Clinical trial NCT00734162: Evaluation of Tenofovir Disoproxil Fumarate in Adolescents With Chronic Hepatitis B Infection
Official title: A Randomized, Double-Blind Evaluation of the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate Versus Placebo in Adolescents With Chronic Hepatitis B Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis B Virus (HBV)
Keywords: tenofovir
adolescents
chronic hepatitis B
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2008-08-14
Enrollment: 106
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary purpose of the study is to evaluate the effectiveness, safety, and tolerability of tenofovir disoproxil fumarate (TDF) in adolescents (aged 12-17 years) with chronic hepatitis B virus (HBV) infection.

The optimal treatment for adolescents with chronic HBV infection is currently unknown. Treatment with interferon alfa, lamivudine, and adefovir dipivoxil in pediatric populations has been shown to be less than optimal. Further, the safety and efficacy of entecavir and telbivudine have not been established in patients \< 16 years of age. A study evaluating TDF in adolescents (ages 12-17) was needed to assess the safety and efficacy of this agent in the treatment of chronic hepatitis B in this patient population. In addition, the study will help to further elucidate the pharmacokinetic (PK) and resistance profiles of TDF. Through their participation, study participants will help generate critical new information to help guide the most optimal treatment of chronic HBV infection in adolescents.

This is a randomized, double-blind study to evaluate the antiviral efficacy, safety, and tolerability of TDF versus placebo in adolescents with chronic HBV infection. TDF treatment-naive participants were randomized in a 1:1 ratio to TDF or placebo. After 72 weeks of blinded treatment, participants were to switch to open-label TDF for an additional 2.5 years of treatment, provided that no safety concerns are identified by the Independent Data Monitoring Committee monitoring the study.


Eligibility criteria: Inclusion Criteria

* Male or female, 12 through 17 years of age, inclusive (consent of parent/legal guardian required)
* Documented chronic HBV infection
* HBeAg positive or HBeAg negative
* Weight \> 35 kg
* Able to swallow oral tablets
* HBV DNA \> 100,000 copies/mL (polymerase chain reaction (PCR) method)
* Alanine aminotransferase (ALT) \> 2 × upper limit of normal (ULN) at screening, OR any history of ALT \> 2 × ULN over the past 24 months
* Willing and able to provide written informed consent/assent (child and parent/legal guardian)
* Negative serum pregnancy test (for postmenarchal females only)
* Estimated glomerular filtration rate (creatinine clearance \[using the Schwartz formula\]) \> 80 mL/min/1.73m\^2
* Adequate hematologic function (absolute neutrophil count ≥ 1,500/mm\^3; hemoglobin ≥ 10.0 g/dL)
* No prior TDF therapy (participants may have received prior interferon or oral anti-HBV nucleoside/nucleotide therapy; participants must have discontinued interferon therapy ≥ 6 months prior to screening; participants experienced on anti-HBV nucleoside/nucleotide therapy must have discontinued therapy ≥ 16 weeks prior to screening to avoid flare if randomized to the placebo arm)

Exclusion Criteria

* Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study
* Males and females of reproductive potential who are not willing to use an effective method of contraception during the study
* Decompensated liver disease
* Receipt of interferon (pegylated or not) therapy within 6 months of the Screening Visit
* Receipt of anti-HBV nucleoside/nucleotide therapy within 16 weeks of the Screening Visit
* Alpha fetoprotein \> 50 ng/mL
* Evidence of hepatocellular carcinoma (HCC)
* Coinfection with HIV, hepatitis C virus (HCV), or hepatitis D virus (HDV)
* History of significant renal disease (eg, nephrotic syndrome, renal dysgenesis, polycystic kidney disease, congenital nephrosis, acute tubular necrosis, other renal disease)
* History of significant bone disease (eg, osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochondroses, multiple bone fractures)
* Significant cardiovascular, pulmonary, or neurological disease
* Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications
* History of solid organ or bone marrow transplantation
* Ongoing therapy with nephrotoxic agents, competitors of renal excretion, systemic chemotherapeutic agents, systemic corticosteroids, interleukin-2 (IL-2), or other immunomodulating or investigational agents
* Known hypersensitivity to the study drugs, the metabolites or formulation excipients
* Any other condition (including alcohol or substance abuse) or prior therapy that, in the opinion of the Investigator, would make the participants unsuitable for the study or unable to comply with dosing requirements

