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The purpose of this study is to investigate the efficacy and safety of adefovir dipivoxil for the treatment of chronic hepatitis B in children and adolescents (age 2 to less than 18 years) following 48 weeks of placebo-controlled, double-blind treatment and following an additional 192 weeks of open-label adefovir dipivoxil treatment.
Weeks 1 through 48 (Study Year 1): The first 48 weeks of the study were a randomized, double-blind, placebo-controlled, parallel-group treatment period. Participants were randomly assigned to treatment in a 2:1 fashion to ADV or PLB. Prior to randomization, eligible participants were classified into 1 of 6 strata based upon age at screening (2 to < 7 years; >= 7 to < 12 years; >= 12 to < 18 years) and prior exposure to treatment for chronic hepatitis B (CHB) (prior treatment; no prior treatment).
Weeks 49 through 240 (Study Years 2 through 5): At Week 48, all placebo-treated participants who did not exhibit HBeAg or hepatitis B surface antigen (HBsAg) seroconversion at Week 44, plus all ADV-treated participants, were offered the opportunity to receive open-label ADV for up to an additional 192 weeks. Any participant with HBV DNA >= 1000 copies/mL at 2 consecutive visits 12 weeks apart was to be discontinued from open-label study treatment. The only exception was for participants in the adolescent age range with prior lamivudine experience who were allowed the opportunity to add lamivudine to ADV; similarly, if combination failed to impart suppression of HBV DNA below 1000 copies/mL (confirmed) discontinuation was necessary. All participants who discontinued study drug due to confirmed seroconversion were requested to continue to return for study visits for the remainder of the study in order to evaluate the durability of seroconversion. Participants who wished to discontinue study treatment and withdraw from the study prior to study completion were requested to return every 4 weeks for 16 weeks for posttreatment evaluations following an early termination visit. Any participants who experienced posttreatment hepatic flares during the 16-week follow-up period were to be followed every 4 weeks until their ALT levels returned to <= 2 times the upper limit of normal (ULN) for a maximum off-treatment follow-up of 6 months. Participants who experienced a severe hepatic flare (per protocol definition) after discontinuation of ADV during the open-label treatment period may have been eligible to receive ADV for treatment of the hepatic flare (after consultation with the Gilead medical monitor).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo (PLB) | Placebo Comparator | Participants randomized to receive placebo received placebo during the first 48 weeks of treatment (double-blind phase) and then all eligible participants were administered open-label ADV for the remainder of the study. |
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| Adefovir Dipivoxil (ADV) | Experimental | Participants randomized to receive ADV received ADV during the first 48 weeks of treatment (double-blind phase) and then all eligible participants were administered open-label ADV for the remainder of the study. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo (PLB) | Drug | Matching placebo |
| |
| Adefovir Dipivoxil (ADV) |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < 1000 Copies/mL (Polymerase Chain Reaction [PCR]-Based Assay) and Normal Alanine Aminotransferase (ALT) at Week 48 (Missing = Failure) | In the absence of biopsy data from these pediatric participants, this endpoint enables assessments of drug effect on viral replication and the underlying degree of inflammation in the liver. | Week 48 |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | ADV baseline |
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Key Inclusion Criteria:
Key Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| John Flaherty, PharmD | Gilead Sciences | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boston | Massachusetts | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | Sokal, E, Kelly, D, et al. The Pharmacokinetics (PK) and Safety of a Single Dose of Adefovir Dipivoxil (ADV) in Children and Adolescents (Aged 2-17) with Chronic Hepatitis B. JHepatol,Vol 40(Suppl 1), P. 132, 2004. |
| Label | URL |
|---|---|
| Related Info | View source |
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First participant screened on 17 May 2004; first participant randomized on 21 June 2004. Participants from Gilead pharmacokinetics Study GS-02-517 were allowed to enroll regardless of screening serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) or alanine aminotransferase (ALT) concentration if they met all other entry criteria.
