Trial Outcomes & Findings for Adefovir Dipivoxil For The Treatment Of Chinese Compensated Chronic Hepatitis B(CHB)Patients (NCT NCT00441974)

NCT ID: NCT00441974

Last Updated: 2009-10-20

Results Overview

HBV (Hepatitis B Virus) DNA level was tested by real-time Polymerase Chain Reaction at Week 48.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 1470 participants
• Primary outcome timeframe: Week 48
• Results posted on: 2009-10-20

Participant Flow

Participant milestones

Measure	10 mg Adefovir Dipivoxil Adefovir Dipivoxil (ADV) 10 mg tablets once daily for 48 weeks
Overall Study STARTED	1470
Overall Study COMPLETED	1342
Overall Study NOT COMPLETED	128

Reasons for withdrawal

Measure	10 mg Adefovir Dipivoxil Adefovir Dipivoxil (ADV) 10 mg tablets once daily for 48 weeks
Overall Study Adverse Event	6
Overall Study Consent Withdrawn	35
Overall Study Lost to Follow-up	80
Overall Study Protocol Violation	7

Baseline Characteristics

Adefovir Dipivoxil For The Treatment Of Chinese Compensated Chronic Hepatitis B(CHB)Patients

Baseline characteristics by cohort

Measure	10 mg Adefovir Dipivoxil n=1467 Participants Adefovir Dipivoxil (ADV) 10 mg tablets once daily for 48 weeks
Age Continuous	31.5 years STANDARD_DEVIATION 9.8 • n=93 Participants
Sex: Female, Male Female	291 Participants n=93 Participants
Sex: Female, Male Male	1176 Participants n=93 Participants
Race/Ethnicity, Customized Asian	1467 participants n=93 Participants

PRIMARY outcome

Timeframe: Week 48

Population: Intent-to-Treat (ITT) Population: all participants who actually received the study medication at least once.

HBV (Hepatitis B Virus) DNA level was tested by real-time Polymerase Chain Reaction at Week 48.

Outcome measures

Measure	HBeAg+ at Baseline n=1108 Participants Participants who had detectable HBeAg (Hepatitis B e Antigens) as measured by a local laboratory	HBeAg- at Baseline n=359 Participants Participants who had undetectable HBeAg as measured by a local laboratory	Total n=1467 Participants Total of HBeAg+ and HBeAg- participants
Number of Participants Achieving HBV DNA (Hepatitis B Virus Deoxyribonucleic Acid) <1000 Copies/Milliliter at Week 48 HBV DNA <1000 copies (cp)/mL	341 participants	243 participants	584 participants
Number of Participants Achieving HBV DNA (Hepatitis B Virus Deoxyribonucleic Acid) <1000 Copies/Milliliter at Week 48 HBV DNA >1000 cp/mL	767 participants	116 participants	883 participants

SECONDARY outcome

Timeframe: Week 48

Population: HBeAg positive chronic hepatitis B participants who underwent liver biopsy at Week 48

Histological improvement (defined as a ≥2 point reduction in the Knodell necroinflammation score without worsening fibrosis) was accessed by two pathologists in HBeAg-positive participants undergoing liver biopsy at baseline and week 48/withdrawal. Knodell/Histological Activity Index (HAI) score = combined scores for necrosis, inflammation, and fibrosis and is the sum of scores for periportal bridging necrosis (0-10: none=0, multilobular necrosis=10), intralobular degeneration and focal necrosis and portal inflammation (0-4: none=0, marked=4), and fibrosis (0-4: none=0, cirrhosis=4).

