Chronic Hepatitis B
Conditions
Keywords
adefovir dipivoxil, e Antigen negative, chronic hepatitis B, Chinese
Brief summary
This is a phase IV, 2-year, multi-center, single arm and open-label study, evaluating the efficacy and safety with using local manufactured adefovir dipivoxil in Chinese subjects with HBeAg negative chronic hepatitis B
Interventions
adefovir dipivoxil once daily 10 mg orally
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects aged 18-65 years inclusive * Documented chronic hepatitis B infection determined by the presence of serum HBsAg for at least 6 months * Documented HBeAg negative and HBeAb positive at the screening visit and with at least a 6 months history of HBeAg negativity. * Serum HBV DNA ≥ 104 copies/mL (Roche COBAS AMPLICORTM HBV MONITOR Test, LLOD 300 copies/mL) at study screening (within 4 weeks before baseline) * ALT value ≥1.3 times the upper limit of normal (ULN) at the time of screening, as determined using laboratory ranges and documented ALT abnormal within 6 month prior to the study screening. * Serum alpha fetoprotein (AFP) \< 50 ng/mL at the first screening visit. If the AFP level is ≥ 50 ng/mL but declined to \< 50 ng/mL between screening and baseline, the patient is eligible. * Compensated liver disease with the following laboratory and clinical parameters at study screening: * Prothrombin time ≤ 2 second above normal range. * Albumin ≥ 35 g/L. * Total bilirubin ≤ 2.5 mg/dL (≤ 43 µmol/L) or normal direct bilirubin. * No history of variceal bleeding. * No history of encephalopathy. * No history of ascites * Adequate renal function defined as serum creatinine ≤ 1.5 mg/dL (≤ 130 µmol/L). * Adequate hematological function defined as: * Absolute neutrophil count ≥ 1 x 10³/mm³ ( ≥ 1 x 10\^9/L); * Platelets ≥ 80 x 10³/mm³ (≥ 80 x 10\^9/L); Platelets ≥ 100 x 10³/mm³ ( ≥ 100 x 10\^9/L) recommended for the patients who will undergo liver biopsy. * Hemoglobin ≥ 10 g/dL (≥ 100 g/L) (males) or ≥ 9 g/dL (≥ 9 g/L) (females). * Willing and able to undergo a minimum of two liver biopsies (prior to dosing, and after 104 weeks of therapy; only apply to subjects who are enrolled to the sites where liver biopsy is required). * A female is eligible to enter and participate in this study if she is of: 1. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); 2. 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 than 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. * Agree not to participate in any other investigational trials or to undertake other HBV systemic antiviral regimens during participation in this study * Able to give written informed consent and comply with the requirements of the study
Exclusion criteria
* Any serious or active medical or psychiatric illnesses other than hepatitis B which, in the opinion of the investigator, would interfere with patient treatment, assessment or compliance with the protocol. This would include, may not limit to, renal, cardiac, pulmonary, vascular, neurogenic, digestive, metabolic (diabetes, thyroid disorders, adrenal disease), immunodeficiency disorders, active infection or cancer. * Documented evidence of active liver disease due to other causes including co-infection hepatitis C (HCV), Subjects who are anti-HCV positive and in whom HCV RNA is undetectable are considered to be HCV seropositive and will not eligible; co-infection with hepatitis delta (HDV); co-infection with HIV; autoimmune hepatitis (antinuclear antibody titre \> 1:160) * Clinical signs of decompensated liver disease at baseline. These may include but are not limited to: serum bilirubin \> 2.5 mg/dL (≤ 43 µmol/L) - prothrombin time \> 2 second prolonged above ULN * serum albumin \< 35g/L * history of ascites, variceal bleeding, or encephalopathy * Alanine aminotransferase (ALT) \>10 times ULN at screening or history of acute exacerbation leading to transient decompensation * Hepatocellular carcinoma as evidenced by one of the following: * suspicious foci on ultrasound or radiological examination * \- where no positive ultrasound finding, but serum alpha-fetoprotein \> 100ng/mL * Active alcohol or drug abuse or history of alcohol or drug abuse considered by the investigator to be sufficient to hinder compliance with treatment, participation in the study or interpretation of results. * Use of immunosuppressive therapy, immunomodulatory therapy (including interferon or thymosin), systemic cytotoxic agents, chronic anti-viral agents excluding lamivudine (e.g. ganciclovir, adefovir dipivoxil, entecavir, famciclovir, FTC, DAPD, LFMAU, HBIg), Chinese herbal medicines known to have activity against HBV within the previous 12 months or during the study; use of agents with effect of ALT reduction (e.g. schisandra agents) during the study * Use of lamivudine within the previous 3 months or during the study * Planned for liver transplantation or previous liver transplantation * Received hepatotoxic drugs (e.g., anabolic steroids, ketaconazole, itraconazole, isoniazid, rifampin, rifabutin) within 2 months prior to study screening or expected to receive these during the course of the study. * Received nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cis-platinum, pentamidine etc.) or competitors of renal excretion (e.g., probenecid) within 2 months prior to study screening or the expectation that patient will receive any of these during the course of the study. * Receiving systemic (intravenous or oral) steroids, immuno-suppressant therapies or chemotherapeutic agents within 2 months of study screening or expected to receive these agents during the course of the study. * History of hypersensitivity to nucleoside and/or nucleotide analogues. * Inability to comply with study requirements. * Lactating females or females with a positive serum pregnancy test. * Organ or bone marrow transplant recipients. * Previous (or planned) participation in an investigational trial involving administration of investigational compound within 2 months prior to the study screening. * Can not comply with the requirements of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving HBV DNA ≤300 Copies/mL at Week 104 | Week 104 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks | Baseline to Week 104 | 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. |
| Change From Baseline in Median Serum HBV DNA Over Time | Baseline and Weeks 13, 26, 39, 52, 65, 78, 91, and 104 | 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. |
| Number of Participants Achieving ALT Normalization at Week 104 | Week 104 | 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. |
| Number of Participants Achieving HBsAg Loss and HBsAg Seroconversion at Week 104 | Week 104 | 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. |
| Number of Participants Achieving Histological Improvement After the 104-week Treatment | 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) |
| Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | Weeks 13, 26, 39, 52, 65, 78, 91, and 104 | 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. |
| Number of Participants Achieving Complete Response at Week 104 | Week 104 | 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. |
| Time to Protocol-defined Complete Response Over a 104-week Treatment Period | Baseline to Week 104 | 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. |
| Number of Participants With ADV-associated Resistance at Week 104 | Week 104 | 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. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 10 mg Adefovir Dipivoxil (ADV) 10 mg ADV tablets once daily for 104 weeks | 533 |
| Total | 533 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Consent Withdrawn | 11 |
| Overall Study | Lost to Follow-up | 22 |
| Overall Study | Other | 2 |
| Overall Study | Protocol Violation | 3 |
Baseline characteristics
| Characteristic | 10 mg Adefovir Dipivoxil (ADV) |
|---|---|
| Age Continuous | 38.7 years STANDARD_DEVIATION 10.4 |
| Race/Ethnicity, Customized Asian | 533 participants |
| Sex: Female, Male Female | 121 Participants |
| Sex: Female, Male Male | 412 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / — |
| serious Total, serious adverse events | 5 / — |
Outcome results
Primary
Number of Participants Achieving HBV DNA ≤300 Copies/mL at Week 104
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL at Week 104 | HBV DNA ≤300 cp/mL | 85 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL at Week 104 | HBV DNA > 300 cp/mL | 403 participants |
Secondary
Change From Baseline in Median Serum HBV DNA Over Time
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| HBeAg- at Baseline | Change From Baseline in Median Serum HBV DNA Over Time | Serum HBV DNA Reduction at week 13 | -3.2 log10 copies/mL |
| HBeAg- at Baseline | Change From Baseline in Median Serum HBV DNA Over Time | Serum HBV DNA Reduction at week 26 | -3.5 log10 copies/mL |
| HBeAg- at Baseline | Change From Baseline in Median Serum HBV DNA Over Time | Serum HBV DNA Reduction at week 39 | -3.6 log10 copies/mL |
| HBeAg- at Baseline | Change From Baseline in Median Serum HBV DNA Over Time | Serum HBV DNA Reduction at week 52 | -3.6 log10 copies/mL |
| HBeAg- at Baseline | Change From Baseline in Median Serum HBV DNA Over Time | Serum HBV DNA Reduction at week 104 | -3.7 log10 copies/mL |
| HBeAg- at Baseline | Change From Baseline in Median Serum HBV DNA Over Time | Serum HBV DNA Reduction at week 65 | -3.7 log10 copies/mL |
| HBeAg- at Baseline | Change From Baseline in Median Serum HBV DNA Over Time | Serum HBV DNA Reduction at week 78 | -3.8 log10 copies/mL |
| HBeAg- at Baseline | Change From Baseline in Median Serum HBV DNA Over Time | Serum HBV DNA Reduction at week 91 | -3.7 log10 copies/mL |
Secondary
Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks
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.
Time frame: Baseline to Week 104
Population: HBeAg negative chronic hepatitis B participants who underwent liver biopsy at Week 48
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HBeAg- 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 |
| HBeAg- at Baseline | 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 |
| HBeAg- at Baseline | 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 |
| HBeAg- at Baseline | 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 |
| HBeAg- at Baseline | 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 |
| HBeAg- at Baseline | 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
Number of Participants Achieving ALT Normalization at Week 104
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HBeAg- at Baseline | Number of Participants Achieving ALT Normalization at Week 104 | ALT normalization | 333 participants |
| HBeAg- at Baseline | Number of Participants Achieving ALT Normalization at Week 104 | ALT non-normalization | 102 participants |
Secondary
Number of Participants Achieving Complete Response at Week 104
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.
Time frame: Week 104
Population: Intent-to-Treat (ITT) Population: all participants who actually received the study medication at least once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HBeAg- at Baseline | Number of Participants Achieving Complete Response at Week 104 | 326 participants |
Secondary
Number of Participants Achieving HBsAg Loss and HBsAg Seroconversion at Week 104
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.
Time frame: Week 104
Population: Intent-to-Treat (ITT) Population: all HBeAg negative participants who actually received the study medication at least once
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HBeAg- at Baseline | Number of Participants Achieving HBsAg Loss and HBsAg Seroconversion at Week 104 | HBsAg loss | 1 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBsAg Loss and HBsAg Seroconversion at Week 104 | HBsAg seroconversion | 0 participants |
Secondary
Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | HBV DNA ≤300 cp/mL, Week 13, n=528 | 262 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | HBV DNA ≤300 cp/mL, Week 26, n=525 | 350 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | HBV DNA ≤300 cp/mL, Week 39, n=523 | 393 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | HBV DNA ≤300 cp/mL, Week 52, n=522 | 413 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | HBV DNA ≤300 cp/mL, Week 65, n=514 | 415 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | HBV DNA ≤300 cp/mL, Week 78, n=513 | 415 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | HBV DNA ≤300 cp/mL, Week 91, n=505 | 421 participants |
| HBeAg- at Baseline | Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | HBV DNA ≤300 cp/mL, Week 104, n=488 | 403 participants |
Secondary
Number of Participants Achieving Histological Improvement After the 104-week Treatment
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)
Time frame: Week 104
Population: HBeAg negative chronic hepatitis B participants who underwent liver biopsy at Week 104
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HBeAg- at Baseline | Number of Participants Achieving Histological Improvement After the 104-week Treatment | Histological worsening | 13 participants |
| HBeAg- at Baseline | Number of Participants Achieving Histological Improvement After the 104-week Treatment | Histological improvement | 21 participants |
| HBeAg- at Baseline | Number of Participants Achieving Histological Improvement After the 104-week Treatment | No histological change | 17 participants |
Secondary
Number of Participants With ADV-associated Resistance at Week 104
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.
Time frame: Week 104
Population: Intent-to-Treat (ITT) Population: all participants who actually received the study medication at least once.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HBeAg- at Baseline | Number of Participants With ADV-associated Resistance at Week 104 | HBV DNA breakthrough | 77 participants |
| HBeAg- at Baseline | Number of Participants With ADV-associated Resistance at Week 104 | ADV-associated resistance | 9 participants |
Secondary
Time to Protocol-defined Complete Response Over a 104-week Treatment Period
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.
Time frame: Baseline to Week 104
Population: Intent-to-Treat (ITT) Population: all participants who actually received the study medication at least once.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HBeAg- at Baseline | Time to Protocol-defined Complete Response Over a 104-week Treatment Period | 301.6 days | Standard Deviation 147 |