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| ID | Title | Description |
|---|---|---|
| FG000 | ADV - ADV | Once daily treatment: children aged 2 to <7 years received 0.3 mg/kg oral suspension; children aged >=7 to <12 years received 0.25 mg/kg oral suspension; children aged >=12 to <18 years received 10 mg tablet. The adefovir dipivoxil (ADV) baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind [DB] ADV [ADV-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240). Lamivudine was to be added to the open-label ADV regimen of subjects between 12 and <18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96. |
| FG001 | PLB - ADV | Placebo (PLB) was matched to adefovir dipivoxil treatment (oral suspension or tablet) by age group. The ADV baseline was defined as the day of first dose of ADV (ie, Week 48 for those originally randomized to placebo [PLB-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the PLB-ADV group could receive only up to 192 weeks of open-label (OL) ADV treatment (ADV Week 192). Lamivudine was to be added to the open-label ADV regimen of subjects between 12 and <18 years old who had prior lamivudine exposure and who had a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Double-Blind (Study Weeks 0 Through 48) |
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| Open-Label (Study Weeks 49 Through 240) |
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| ID | Title | Description |
|---|---|---|
| BG000 | ADV - ADV | Once daily treatment: children aged 2 to <7 years received 0.3 mg/kg oral suspension; children aged >=7 to <12 years received 0.25 mg/kg oral suspension; children aged >=12 to <18 years received 10 mg tablet. The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to DB ADV [ADV-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240). |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < 1000 Copies/mL (Polymerase Chain Reaction [PCR]-Based Assay) and Normal Alanine Aminotransferase (ALT) at Week 48 (Missing = Failure) | In the absence of biopsy data from these pediatric participants, this endpoint enables assessments of drug effect on viral replication and the underlying degree of inflammation in the liver. | All randomized participants who received >= 1 dose study medication. If either endpoint was missing a Week 48 value, Week 44 value was substituted and used in the combined endpoint. If participant did not have serum HBV DNA value at Weeks 44 and 48 or ALT value at Weeks 44 and 48, then participant was considered a failure for the Week-48 analysis. | Posted | Number | percentage of participants | Week 48 |
|
Adverse events were collected over the entire 240-week duration of the study (ie, during the 48 weeks of randomized treatment and subsequent 192 weeks of open-label treatment).
Treatment-emergent AEs included AEs collected from the date of the first dose of study drug up to the last day on study (including the follow-up, off study medication period of the study). For those participants who did not enter open-label treatment, AEs were collected until 30 days after last double-blind dose. Only on-treatment AEs are shown.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | ADV (Double-Blind) | Once daily treatment during the DB treatment period: children aged 2 to <7 years received 0.3 mg/kg oral suspension; children aged >=7 to <12 years received 0.25 mg/kg oral suspension; children aged >=12 to <18 years received 10 mg tablet. Treatment-emergent adverse events (AEs) for the DB period are events that occurred up to the last dose of DB treatment + 4 days or if discontinued early, 30 days after last DB dose. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| diarrhoea | Gastrointestinal disorders | MedDRA (9.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| abdominal pain | Gastrointestinal disorders | MedDRA (9.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John Flaherty, PharmD, Director, Clinical Research | Gilead Sciences | 650-522-5592 | John.Flaherty@gilead.com |
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| ID | Term |
|---|---|
| D019694 | Hepatitis B, Chronic |
| D006509 | Hepatitis B |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D018347 | Hepadnaviridae Infections |
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| ID | Term |
|---|---|
| C106812 | adefovir dipivoxil |
| D019259 | Lamivudine |
| ID | Term |
|---|---|
| D016047 | Zalcitabine |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
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| Drug |
10-mg tablet or 2-mg/mL oral suspension |
|
| Lamivudine | Drug | 100-mg tablet administered according to package labeling. Lamivudine was to be added to the open-label ADV regimen of subjects with a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96. If the HBV DNA concentration remained >= 1000 copies/mL at 2 consecutive study visits after the addition of lamivudine, the investigator was required to discontinue all study drugs, perform the early termination ssessments, and have the subject return every 4 weeks for 16 weeks of posttreatment evaluations. |
|
| Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment - Missing = Failure) (ADV Week 192) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | ADV Week 192 |
| Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240) | ADV Week 240 |
| Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | ADV baseline |
| Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 192) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | ADV Week 192 |
| Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240) | ADV Week 240 |
| Adefovir (ADV) Baseline Serum HBV DNA | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | ADV baseline |
| Change From ADV Baseline to ADV Week 192 for Serum HBV DNA | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | ADV baseline to ADV 192 weeks |
| Change From ADV Baseline to ADV Week 240 for Serum HBV DNA | ADV baseline to ADV 240 weeks |
| ADV Baseline ALT | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | ADV baseline |
| Change From ADV Baseline to ADV Week 192 for ALT | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | ADV baseline to ADV 192 weeks |
