Trial Outcomes & Findings for Adefovir Dipivoxil Tablets (10mg) In Chinese Subjects With HBe Antigen Negative Chronic Hepatitis B (NCT NCT00324961)

NCT ID: NCT00324961

Last Updated: 2009-10-28

Results Overview

Hepatitis B Virus (HBV) DNA level is tested in blood serum by real-time Polymerase Chain Reaction with the lower limit of detection (LLD) as 300 copies/milliliter in a central laboratory.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 533 participants
• Primary outcome timeframe: Week 104
• Results posted on: 2009-10-28

Participant Flow

Participant milestones

Measure	10 mg Adefovir Dipivoxil (ADV) 10 mg ADV tablets once daily for 104 weeks
Overall Study STARTED	533
Overall Study COMPLETED	490
Overall Study NOT COMPLETED	43

Reasons for withdrawal

Measure	10 mg Adefovir Dipivoxil (ADV) 10 mg ADV tablets once daily for 104 weeks
Overall Study Adverse Event	5
Overall Study Consent Withdrawn	11
Overall Study Lost to Follow-up	22
Overall Study Protocol Violation	3
Overall Study Other	2

Baseline Characteristics

Adefovir Dipivoxil Tablets (10mg) In Chinese Subjects With HBe Antigen Negative Chronic Hepatitis B

Baseline characteristics by cohort

Measure	10 mg Adefovir Dipivoxil (ADV) n=533 Participants 10 mg ADV tablets once daily for 104 weeks
Age Continuous	38.7 years STANDARD_DEVIATION 10.4 • n=5 Participants
Sex: Female, Male Female	121 Participants n=5 Participants
Sex: Female, Male Male	412 Participants n=5 Participants
Race/Ethnicity, Customized Asian	533 participants n=5 Participants

PRIMARY outcome

Timeframe: Week 104

Population: Intent-to-Treat (ITT) Population: all HBeAg participants who actually received the study medication at least once. Participants with missing data were not included in the analysis.

Hepatitis B Virus (HBV) DNA level is tested in blood serum by real-time Polymerase Chain Reaction with the lower limit of detection (LLD) as 300 copies/milliliter in a central laboratory.

Outcome measures

Measure	HBeAg- at Baseline n=488 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Number of Participants Achieving HBV DNA ≤300 Copies/mL at Week 104 HBV DNA ≤300 cp/mL	85 participants
Number of Participants Achieving HBV DNA ≤300 Copies/mL at Week 104 HBV DNA > 300 cp/mL	403 participants

SECONDARY outcome

Timeframe: Week 104

Population: HBeAg negative chronic hepatitis B participants who underwent liver biopsy at Week 104

Histological improvement (defined as ≥2 point reduction in the Knodell necroinflammation score without worsening fibrosis) was assessed by 2 independent pathologists in the HBeAg-negative participants who underwent 2 sequential liver biopsies at baseline and week 104/withdrawal. The Knodell/histological activity index (HAI) scoring system represents the sum of scores for periportal, bridging necrosis (0-10: none=0, 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, cirrhosis=4)

Outcome measures

Measure	HBeAg- at Baseline n=51 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Number of Participants Achieving Histological Improvement After the 104-week Treatment Histological improvement	21 participants
Number of Participants Achieving Histological Improvement After the 104-week Treatment No histological change	17 participants
Number of Participants Achieving Histological Improvement After the 104-week Treatment Histological worsening	13 participants

SECONDARY outcome

Timeframe: Baseline to Week 104

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

The Knodell/histological activity index (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 independent pathologists in the HBeAg negative participants with 2 sequential liver biopsies during the period of 104 weeks.

Outcome measures

Measure	HBeAg- at Baseline n=51 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks Knodell score at baseline	8.0 Points on a scale Standard Deviation 3.8
Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks Knodell score at week 104/withdrawal	5.4 Points on a scale Standard Deviation 2.8
Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks Necroinflammation score at baseline	6.3 Points on a scale Standard Deviation 3.0
Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks Necroinflammation score at week 104/withdrawal	3.2 Points on a scale Standard Deviation 2.0
Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks Fibrosis score at baseline	1.6 Points on a scale Standard Deviation 0.9
Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks Fibrosis score at week 104/withdrawal	2.1 Points on a scale Standard Deviation 1.2

SECONDARY outcome

Timeframe: Baseline and Weeks 13, 26, 39, 52, 65, 78, 91, and 104

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

The HBV DNA level was tested in blood serum by real-time PCR with the LLD as 300 copies/mL at baseline and Weeks 13, 26, 39, 52, 65, 78, 91, and 104 in a central laboratory.

Outcome measures

Measure	HBeAg- at Baseline n=533 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Change From Baseline in Median Serum HBV DNA Over Time Serum HBV DNA Reduction at week 13	-3.2 log10 copies/mL Interval -7.0 to 3.4
Change From Baseline in Median Serum HBV DNA Over Time Serum HBV DNA Reduction at week 26	-3.5 log10 copies/mL Interval -7.1 to 1.4
Change From Baseline in Median Serum HBV DNA Over Time Serum HBV DNA Reduction at week 39	-3.6 log10 copies/mL Interval -7.2 to 2.5
Change From Baseline in Median Serum HBV DNA Over Time Serum HBV DNA Reduction at week 52	-3.6 log10 copies/mL Interval -7.2 to 2.4
Change From Baseline in Median Serum HBV DNA Over Time Serum HBV DNA Reduction at week 65	-3.7 log10 copies/mL Interval -7.2 to 2.9
Change From Baseline in Median Serum HBV DNA Over Time Serum HBV DNA Reduction at week 78	-3.8 log10 copies/mL Interval -7.2 to 2.9
Change From Baseline in Median Serum HBV DNA Over Time Serum HBV DNA Reduction at week 91	-3.7 log10 copies/mL Interval -7.2 to 3.2
Change From Baseline in Median Serum HBV DNA Over Time Serum HBV DNA Reduction at week 104	-3.7 log10 copies/mL Interval -7.2 to 2.1

SECONDARY outcome

Timeframe: Week 104

Population: Intent-to-Treat (ITT) Population: all HBeAg negative participants who actually received the study medication at least once. A total of 435 participants had a baseline ALT value above the ULN.

