Evaluation of Tenofovir Disoproxil Fumarate in Adolescents With Chronic Hepatitis B Infection

NCT00734162 | Completed Phase 3 Results DMC

• 1 other identifier: GS-US-174-0115
• Study Type: interventional
• Target: 106
• Locations: 7 countries
• Sites: 21

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.

Conditions

Hepatitis B Virus (HBV)

Keywords

tenofovir; adolescents; chronic hepatitis B

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With HBV DNA < 400 Copies/mL at Week 72

  The percentage of participants with HBV DNA \< 400 copies/mL at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the missing = failure (M = F) analysis with the double-blind efficacy evaluation (DBEE) algorithm. In the M = F analysis method, all missing data were considered as failure to meet the outcome measure threshold. This method was combined with the DBEE algorithm, which included all available data for the double-blind period, and any data for the open-label period were not included; data generated during treatment-free follow-up from subjects who achieved HBsAg loss and entered treatment-free follow-up during double-blind treatment period were included.

  Week 72

• Percentage of Participants With at Least a 6% Decrease From Baseline in Bone Mineral Density (BMD) of the Spine at Week 72

  Data were summarized by treatment and age group (grouped by baseline age for analysis). In contrast with what was previously reported in the interim results posting, 1 participant met the primary safety endpoint of at least a 6% decrease from baseline in spine BMD at Week 72, based on the final BMD data analysis. The apparent discrepancy was due to the correction factor applied to the subject-specific BMD calculations performed at the time of the Interim Week 72 clinical study report that could not take into account the actual Week 72 phantom data (ie, calibration test used in longitudinal clinical trials to monitor and adjust for shifts in the dual-energy x-ray absorptiometry (DXA) scanner calibration over time), which were not provided by the site at that time. The correction factor applied to the final analysis has been properly based on all phantom data through the end of Week 72, as well as through the end of Week 192.

  Baseline to Week 72

Secondary Outcomes (35)

• Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 96, 144, and 192

  Weeks 48, 96, 144, and 192

• Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Weeks 48, 72, 96, 144, and 192

  Weeks 48, 72, 96, 144, and 192

• Percentage of Participants With HBV DNA < 400 Copies/mL and Normal ALT at Weeks 48, 72, 96, 144, and 192

  Weeks 48, 72, 96, 144, and 192

• Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 72, 96, 144, and 192

  Weeks 48, 72, 96, 144, and 192

• Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48, 72, 96, 144, and 192

  Baseline; Weeks 48, 72, 96, 144, and 192

Study Arms (2)

Tenofovir disoproxil fumarate (TDF)

EXPERIMENTAL

Drug: Tenofovir disoproxil fumarate (TDF)

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Tenofovir disoproxil fumarate (TDF) DRUG

TDF administered as a 300-mg tablet once daily

Also known as: Viread®

Tenofovir disoproxil fumarate (TDF)

Placebo DRUG

TDF placebo tablet once daily

Placebo

Eligibility Criteria

• Age: 12 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (21)

Children's Hospital & Research Center at Oakland

Oakland, California, 94609, United States

Location

Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

Children's Hospital & Regional Medical Center, d/b/a Seattle Children's Research Institute

Seattle, Washington, 98105, United States

Location

Multiprofile Hospital for Active Treatment Sveti Georgi

Plovdiv, 4002, Bulgaria

Location

Clinic of Gastroenterology, Specialized Hospital for Active Treatment of Pediatric Diseases, Sofia

Sofia, 1606, Bulgaria

Location

Hopital Femmes Meres Enfants

Bron, 69677, France

Location

Hôpital Claude Huriez

Lille, 59037, France

Location

Samodzielny Publiczny Dzieciecy Szpital Kliniczny Akademii Medycznej w Bialymstoku

Bialystok, 15-274, Poland

Location

Wojewodzki Specjalistyczny Szpital im Bieganskiego

Bydgoszcz, 85-030, Poland

Location

Wojewodzki Szpital Obserwacyjno-Zakazny im. T. Browicza

Bydgoszcz, 85-030, Poland

Location

Krakowski Szpital Specjalistyczny im. Jana Pawla II

Krakow, 31-202, Poland

Location

Samodzielny Publiczny Szpital Kliniczny im. Karola Johschera

Poznan, 60-572, Poland

Location

Specjalistyczny Zespol Opieki Zdrowotnej nad Matka i Dzieckiem

Poznan, 61-734, Poland

Location

Wojewodzki Szpital Zakazny

Warsaw, 01-201, Poland

Location

Samodzielny Publiczny Szpital Kliniczny Nr 1

Wroclaw, 50-368, Poland

Location

Fundeni Clinical Institute

Bucharest, 022328, Romania

Location

Institute for Infectious Diseases

Bucharest, 21105, Romania

Location

Cluj Childrens Emergency Hospital

Napaco, 400217, Romania

Location

Hosp Univ y Politecnico La Fe de Valencia

Madrid, 28046, Spain

Location

Hospital Universitario De Getafe

Madrid, 46009, Spain

Location

Ege Universitesi Tip Fakultesi Hastanesi

Izmir, 35100, Turkey (Türkiye)

Location

Related Publications (1)

• 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.

  PMID: 22544804 RESULT

MeSH Terms

Conditions

Hepatitis B; Hepatitis B, Chronic

Interventions

Tenofovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Clinical Trial Disclosures
• Organization: Gilead Sciences

ClinicalTrialDisclosures@gilead.com

Study Officials

• Benedetta Massetto, MD, PhD

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 13, 2008
• First Posted: August 14, 2008
• Study Start: December 1, 2008
• Primary Completion: March 1, 2011
• Study Completion: December 1, 2015
• Last Updated: September 1, 2016
• Results First Posted: November 7, 2012

Record last verified: 2016-07

Locations

US (3); FR (2); PL (8); ES (2); BU (2); RO (3); TU (1)