| Change From ADV Baseline to ADV Week 240 for ALT | ADV baseline to ADV 240 weeks |
| Percentage of Participants With Normal ALT at Adefovir Baseline (Missing = Failure) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | ADV baseline |
| Percentage of Participants With Normal ALT at ADV Week 192 (Missing = Failure) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | ADV Week 192 |
| Percentage of Participants With Normal ALT at ADV Week 240 (Missing = Failure) | Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | ADV Week 240 |
| Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss or Seroconversion by End of Blinded Treatment (Study Week 48; Randomized and Treated Analysis Set) | HBeAg loss is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and hepatitis B e antibody + (anti-HBe+) post baseline. | Study Week 0 to Study Week 48 (double-blind period) |
| Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 192 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) | ADV baseline = 1st ADV-dose day = Week 0 for ADV-ADV group and Week 48 for PLB-ADV group. ADV week = windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). HBeAg loss is defined per individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and anti-HBe+ post baseline. | ADV baseline to ADV Week 192 |
| Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 240 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) | Per protocol, participants could discontinue study medication due to HBeAg seroconversion and remain in the study in order to evaluate the durability of seroconversion. HBeAg loss is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and anti-HBe+ post baseline. | ADV baseline to ADV Week 240 |
| Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) | Resistance surveillance was conducted annually for all participants who remained on treatment and had HBV DNA concentrations greater than or equal to the level of detection (>= 169 copies/mL) by PCR. The last on-ADV sample for all participants in the study was analyzed in the cumulative Week 240 resistance surveillance analysis. | 240 weeks |
| Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) for Subjects Who Received Combination ADV + Lamivudine Therapy | Resistance surveillance was conducted at Week 240/last on-treatment study visit for all participants who had HBV DNA concentrations greater than or equal to the level of detection (>= 169 copies/mL) by PCR while on combination ADV + lamivudine treatment. | 240 weeks |
| Percentage of Participants With Durable HBeAg Seroconversion | A participant was defined to have durable HBeAg seroconversion only if she/he remained in a seroconverted state (HBeAg-, hepatitis B e antibody + [anti-HBe+]) from the date that she/he first seroconverted through and including her/his last study visit. This endpoint could only be assessed for participants who (HBeAg-) seroconverted on-treatment and subsequently discontinued open-label dosing. | 240 weeks |
| Study Results | View source |
| COMPLETED |
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| NOT COMPLETED |
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| BG001 | PLB - ADV | Placebo was matched to adefovir dipivoxil treatment (oral suspension or tablet) by age group. The ADV baseline was defined as the day of first dose of ADV (ie, Week 48 for those originally randomized to placebo [PLB-ADV group]). Additionally, ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Body Mass Index (Males) | Mean | Standard Deviation | kg/cm^2 |
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| Body Mass Index (Females) | Mean | Standard Deviation | kg/cm^2 |
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| Prior Exposure to Hepatitis B Treatment | Number | participants |
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| HBV DNA | Mean | Standard Deviation | log10 copies/mL |
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| Hepatitis B Surface Antigen (HBsAg) | Number | participants |
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| Antibody to HBsAg (HBsAb) | Number | participants |
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| Hepatitis B e Antigen (HBeAg) | Number | participants |
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| Antibody to HBeAg (HBeAb) | Number | participants |
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| ALT | Mean | Standard Deviation | U/L |
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| ALT | Number | participants |
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| ALT as Multiple of ULN | Number | participants |
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| ALT Category | Number | participants |
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| ALT (Multiples of ULN) | Mean | Standard Deviation | multiples |
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| Genotype | Identification of specific HBV genotype (ie, Genotype A, B, C, D, E, or F). | Number | participants |
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| Time Since HBV Diagnosis | Mean | Standard Deviation | years until enrollment |
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| Mode of HBV Acquisition | Number | participants |
|
| Symptoms of Acute Hepatitis B | Symptoms of acute HBV infection include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, clay-colored bowel movements, joint pain, and jaundice. - cdc.gov [homepage on the Internet]. Atlanta: Centers for Disease Control and Prevention. Hepatitis B Information for Health Professionals; [updated 2011 April 4]. Available from: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm. | Number | participants |
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| Hepatitis B Flares (Acute Exacerbation) | A hepatic flare was defined as a) serum ALT > 2 x study baseline and > 10 x ULN or b) an ALT 1-grade shift or ALT 2 x previous value and total bilirubin > 2.5 mg/dL or change from study baseline in total bilirubin = 1.0 mg/dL or change from study baseline in prothrombin time > 2 seconds or serum albumin < 3.0 g/dL or change from study baseline in serum albumin <= -1.0 g/dL. | Number | participants |
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| Current Alcohol Consumption | Number | participants |
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| Any Prior Hepatitis B Medication | Number | participants |
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| Prior Use of Famciclovir | Number | participants |
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| Prior Use of Lamivudine | Number | participants |
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| Prior Use of Interferon Alpha | Number | participants |
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| Prior Use of ADV | Number | participants |
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| Prior Use of Other Hepatitis B Medications | "Other hepatitis B medications" include any medications other than famciclovir, lamivudine, lobucavir, thymosin alpha, ganciclovir, interferon alpha, hepatitis B immune globulin (HBIG), entecavir, clevudine, emtricitabine, and ADV. | Number | participants |
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| OG001 | Placebo (PLB) | Placebo was matched to adefovir dipivoxil treatment (oral suspension or tablet) by age group. |
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| Secondary | Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded. | Posted | Number | percentage of participants | ADV baseline |
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| Secondary | Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment - Missing = Failure) (ADV Week 192) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded. | Posted | Number | percentage of participants | ADV Week 192 |
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| Secondary | Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240) | The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded. | Posted | Number | percentage of participants | ADV Week 240 |
|
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| Secondary | Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded. | Posted | Number | percentage of participants | ADV baseline |
|
|
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| Secondary | Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 192) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded. | Posted | Number | percentage of participants | ADV Week 192 |
|
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| Secondary | Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240) | The OL analysis set was used for this endpoint and included any participant who took at least 1 dose of open-label ADV. Participants with missing values were considered as failures rather than excluded. | Posted | Number | percentage of participants | ADV Week 240 |
|
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| Secondary | Adefovir (ADV) Baseline Serum HBV DNA | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment. | Posted | Mean | Standard Deviation | log10 HBV DNA copies/mL | ADV baseline |
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| Secondary | Change From ADV Baseline to ADV Week 192 for Serum HBV DNA | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment. | Posted | Mean | Standard Deviation | log10 HBV DNA copies/mL | ADV baseline to ADV 192 weeks |
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| Secondary | Change From ADV Baseline to ADV Week 240 for Serum HBV DNA | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment. | Posted | Mean | Standard Deviation | log10 HBV DNA copies/mL | ADV baseline to ADV 240 weeks |
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| Secondary | ADV Baseline ALT | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment. | Posted | Mean | Standard Deviation | U/L | ADV baseline |
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| Secondary | Change From ADV Baseline to ADV Week 192 for ALT | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment. | Posted | Mean | Standard Deviation | U/L | ADV baseline to ADV 192 weeks |
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| Secondary | Change From ADV Baseline to ADV Week 240 for ALT | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Analysis set included only data from participants while on study treatment. | Posted | Mean | Standard Deviation | U/L | ADV baseline to ADV 240 weeks |
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| Secondary | Percentage of Participants With Normal ALT at Adefovir Baseline (Missing = Failure) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was also subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were considered as failures rather than excluded. Analysis set included only data from participants while on study treatment. | Posted | Number | percentage of participants | ADV baseline |
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| Secondary | Percentage of Participants With Normal ALT at ADV Week 192 (Missing = Failure) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were considered as failures rather than excluded. Analysis set included only data from participants while on study treatment. | Posted | Number | percentage of participants | ADV Week 192 |
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| Secondary | Percentage of Participants With Normal ALT at ADV Week 240 (Missing = Failure) | Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were considered as failures rather than excluded. Analysis set included only data from participants while on study treatment. | Posted | Number | percentage of participants | ADV Week 240 |
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| Secondary | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss or Seroconversion by End of Blinded Treatment (Study Week 48; Randomized and Treated Analysis Set) | HBeAg loss is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and hepatitis B e antibody + (anti-HBe+) post baseline. | The randomized and treated analysis set included all participants who were randomized into the study and received at least one dose of study medication. For Week 48 data; if Week 48 was missing, Week 44 was carried forward; if Week 44 was missing, missing = failure. | Posted | Number | percentage of participants | Study Week 0 to Study Week 48 (double-blind period) |
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| Secondary | Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 192 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) | ADV baseline = 1st ADV-dose day = Week 0 for ADV-ADV group and Week 48 for PLB-ADV group. ADV week = windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). HBeAg loss is defined per individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and anti-HBe+ post baseline. | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were excluded. Analysis set included only data from participants while on study treatment. | Posted | Number | percentage of participants | ADV baseline to ADV Week 192 |
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| Secondary | Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 240 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) | Per protocol, participants could discontinue study medication due to HBeAg seroconversion and remain in the study in order to evaluate the durability of seroconversion. HBeAg loss is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and anti-HBe+ post baseline. | The OL analysis set included any participant who took at least one dose of open-label ADV. This analysis set was subdivided based on DB drug, as ADV-ADV or PLB-ADV. Participants with missing values were excluded. Analysis set included only data from participants while on study treatment. | Posted | Number | percentage of participants | ADV baseline to ADV Week 240 |
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| Secondary | Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) | Resistance surveillance was conducted annually for all participants who remained on treatment and had HBV DNA concentrations greater than or equal to the level of detection (>= 169 copies/mL) by PCR. The last on-ADV sample for all participants in the study was analyzed in the cumulative Week 240 resistance surveillance analysis. | Last on-ADV sample through Week 240 was analyzed, and participant was excluded from the cumulative Week 240 analysis if HBV DNA value was < 169 copies/mL at Week 240/last time point or if participant discontinued study drug but remained in study. One ADV-ADV participant had an ADV-specific, conserved-site mutation and is counted twice in the table. | Posted | Number | Participants | 240 weeks |
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| Secondary | Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) for Subjects Who Received Combination ADV + Lamivudine Therapy | Resistance surveillance was conducted at Week 240/last on-treatment study visit for all participants who had HBV DNA concentrations greater than or equal to the level of detection (>= 169 copies/mL) by PCR while on combination ADV + lamivudine treatment. | 32/173 added lamivudine from Weeks 108 - 144. Last on-ADV sample through Week 240 analyzed; participant omitted from cumulative Week 240 analysis if HBV DNA <169 copies/mL at Week 240/last time point or stopped study drug but remained in study. 2 ADV-ADV participants had ADV/lamivudine-specific, conserved-site mutation, and counted 2x in table. | Posted | Number | Participants | 240 weeks |
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| Secondary | Percentage of Participants With Durable HBeAg Seroconversion | A participant was defined to have durable HBeAg seroconversion only if she/he remained in a seroconverted state (HBeAg-, hepatitis B e antibody + [anti-HBe+]) from the date that she/he first seroconverted through and including her/his last study visit. This endpoint could only be assessed for participants who (HBeAg-) seroconverted on-treatment and subsequently discontinued open-label dosing. | Participants who discontinued treatment because of confirmed HBeAg seroconversion in Weeks 49 to 240 were to remain in the study through Week 240 to monitor the durability of seroconversion. Any participant who formally stopped drug early and restarted, by definition, did not have durable HBeAg seroconversion. | Posted | Number | Percentage of participants | 240 weeks |
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| 7 |
| 115 |
| 95 |
| 115 |
| EG001 | PLB (Double-Blind) | Placebo was matched to adefovir dipivoxil treatment (oral suspension or tablet) by age group for the DB treatment period. Treatment-emergent AEs for the DB period are events that occurred up to the last dose of DB treatment + 4 days or if discontinued early, 30 days after last DB dose. | 5 | 58 | 47 | 58 |
| EG002 | ADV - ADV | Double-blind once daily ADV treatment: children aged 2 to <7 years received 0.3 mg/kg oral suspension; children aged >=7 to <12 years received 0.25 mg/kg oral suspension; children aged >=12 to <18 years received 10 mg tablet. At Week 48, ADV-treated participants were offered the opportunity to receive open-label ADV for up to an additional 192 weeks (ie, OL Weeks 49 - 240). ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to DB ADV [ADV-ADV group]). ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240). Treatment-emergent AEs for the OL period are events that began on or after the date of the first dose of OL ADV, and include only new events (ie, events that were never observed during the DB period, or, events observed during the DB period but with greater severity during the OL period). | 10 | 108 | 73 | 108 |
| EG003 | PLB - ADV | Placebo was matched to ADV treatment (oral suspension or tablet) by age group for the DB treatment period. At Week 48, all placebo-treated participants who did not exhibit HBeAg or hepatitis B surface antigen seroconversion at Week 44 were offered the opportunity to receive OL ADV for up to an additional 192 weeks (ie, enter the OL study period; Weeks 49 - 240).The ADV baseline was defined as the day of first dose of ADV (ie, Week 48 for those originally randomized to placebo [PLB-ADV group]). ADV week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). Treatment-emergent AEs for the OL period are events that began on or after the date of the first dose of OL ADV, and include only new events (ie, events that were never observed during the DB period, or, events observed during the DB period but with greater severity during the OL period). | 3 | 54 | 46 | 54 |
| dyspepsia | Gastrointestinal disorders | MedDRA (9.0) | Systematic Assessment |
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| gastritis | Gastrointestinal disorders | MedDRA (9.0) | Systematic Assessment |
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| pyrexia | General disorders | MedDRA (9.0) | Systematic Assessment |
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| hepatitis | Hepatobiliary disorders | MedDRA (9.0) | Systematic Assessment |
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| gastroenteritis bacterial | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| pneumonia | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| fracture | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| head injury | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| alcohol poisoning | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| joint injury | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| excoriation | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| facial bones fracture | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| hand fracture | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| joint dislocation | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| lower limb fracture | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
|
| road traffic accident | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| alanine aminotransferase increased | Investigations | MedDRA (9.0) | Systematic Assessment |
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| hepatic enzyme increased | Investigations | MedDRA (9.0) | Systematic Assessment |
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| syncope vasovagal | Nervous system disorders | MedDRA (9.0) | Systematic Assessment |
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| convulsion | Nervous system disorders | MedDRA (9.0) | Systematic Assessment |
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| abnormal behavior | Psychiatric disorders | MedDRA (9.0) | Systematic Assessment |
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| depression | Psychiatric disorders | MedDRA (9.0) | Systematic Assessment |
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| osteochondrosis | Musculoskeletal and connective tissue disorders | MedDRA (9.0) | Systematic Assessment |
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| dermatitis | Skin and subcutaneous tissue disorders | MedDRA (9.0) | Systematic Assessment |
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| wound | Injury, poisoning and procedural complications | MedDRA (9.0) | Systematic Assessment |
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| diarrhoea | Gastrointestinal disorders | MedDRA (9.0) | Systematic Assessment |
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| vomiting | Gastrointestinal disorders | MedDRA (9.0) | Systematic Assessment |
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| abdominal pain upper | Gastrointestinal disorders | MedDRA (9.0) | Systematic Assessment |
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| toothache | Gastrointestinal disorders | MedDRA (9.0) | Systematic Assessment |
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| pyrexia | General disorders | MedDRA (9.0) | Systematic Assessment |
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| nasopharyngitis | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| pharyngitis | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| upper respiratory tract infection | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| rhinitis | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| bronchitis | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| influenza | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| gastroenteritis | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| tonsillitis | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| otitis media | Infections and infestations | MedDRA (9.0) | Systematic Assessment |
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| headache | Nervous system disorders | MedDRA (9.0) | Systematic Assessment |
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| cough | Respiratory, thoracic and mediastinal disorders | MedDRA (9.0) | Systematic Assessment |
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| pharyngolaryngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (9.0) | Systematic Assessment |
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| epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (9.0) | Systematic Assessment |
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| rash | Skin and subcutaneous tissue disorders | MedDRA (9.0) | Systematic Assessment |
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| blood creatine phosphokinase increased | Investigations | MedDRA (9.0) | Systematic Assessment |
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Publication must include results in their entirety and not as individual center data. Results may be published/presented at scientific meetings. All manuscripts/abstracts must be submitted to Gilead prior to submission. Any formal publication of the study in which input of Gilead personnel exceeded that of conventional monitoring will be considered as a joint publication by the investigator and the appropriate Gilead personnel.
| D004266 |
| DNA Virus Infections |
| D014777 | Virus Diseases |
| D006525 | Hepatitis, Viral, Human |
| D006521 | Hepatitis, Chronic |
| D006505 | Hepatitis |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011743 |
| Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D015224 | Dideoxynucleosides |
Comparison of HBeAg Seroconversion |
| No |
| Superiority or Other |
| Changes at conserved sites in HBV polymerase |
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| Developed mutations specific to ADV/lamivudine |
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| Unable to be genotyped |
|
| Changes at conserved sites in HBV polymerase |
|
| Developed mutations specific to ADV and/or LAM |
|
| Unable to be genotyped |
|