational Site	Taipei		Taiwan	114
12	GSK Investigational Site	Ho Chi Minh City		Vietnam

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00347009
• Other Study ID Numbers: ADF104070
• First Posted: Jul 4, 2006
• Last Update Posted: Jun 4, 2012
• Last Verified: Mar 1, 2011

• Keywords provided by GlaxoSmithKline: Cirrhosis; Advanced Fibrosis; Chronic Hepatitis B; Adefovir Dipivoxil
• Additional relevant MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic; Liver Cirrhosis; Fibrosis; Adefovir; Adefovir dipivoxil

Study Results

Participant Flow

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Period Title: Overall Study
STARTED	155
COMPLETED	128
NOT COMPLETED	27

Baseline Characteristics

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Overall Participants	155
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	47.7 (9.5)
Sex: Female, Male (Count of Participants)
Female	39 25.2%
Male	116 74.8%
Race/Ethnicity, Customized (participants) [Number]
Asian	155 100%
Other	0 0%
Time since Diagnosis of Chronic Hepatitis B (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.29 (8.40)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Histologic Improvement at Month 36 (Intent-to-Treat Population)
Description	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.
Time Frame	Screening and Month 36

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants who received at least one dose of study medication, regardless of whether the participants completed the planned duration of the study

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Number [participants]	52 33.5%

2. Secondary Outcome

Title	Number of Participants With a Reduction From Baseline in the Child-Pugh Score by 2 Points or More at Months 12, 24, and 36
Description	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).
Time Frame	Baseline and Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	0 0%
Month 24	2 1.3%
Month 36	1 0.6%

3. Secondary Outcome

Title	Number of Participants With a Reduction From Screening of at Least 2 Points in the Knodell Necroinflammation Score at Month 36
Description	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.
Time Frame	Screening and Month 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Number [participants]	64 41.3%

4. Secondary Outcome

Title	Change From Baseline in Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Level at Months 12, 24, and 36
Description	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.
Time Frame	Baseline and Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	-4.557 (1.639)
Month 24	-4.536 (2.115)
Month 36	-4.454 (2.436)

5. Secondary Outcome

Title	Number of Participants Achieving Virological Response (HBV DNA Level <= 10^3 Copies/ml) at Months 12, 24, and 36
Description	Virological response was defined as an HBV DNA level <= 10^3 copies/ml.
Time Frame	Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	91 58.7%
Month 24	99 63.9%
Month 36	102 65.8%

6. Secondary Outcome

Title	Number of Participants Achieving Virological Response (HBV DNA Level <= 10^4 Copies/ml) at Months 12, 24, and 36
Description	Virological response was defined as an HBV DNA level <= 10^4 copies/ml.
Time Frame	Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	110 71%
Month 24	114 73.5%
Month 36	109 70.3%

7. Secondary Outcome

Title	Number of Participants With Undetectable HBV DNA at Months 12, 24, and 36
Description	Undetectable HBV DNA was defined as an HBV DNA level below the lower limit of detection (LLOD) of 300 copies/ml.
Time Frame	Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	83 53.5%
Month 24	95 61.3%
Month 36	90 58.1%

8. Secondary Outcome

Title	Number of Participants With Virological Breakthrough at Months 12, 24, and 36
Description	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.
Time Frame	Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	3 1.9%
Month 24	16 10.3%
Month 36	21 13.5%

9. Secondary Outcome

Title	Number of Participants With Alanine Aminotransferase (ALT) Normalization at Months 12, 24, and 36
Description	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.
Time Frame	Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	87 56.1%
Month 24	91 58.7%
Month 36	91 58.7%

10. Secondary Outcome

Title	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
Description	HBeAg positive was defined as the presence of a detectable level of HBeAg.
Time Frame	Baseline and Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	17 11%
Month 24	27 17.4%
Month 36	28 18.1%

11. Secondary Outcome

Title	Number of Participants Who Were HBeAg Positive at Baseline, With HBeAg Seroconversion at Months 12, 24, and 36
Description	HBeAg seroconversion was defined as a decrease in HBeAg to undetectable levels and a gain of detectable levels of Hepatitis B envelope antibody (HBeAb).
Time Frame	Baseline and Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	10 6.5%
Month 24	18 11.6%
Month 36	15 9.7%

12. Secondary Outcome

Title	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
Description	HBsAg positive was defined as the presence of a detectable level of HBsAg.
Time Frame	Baseline and Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	0 0%
Month 24	0 0%
Month 36	0 0%

