Clinical trial NCT00095121: Safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents With Chronic Hepatitis B
Official title: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents (Age 2 to Less Than 18) With Chronic Hepatitis B
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Hepatitis B
Keywords: Hepatitis B
Children
Pediatric
Adefovir Dipivoxil
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2004-11-01
Enrollment: 173
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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).

Eligibility criteria: Key Inclusion Criteria:

* Positive HBsAg \>= 6 months prior to randomization and positive HBeAg at screening.
* Serum HBV DNA greater than or equal to 1 x 100,000 copies/mL (PCR assay) at initial or confirmatory screening visit.
* Serum ALT levels greater than or equal to 1.5 x ULN at both initial and confirmatory screening visits.
* Compensated liver disease with anticipated survival greater than 12 months and with the following laboratory and clinical parameters within 4 weeks of baseline: \*Prothrombin time less than or equal to 1 second above normal range. \*Total bilirubin less than 1.3 mg/dL or normal direct bilirubin. \*Serum albumin greater than 3 g/dL (greater than 30 g/L). \*No clinical history of ascites, variceal bleeding, encephalopathy or splenomegaly. \*Adequate renal function defined as creatinine clearance greater than or equal to 80 mL/min (calculated using Schwartz Formula).

Key Exclusion Criteria:

* Received immunoglobulin, interferon or lamivudine therapy within 6 months prior to initial screening visit.
* Participated in any investigational trial with any investigational compound within 2 months prior to initial screening.
* Organ or bone marrow transplant recipients.
* Clinical evidence of decompensated liver disease.
* A Child-Pugh-Turcotte score greater than 6.
* Inability to comply with study requirements.

Primary outcomes:
measure: 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)
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline)
timeFrame: ADV baseline
measure: Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment - Missing = Failure) (ADV Week 192)
timeFrame: ADV Week 192
measure: Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240)
timeFrame: ADV Week 240
measure: Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline)
timeFrame: ADV baseline
measure: Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 192)
timeFrame: ADV Week 192
measure: Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240)
timeFrame: ADV Week 240
measure: Adefovir (ADV) Baseline Serum HBV DNA
timeFrame: ADV baseline
measure: Change From ADV Baseline to ADV Week 192 for Serum HBV DNA
timeFrame: ADV baseline to ADV 192 weeks
measure: Change From ADV Baseline to ADV Week 240 for Serum HBV DNA
timeFrame: ADV baseline to ADV 240 weeks
measure: ADV Baseline ALT
timeFrame: ADV baseline
measure: Change From ADV Baseline to ADV Week 192 for ALT
timeFrame: ADV baseline to ADV 192 weeks
measure: Change From ADV Baseline to ADV Week 240 for ALT
timeFrame: ADV baseline to ADV 240 weeks
measure: Percentage of Participants With Normal ALT at Adefovir Baseline (Missing = Failure)
timeFrame: ADV baseline
measure: Percentage of Participants With Normal ALT at ADV Week 192 (Missing = Failure)
timeFrame: ADV Week 192
measure: Percentage of Participants With Normal ALT at ADV Week 240 (Missing = Failure)
timeFrame: ADV Week 240
measure: 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)
timeFrame: Study Week 0 to Study Week 48 (double-blind period)
measure: 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)
timeFrame: ADV baseline to ADV Week 192
measure: 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)
timeFrame: ADV baseline to ADV Week 240
measure: Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance)
timeFrame: 240 weeks
measure: Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) for Subjects Who Received Combination ADV + Lamivudine Therapy
timeFrame: 240 weeks
measure: Percentage of Participants With Durable HBeAg Seroconversion
timeFrame: 240 weeks
Other outcomes:
Locations:
city: Boston
country: United States
state: Massachusetts
Study officials:
affiliation: Gilead Sciences
name: John Flaherty, PharmD
role: STUDY_DIRECTOR
References:
citation: 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.