Serum alanine aminotransferase (ALT) normalization was defined as a serum ALT level at or below the upper limit of the normal (ULN) range after a baseline value above the ULN, as determined using central laboratory ranges.

Outcome measures

Measure	HBeAg- at Baseline n=435 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Number of Participants Achieving ALT Normalization at Week 104 ALT normalization	333 participants
Number of Participants Achieving ALT Normalization at Week 104 ALT non-normalization	102 participants

SECONDARY outcome

Timeframe: Week 104

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

HBsAg loss and HBsAg seroconversion (HBsAg loss and HBsAb detected) were assessed for all participants who were HBeAg negative at Weeks 0 and 104. Confirmed HBsAg loss was defined as undetectable HBeAg.

Outcome measures

Measure	HBeAg- at Baseline n=533 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Number of Participants Achieving HBsAg Loss and HBsAg Seroconversion at Week 104 HBsAg loss	1 participants
Number of Participants Achieving HBsAg Loss and HBsAg Seroconversion at Week 104 HBsAg seroconversion	0 participants

SECONDARY outcome

Timeframe: Week 104

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

Week 104 serum samples from participants who reached a HBV DNA breakthrough were assessed for the development of ADV (Adefovir dipivoxil) mutations (N236T and A181V) in the HBV polymerase. HBV DNA breakthrough was defined as an increase in HBV DNA level by 1 log10 copies/mL or more from the treatment nadir during Weeks 0 to 104.

Outcome measures

Measure	HBeAg- at Baseline n=533 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Number of Participants With ADV-associated Resistance at Week 104 HBV DNA breakthrough	77 participants
Number of Participants With ADV-associated Resistance at Week 104 ADV-associated resistance	9 participants

SECONDARY outcome

Timeframe: Weeks 13, 26, 39, 52, 65, 78, 91, and 104

Population: Intent-to-Treat (ITT) Population: all participants who actually received the study medication at least once. Missing data were not included in statistical analysis.

Hepatitis B Virus (HBV) DNA level is tested in blood serum by real-time Polymerase Chain Reaction with the lower limit of detection (LLD) as 300 copies/milliliter in a central laboratory.

Outcome measures

Measure	HBeAg- at Baseline n=533 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time HBV DNA ≤300 cp/mL, Week 13, n=528	262 participants
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time HBV DNA ≤300 cp/mL, Week 26, n=525	350 participants
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time HBV DNA ≤300 cp/mL, Week 39, n=523	393 participants
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time HBV DNA ≤300 cp/mL, Week 52, n=522	413 participants
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time HBV DNA ≤300 cp/mL, Week 65, n=514	415 participants
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time HBV DNA ≤300 cp/mL, Week 78, n=513	415 participants
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time HBV DNA ≤300 cp/mL, Week 91, n=505	421 participants
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time HBV DNA ≤300 cp/mL, Week 104, n=488	403 participants

SECONDARY outcome

Timeframe: Week 104

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

Complete response was defined as an HBV DNA level ≤ 300 copies/mL by the Roche COBAS AMPLICOR HBV MONITOR Test and ALT normalized for two consecutive visits at least 3 months apart.

Outcome measures

Measure	HBeAg- at Baseline n=533 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Number of Participants Achieving Complete Response at Week 104	326 participants

SECONDARY outcome

Timeframe: Baseline to Week 104

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

Time to response was defined as the time to participants achieving protocol-defined complete response at week 104 from baseline. Protocol-defined complete response was an HBV DNA level ≤ 300 copies/mL by Roche COBAS AMPLICOR HBV MONITOR Test and ALT normalized for two consecutive visits at least 3 months apart.

Outcome measures

Measure	HBeAg- at Baseline n=533 Participants All participants who were Hepatitis B e Antigen (HBeAg) negative at baseline
Time to Protocol-defined Complete Response Over a 104-week Treatment Period	301.6 days Standard Deviation 147.0

Adverse Events

10 mg Adefovir Dipivoxil (ADV)

Serious events: 5 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Measure	10 mg Adefovir Dipivoxil (ADV) 10 mg ADV tablets once daily for 104 weeks
Infections and infestations Hepatitis B	0.19% 1/533
Investigations Alanine aminotransferase increased	0.19% 1/533
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm malignant	0.19% 1/533
Nervous system disorders Neurilemmoma	0.19% 1/533
Respiratory, thoracic and mediastinal disorders Bronchitis chronic	0.19% 1/533
Vascular disorders Cerebral hemorrhage	0.19% 1/533

Other adverse events

Measure	10 mg Adefovir Dipivoxil (ADV) 10 mg ADV tablets once daily for 104 weeks
Infections and infestations Nasopharyngitis	7.1% 38/533

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