13. Secondary Outcome

Title	Number of Participants Who Were HBsAg Positive at Baseline, With HBsAg Seroconversion at Months 12, 24, and 36
Description	HBsAg seroconversion was defined as a decrease in HBsAg to undetectable levels and a gain of detectable levels of Hepatitis B surface antibody (HBsAb).
Time Frame	Baseline and Months 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	155
Month 12	0 0%
Month 24	0 0%
Month 36	0 0%

14. Primary Outcome

Title	Number of Participants With Histologic Improvement at Month 36 (Per Protocol Population)
Description	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.
Time Frame	Screening and Month 36

Outcome Measure Data

Analysis Population Description

Per Protocol (PP) Population: all participants in the ITT Population with interpretable liver biopsies at baseline and at the 36-month follow-up visit and without major violations of the protocol

Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
Measure Participants	114
Number [participants]	52 33.5%

Adverse Events

Time Frame	Screening to Month 42
Adverse Event Reporting Description	Adverse events (AEs) were reported spontaneously by the participant or determined by the investigator through questioning the participant in a general way; the severity, outcome and cause of each reported AE were assessed and recorded.
Arm/Group Title	Adefovir Dipivoxil 10 Milligrams (mg)
Arm/Group Description	Adefovir Dipivoxil 10 mg, once daily
All Cause Mortality
	Adefovir Dipivoxil 10 Milligrams (mg)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Adefovir Dipivoxil 10 Milligrams (mg)
	Affected / at Risk (%)	# Events
Total	20/155 (12.9%)
Gastrointestinal disorders
Duodenal ulcer	1/155 (0.6%)
Duodenal ulcer haemorrhage	1/155 (0.6%)
Inguinal hernia	1/155 (0.6%)
Oesophageal obstruction	1/155 (0.6%)
Hepatobiliary disorders
Bile duct stone	1/155 (0.6%)
Cholangitis	1/155 (0.6%)
Jaundice cholestatic	1/155 (0.6%)
Infections and infestations
Acute sinusitis	1/155 (0.6%)
Appendicitis	1/155 (0.6%)
Hepatitis B	1/155 (0.6%)
Periorbital cellulitis	1/155 (0.6%)
Pneumonia bacterial	1/155 (0.6%)
Injury, poisoning and procedural complications
Drug exposure during pregnancy	1/155 (0.6%)
Excoriation	1/155 (0.6%)
Femur fracture	1/155 (0.6%)
Ribs fracture	1/155 (0.6%)
Wrist fracture	1/155 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic neoplasm malignant	7/155 (4.5%)
Hepatic neoplasm malignant recurrent	2/155 (1.3%)
Cerebellar tumour	1/155 (0.6%)
Nervous system disorders
Hepatic encephalopathy	1/155 (0.6%)
Presyncope	1/155 (0.6%)
Psychiatric disorders
Depression	1/155 (0.6%)
Suicide attempt	1/155 (0.6%)
Renal and urinary disorders
Diabetic nephropathy	1/155 (0.6%)
Respiratory, thoracic and mediastinal disorders
Haemothorax	2/155 (1.3%)
Pleural effusion	1/155 (0.6%)
Other (Not Including Serious) Adverse Events
	Adefovir Dipivoxil 10 Milligrams (mg)
	Affected / at Risk (%)	# Events
Total	99/155 (63.9%)
Gastrointestinal disorders
Abdominal pain upper	15/155 (9.7%)
Diarrhoea	11/155 (7.1%)
Abdominal distension	10/155 (6.5%)
Gastritis	9/155 (5.8%)
General disorders
Fatigue	13/155 (8.4%)
Infections and infestations
Upper respiratory tract infection	40/155 (25.8%)
Investigations
Alanine aminotransferase increased	26/155 (16.8%)
Aspartate aminotransferase increased	23/155 (14.8%)
Hepatitis B DNA increased	9/155 (5.8%)
Alpha 1 fetoprotein increased	8/155 (5.2%)
Musculoskeletal and connective tissue disorders
Back pain	12/155 (7.7%)
Nervous system disorders
Headache	8/155 (5.2%)
Psychiatric disorders
Insomnia	8/155 (5.2%)
Respiratory, thoracic and mediastinal disorders
Cough	16/155 (10.3%)
Oropharyngeal pain	9/155 (5.8%)
Skin and subcutaneous tissue disorders
Pruritus	10/155 (6.5%)
Vascular disorders
Hypertension	8/155 (5.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.