Outcome measures

Measure	HBeAg+ at Baseline n=71 Participants Participants who had detectable HBeAg (Hepatitis B e Antigens) as measured by a local laboratory	HBeAg- at Baseline Participants who had undetectable HBeAg as measured by a local laboratory	Total Total of HBeAg+ and HBeAg- participants
Number of HBeAg Positive Participants Achieving Histological Improvement at Week 48 Histological improvement	46 participants	—	—
Number of HBeAg Positive Participants Achieving Histological Improvement at Week 48 No histological improvement	25 participants	—	—

SECONDARY outcome

Timeframe: Baseline to Week 48

Population: HBeAg positive chronic hepatitis B participants who underwent liver biopsy at Week 48

A ranked assessment with the Knodell/HAI scoring system that represents the sum of scores for periportal bridging necrosis (0-10: none=0, moderate piecemeal necrosis plus bridging necrosis=5, multilobular necrosis=10); interlobular degeneration and focal necrosis (0-4: none=0, marked=4); portal inflammation (0-4: none=0, marked=4) and fibrosis (0-4: none=0, fibrous portal expansion=1, bridging fibrosis=3, cirrhosis=4) was carried out by two pathologists in the HBeAg positive participants who underwent liver biopsy at baseline and Week 48/withdrawal.

Outcome measures

Measure	HBeAg+ at Baseline n=71 Participants Participants who had detectable HBeAg (Hepatitis B e Antigens) as measured by a local laboratory	HBeAg- at Baseline Participants who had undetectable HBeAg as measured by a local laboratory	Total Total of HBeAg+ and HBeAg- participants
Ranked Assessment of Liver Histology in HBeAg Positive Participants From Baseline to Week 48 Knodell score at baseline	7.7 points on a scale Standard Deviation 3.9	—	—
Ranked Assessment of Liver Histology in HBeAg Positive Participants From Baseline to Week 48 Knodell score at Week 48/withdrawal	5.2 points on a scale Standard Deviation 2.6	—	—
Ranked Assessment of Liver Histology in HBeAg Positive Participants From Baseline to Week 48 Necroinflammation score at baseline	6.3 points on a scale Standard Deviation 3.2	—	—
Ranked Assessment of Liver Histology in HBeAg Positive Participants From Baseline to Week 48 Necroinflammation score at Week 48/withdrawal	3.6 points on a scale Standard Deviation 1.9	—	—
Ranked Assessment of Liver Histology in HBeAg Positive Participants From Baseline to Week 48 Fibrosis score at baseline	1.4 points on a scale Standard Deviation 1.0	—	—
Ranked Assessment of Liver Histology in HBeAg Positive Participants From Baseline to Week 48 Fibrosis score at Week 48/withdrawal	1.5 points on a scale Standard Deviation 0.9	—	—

SECONDARY outcome

Timeframe: Weeks 24 and 48

Population: Intent-to-Treat (ITT) Population: all participants who actually received the study medication at least once.

The HBV DNA level was tested in blood serum by real-time Polymerase Chain Reaction with the LLD (lower limit of detection) as 300 copies/milliliter (cp/mL) at screening, week 24, and week 48 in a central laboratory. The change in HBV DNA from screening to week 24 and week 48 was conducted.

Outcome measures

Measure	HBeAg+ at Baseline n=1108 Participants Participants who had detectable HBeAg (Hepatitis B e Antigens) as measured by a local laboratory	HBeAg- at Baseline n=359 Participants Participants who had undetectable HBeAg as measured by a local laboratory	Total Total of HBeAg+ and HBeAg- participants
Change From Screening in Median Serum HBV DNA at Weeks 24 and 48 Serum HBV DNA Change at Week 24	-4.1 log10 copies/milliliter Interval -9.4 to 2.8	-4.3 log10 copies/milliliter Interval -9.0 to 1.8	—
Change From Screening in Median Serum HBV DNA at Weeks 24 and 48 Serum HBV DNA Change at Week 48	-4.6 log10 copies/milliliter Interval -9.4 to 3.5	-4.6 log10 copies/milliliter Interval -9.0 to 1.6	—

SECONDARY outcome

Timeframe: Week 48

Population: Intent-to-Treat (ITT) Population: all participants who actually received the study medication at least once.

Elevated serum ALT levels are defined as serum ALT levels greater than the upper limit of the normal range (ULN), as determined using local laboratory ranges. ALT normalization was defined as ALT measurements at or below the ULN after a baseline value above the ULN.