Primary outcomes:
measure: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 72
timeFrame: Week 72
measure: Percentage of Participants With at Least a 6% Decrease From Baseline in Bone Mineral Density (BMD) of the Spine at Week 72
timeFrame: Baseline to Week 72
Secondary outcomes:
measure: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 96, 144, and 192
timeFrame: Weeks 48, 96, 144, and 192
measure: Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Weeks 48, 72, 96, 144, and 192
timeFrame: Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants With HBV DNA < 400 Copies/mL and Normal ALT at Weeks 48, 72, 96, 144, and 192
timeFrame: Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 72, 96, 144, and 192
timeFrame: Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants With HBsAg Seroconversion at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants With at Least a 6% Decrease From Baseline in Spine BMD at Weeks 48, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 96, 144, and 192
measure: Percentage of Participants With at Least a 6% Decrease From Baseline in Whole Body BMD at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
measure: Percent Change From Baseline in Spine Bone Mineral Density (BMD) at Week 48
timeFrame: Baseline; Week 48
measure: Percent Change From Baseline in Spine BMD at Week 72
timeFrame: Baseline; Week 72
measure: Percent Change From Baseline in Spine BMD at Week 96
timeFrame: Baseline; Week 96
measure: Percent Change From Baseline in Spine BMD at Week 144
timeFrame: Baseline; Week 144
measure: Percent Change From Baseline in Spine BMD at Week 192
timeFrame: Baseline; Week 192
measure: Percent Change From Baseline in Whole Body BMD at Week 48
timeFrame: Baseline; Week 48
measure: Percent Change From Baseline in Whole Body BMD at Week 72
timeFrame: Baseline; Week 72
measure: Percent Change From Baseline in Whole Body BMD at Week 96
timeFrame: Baseline; Week 96
measure: Percent Change From Baseline in Whole Body BMD at Week 144
timeFrame: Baseline; Week 144
measure: Percent Change From Baseline in Whole Body BMD at Week 192
timeFrame: Baseline; Week 192
measure: Change From Baseline in Z-score for Spine BMD at Week 48
timeFrame: Baseline; Week 48
measure: Change From Baseline in Z-score for Spine BMD at Week 72
timeFrame: Baseline; Week 72
measure: Change From Baseline in Z-score for Spine BMD at Week 96
timeFrame: Baseline; Week 96
measure: Change From Baseline in Z-score for Spine BMD at Week 144
timeFrame: Baseline; Week 144
measure: Change From Baseline in Z-score for Spine BMD at Week 192
timeFrame: Baseline; Week 192
measure: Change From Baseline in Z-score for Whole Body BMD at Week 48
timeFrame: Baseline; Week 48
measure: Change From Baseline in Z-score for Whole Body BMD at Week 72
timeFrame: Baseline; Week 72
measure: Change From Baseline in Z-score for Whole Body BMD at Week 96
timeFrame: Baseline; Week 96
measure: Change From Baseline in Z-score for Whole Body BMD at Week 144
timeFrame: Baseline; Week 144
measure: Change From Baseline in Z-score for Whole Body BMD at Week 192
timeFrame: Baseline; Week 192
measure: Number of Participants With Changes in Drug-Resistant Mutations During the Study
timeFrame: Baseline through Week 192
measure: Percentage of Participants Who Were HBeAg-Positive at Baseline and Who Had HBeAg Loss at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants Who Were HBeAg-Positive at Baseline and Who Had HBeAg Seroconversion at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants Who Were HBeAg-Positive at Baseline Who Had HBV DNA < 400 Copies/mL, Normal ALT, and HBeAg Loss/Seroconversion at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants With Abnormal ALT at Baseline Who Had Normalized ALT at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants With Abnormal ALT at Baseline Who Had HBV DNA < 400 Copies/mL and Normalized ALT at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
measure: Percentage of Participants Who Were HBeAg-Positive With Abnormal ALT at Baseline Who Had HBV DNA < 400 Copies/mL, Normalized ALT, and HBeAg Loss/Seroconversion at Weeks 48, 72, 96, 144, and 192
timeFrame: Baseline; Weeks 48, 72, 96, 144, and 192
Other outcomes:
Locations:
city: Oakland
country: United States
facility: Children's Hospital & Research Center at Oakland
state: California
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Seattle
country: United States
facility: Children's Hospital & Regional Medical Center, d/b/a Seattle Children's Research Institute
state: Washington
city: Plovdiv
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Sveti Georgi
city: Sofia
country: Bulgaria
facility: Clinic of Gastroenterology, Specialized Hospital for Active Treatment of Pediatric Diseases, Sofia
city: Bron Cedex
country: France
facility: Hopital Femmes Meres Enfants
city: Lille Cedex
country: France
facility: Hôpital Claude Huriez
city: Białystok
country: Poland
facility: Samodzielny Publiczny Dzieciecy Szpital Kliniczny Akademii Medycznej w Bialymstoku
city: Bydgoszcz
country: Poland
facility: Wojewodzki Specjalistyczny Szpital im Bieganskiego
city: Bydgoszcz
country: Poland
facility: Wojewodzki Szpital Obserwacyjno-Zakazny im. T. Browicza
city: Kraków
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawla II
city: Poznan
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny im. Karola Johschera
city: Poznań
country: Poland
facility: Specjalistyczny Zespol Opieki Zdrowotnej nad Matka i Dzieckiem
city: Warszawa
country: Poland
facility: Wojewodzki Szpital Zakazny
city: Wrocław
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1
city: Bucharest
country: Romania
facility: Fundeni Clinical Institute
city: Bucharest
country: Romania
facility: Institute for Infectious Diseases
city: Napaco
country: Romania
facility: Cluj Childrens Emergency Hospital
city: Madrid
country: Spain
facility: Hosp Univ y Politecnico La Fe de Valencia
city: Madrid
country: Spain
facility: Hospital Universitario De Getafe
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi Hastanesi
Study officials:
affiliation: Gilead Sciences
name: Benedetta Massetto, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Murray KF, Szenborn L, Wysocki J, Rossi S, Corsa AC, Dinh P, McHutchison J, Pang PS, Luminos LM, Pawlowska M, Mizerski J. Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology. 2012 Dec;56(6):2018-26. doi: 10.1002/hep.25818. Epub 2012 Aug 27.