Outcome measures

Measure	HBeAg+ at Baseline n=1108 Participants Participants who had detectable HBeAg (Hepatitis B e Antigens) as measured by a local laboratory	HBeAg- at Baseline n=359 Participants Participants who had undetectable HBeAg as measured by a local laboratory	Total Total of HBeAg+ and HBeAg- participants
Number of Participants Achieving ALT (Alanine Aminotransferase) Normalization at Week 48 ALT normalization	780 participants	258 participants	—
Number of Participants Achieving ALT (Alanine Aminotransferase) Normalization at Week 48 ALT non-normalization	328 participants	101 participants	—

SECONDARY outcome

Timeframe: Week 48

Population: Intent-to-Treat (ITT) Population: all HBeAg positive participants who actually received the study medication at least once

HBeAg loss and HBeAg seroconversion (HBeAg loss and HBeAb detected) were assessed in participants who were HBeAg positive at Weeks 0 and 48. Confirmed HBeAg loss was defined as undetectable HBeAg.

Outcome measures

Measure	HBeAg+ at Baseline n=1108 Participants Participants who had detectable HBeAg (Hepatitis B e Antigens) as measured by a local laboratory	HBeAg- at Baseline Participants who had undetectable HBeAg as measured by a local laboratory	Total Total of HBeAg+ and HBeAg- participants
Number of HBeAg Positive Participants Achieving HBeAg Loss and HBeAg Seroconversion at Week 48 HBeAg loss	289 participants	—	—
Number of HBeAg Positive Participants Achieving HBeAg Loss and HBeAg Seroconversion at Week 48 HBeAg seroconversion	151 participants	—	—

SECONDARY outcome

Timeframe: Week 48

Population: Intent-to-Treat (ITT) Population: all participants who actually received the study medication at least once.

Week 48 serum samples from participants, who reached a HBV DNA breakthrough or have HBV DNA≥5 log copies/mL at Weeks 24 and 48 were assessed for the development of ADV (Adefovir dipivoxil) mutation (N236T and A181V) in the HBV polymerase. Virologic breakthrough was defined as an increase in the level of HBV DNA 1 log10 copy/mL from Week 24 to Week 48. ADV-associated resistance was defined as participants with both virologic breakthrough and ADV mutation.

Outcome measures

Measure	HBeAg+ at Baseline n=1467 Participants Participants who had detectable HBeAg (Hepatitis B e Antigens) as measured by a local laboratory	HBeAg- at Baseline Participants who had undetectable HBeAg as measured by a local laboratory	Total Total of HBeAg+ and HBeAg- participants
Number of Participants With ADV-associated Resistance at Week 48 HBV DNA breakthrough	66 participants	—	—
Number of Participants With ADV-associated Resistance at Week 48 ADV-associated resistance	7 participants	—	—
Number of Participants With ADV-associated Resistance at Week 48 HBV DNA≥5 log copies/ml at Weeks 24 and 48	322 participants	—	—

Adverse Events

10 mg Adefovir Dipivoxil

Serious events: 18 serious events

Other events: 86 other events

Deaths: 0 deaths

Serious adverse events

Measure	10 mg Adefovir Dipivoxil Adefovir Dipivoxil (ADV) 10 mg tablets once daily for 48 weeks
Hepatobiliary disorders Hepatic mass	0.07% 1/1467
Infections and infestations Hepatitis B	0.48% 7/1467
Investigations Alanine aminotransferase increased	0.14% 2/1467
Investigations Transaminases increased	0.07% 1/1467
Musculoskeletal and connective tissue disorders Muscle mass	0.07% 1/1467
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm malignant	0.20% 3/1467
Renal and urinary disorders Nephrolithiasis	0.07% 1/1467
Reproductive system and breast disorders Breast cancer	0.07% 1/1467
Reproductive system and breast disorders Ovarian cyst	0.07% 1/1467

Other adverse events

Measure	10 mg Adefovir Dipivoxil Adefovir Dipivoxil (ADV) 10 mg tablets once daily for 48 weeks
Infections and infestations Nasopharyngitis	5.9% 86/1467

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER