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

Hepatitis B Virus (HBV) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00734162
• Other study ID #: GS-US-174-0115
• Status: Completed
• Phase: Phase 3
• First received: August 13, 2008
• Last updated: February 2, 2016
• Start date: December 2008
• Est. completion date: December 2015

Study information

• Verified date: February 2016
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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. One hundred TDF treatment-naive participants were randomized in a 1:1 ratio to TDF or placebo. After 72 weeks of blinded treatment, all 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: December 2015
• Est. primary completion date: March 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years to 17 Years

Eligibility

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)

• 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, HCV, or 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B Virus (HBV)
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Tenofovir disoproxil fumarate (TDF)
TDF administered as a 300-mg tablet, once daily (QD)
• Placebo
Placebo to match TDF QD

Locations

Country	Name	City	State
Bulgaria	Multiprofile Hospital for Active Treatment Sveti Georgi	Plovdiv
Bulgaria	Clinic of Gastroenterology, Specialized Hospital for Active Treatment of Pediatric Diseases, Sofia	Sofia
France	Hopital Femmes Meres Enfants	Bron Cedex
France	Hôpital Claude Huriez	Lille Cedex
Poland	Samodzielny Publiczny Dzieciecy Szpital Kliniczny Akademii Medycznej w Bialymstoku	Bialystok
Poland	Wojewodzki Specjalistyczny Szpital im Bieganskiego	Bydgoszcz
Poland	Wojewodzki Szpital Obserwacyjno-Zakazny im. T. Browicza	Bydgoszcz
Poland	Krakowski Szpital Specjalistyczny im. Jana Pawla II	Kraków
Poland	Samodzielny Publiczny Szpital Kliniczny im. Karola Johschera	Poznan
Poland	Specjalistyczny Zespol Opieki Zdrowotnej nad Matka i Dzieckiem	Poznan
Poland	Wojewodzki Szpital Zakazny	Warszawa
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1	Wroclaw
Romania	Fundeni Clinical Institute	Bucharest
Romania	Institute for Infectious Diseases	Bucharest
Romania	Cluj Childrens Emergency Hospital	Napaco
Spain	Hosp Univ y Politecnico La Fe de Valencia	Madrid
Spain	Hospital Universitario De Getafe	Madrid
Turkey	Ege Universitesi Tip Fakultesi Hastanesi	Izmir
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Children's Hospital & Research Center at Oakland	Oakland	California
United States	Children's Hospital & Regional Medical Center, d/b/a Seattle Children's Research Institute	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Bulgaria,  France,  Poland,  Romania,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With HBV Deoxyribonucleic Acid (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	No
Primary	Number of Participants With at Least a 6% Decrease From Baseline in Bone Mineral Density (BMD) of the Spine at Week 72	The number of participants with at least a 6% decrease from baseline in spine BMD at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis).	Baseline to Week 72	Yes
Secondary	Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48	The percentage of participants with HBV DNA < 400 copies/mL at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Week 48	No
Secondary	Percentage of Participants With HBV DNA < 169 Copies/mL at Week 48	The percentage of participants with HBV DNA < 169 copies/mL at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis, using the M = F analysis with the DBEE algorithm.	Week 48	No
Secondary	Percentage of Participants With HBV DNA < 169 Copies/mL at Week 72	The percentage of participants with HBV DNA < 169 copies/mL at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Week 72	No
Secondary	Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 48	The percentage of participants with normal ALT at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm. Normal ALT was defined as having a value less than or equal to the upper limit of normal range (ULN).	Week 48	No
Secondary	Percentage of Participants With Normal ALT at Week 72	The percentage of participants with normal ALT at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Week 72	No
Secondary	Percentage of Participants With Abnormal ALT at Baseline Who Had Normalized ALT at Week 48	The percentage of participants with abnormal ALT at baseline who had normalized ALT at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm. Normalized ALT was defined as having a baseline ALT value > ULN, and a decrease in ALT value to = ULN at the given time point.	Baseline to Week 48	No
Secondary	Percentage of Participants With Abnormal ALT at Baseline Who Had Normalized ALT at Week 72	The percentage of participants with abnormal ALT at baseline who had normalized ALT at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants With HBV DNA < 400 Copies/mL and Normal ALT at Week 48	The percentage of participants with both HBV DNA < 400 copies/mL and normal ALT at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Week 48	No
Secondary	Percentage of Participants With HBV DNA < 400 Copies/mL and Normal ALT at Week 72	The percentage of participants with both HBV DNA < 400 copies/mL and normal ALT at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Week 72	No
Secondary	Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Week 48	The percentage of participants with HBsAg loss at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm. Loss of HBsAg was defined as change of detectable HBsAg from positive to negative.	Baseline to Week 48	No
Secondary	Percentage of Participants With HBsAg Loss at Week 72	The percentage of participants with HBsAg loss at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Week 48	The percentage of participants with seroconversion to anti-HBs at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative to positive.	Baseline to Week 48	No
Secondary	Percentage of Participants With Seroconversion to Anti-HBs at Week 72	The percentage of participants with seroconversion to anti-HBs at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants Who Were HBV Early Antigen (HBeAg) Positive at Baseline and Who Had HBeAg Loss at Week 48	The percentage of participants who were HBeAg positive at baseline and who had HBeAg loss at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative.	Baseline to Week 48	No
Secondary	Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had HBeAg Loss at Week 72	The percentage of participants who were HBeAg positive at baseline and who had HBeAg loss at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had Seroconversion to Antibody Against HBV Early Antigen (Anti-HBe) at Week 48	The percentage of participants who were HBeAg positive at baseline and who had seroconversion to anti-HBe at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative to positive.	Baseline to Week 48	No
Secondary	Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had Seroconversion to Anti-HBe at Week 72	The percentage of participants who were HBeAg positive at baseline and who had seroconversion to anti-HBe at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had HBV DNA < 400 Copies/mL, Normal ALT, and HBeAg Loss at Week 48	The percentage of participants who were HBeAg positive at baseline and who had HBV DNA < 400 copies/mL, normal ALT, and HBeAg Loss at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 48	No
Secondary	Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had HBV DNA < 400 Copies/mL, Normal ALT, and HBeAg Loss at Week 72	The percentage of participants who were HBeAg positive at baseline and who had HBV DNA < 400 copies/mL, normal ALT, and HBeAg Loss at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had HBV DNA < 400 Copies/mL, Normal ALT, and Seroconversion to HBeAg at Week 48	The percentage of participants who were HBeAg positive at baseline and who had HBV DNA < 400 copies/mL, normal ALT, and seroconversion to HBeAg at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 48	No
Secondary	Percentage of Participants Who Were HBeAg Positive at Baseline and Who Had HBV DNA < 400 Copies/mL, Normal ALT, and Seroconversion to HBeAg at Week 72	The percentage of participants who were HBeAg positive at baseline and who had HBV DNA < 400 copies/mL, normal ALT, and seroconversion to HBeAg at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants Who Had Abnormal ALT at Baseline and Who Had HBV DNA < 400 Copies/mL and ALT Normalized at Week 48	The percentage of participants who had abnormal ALT at baseline and who had HBV DNA < 400 copies/mL and ALT normalized at Week 48 was summarized, using the M = F analysis with the DBEE algorithm.	Baseline to Week 48	No
Secondary	Percentage of Participants Who Had Abnormal ALT at Baseline and Who Had HBV DNA < 400 Copies/mL and ALT Normalized at Week 72	The percentage of participants who had abnormal ALT at baseline and who had HBV DNA < 400 copies/mL and ALT normalized at Week 72 was summarized, using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants Who Were HBeAG Positive With Abnormal ALT at Baseline, and Who Had HBV DNA < 400 Copies/mL, ALT Normalized, and HBeAg Loss at Week 48	The percentage of participants who were HBeAG positive with abnormal ALT at baseline, and who had HBV DNA < 400 copies/mL, ALT normalized, and HBeAg loss at Week 48 was summarized, using the M = F analysis with the DBEE algorithm.	Baseline to Week 48	No
Secondary	Percentage of Participants Who Were HBeAG Positive With Abnormal ALT at Baseline, and Who Had HBV DNA < 400 Copies/mL, ALT Normalized, and HBeAg Loss at Week 72	The percentage of participants who were HBeAG positive with abnormal ALT at baseline, and who had HBV DNA < 400 copies/mL, ALT normalized, and HBeAg loss at Week 72 was summarized, using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Percentage of Participants Who Were HBeAG Positive With Abnormal ALT at Baseline, and Who Had HBV DNA < 400 Copies/mL, ALT Normalized, and Seroconversion to HBeAg at Week 48	The percentage of participants who were HBeAG positive with abnormal ALT at baseline, and had HBV DNA < 400 copies/mL, ALT normalized, and seroconversion to HBeAg at Week 48 was summarized, using the M = F analysis with the DBEE algorithm.	Baseline to Week 48	No
Secondary	Percentage of Participants Who Were HBeAG Positive With Abnormal ALT at Baseline, and Who Had HBV DNA < 400 Copies/mL, ALT Normalized, and Seroconversion to HBeAg at Week 72	The percentage of participants who were HBeAG positive with abnormal ALT at baseline, and who had HBV DNA < 400 copies/mL, ALT normalized, and seroconversion to HBeAg at Week 72 was summarized, using the M = F analysis with the DBEE algorithm.	Baseline to Week 72	No
Secondary	Number of Participants With at Least a 6% Decrease From Baseline in Spine BMD at Week 48	The number of participants with at least a 6% decrease from baseline in spine BMD at Week 48 was summarized by treatment and age group (grouped by baseline age for analysis).	Baseline to Week 48	Yes
Secondary	Percent Change From Baseline in Spine BMD at Week 48	The mean (standard deviation [SD]) percent change from baseline in spine BMD at Week 48 was summarized.	Baseline to Week 48	Yes
Secondary	Percent Change From Baseline in Spine BMD at Week 72	The mean (standard deviation [SD]) percent change from baseline in spine BMD at Week 72 was summarized.	Baseline to Week 72	Yes
Secondary	Change in Z-score for Spine BMD at Week 48	The change in mean (SD) Z-score for spine BMD at Week 48 was summarized. To assess any effect of treatment on growth, Z-scores were used to express the deviation from a reference population for lumbar spine BMD. A Z-score of 0 indicated that a subject was typical of the population for their age, ethnicity, and gender. A negative Z-score indicated that the subject's recorded value was lower than typical for their age, ethnicity, and gender. A positive Z-score indicates that the subject's recorded value was higher than typical for their age, ethnicity, and gender.	Baseline to Week 48	Yes
Secondary	Change in Z-score for Spine BMD at Week 72	The change in mean (SD) Z-score for spine BMD at Week 72 was summarized.	Baseline to Week 72	Yes
Secondary	Percent Change From Baseline in Whole Body BMD at Week 48	The mean (SD) percent change from baseline in whole body BMD at Week 48 was summarized.	Baseline to Week 48	Yes
Secondary	Percent Change From Baseline in Whole Body BMD at Week 72	The mean (SD) percent change from baseline in whole body BMD at Week 72 was summarized.	Baseline to Week 72	Yes
Secondary	Change in Z-score for Whole Body BMD at Week 48	The change in mean (SD) Z-score for whole body BMD at Week 48 was summarized. To assess any effect of treatment on growth, Z-scores were used to express the deviation from a reference population for whole body spine BMD. A Z-score of 0 indicated that a subject was typical of the population for their age, ethnicity, and gender. A negative Z-score indicated that the subject's recorded value was lower than typical for their age, ethnicity, and gender. A positive Z-score indicates that the subject's recorded value was higher than typical for their age, ethnicity, and gender.	Baseline to Week 48	Yes
Secondary	Change in Z-score for Whole Body BMD at Week 72	The change in mean (SD) Z-score for whole body BMD at Week 72 was summarized.	Baseline to Week 72	Yes
Secondary	Number of Participants With Changes in Drug-resistant Mutations at Week 48	The number of participants with changes in drug-resistant mutations from baseline at Week 48 was summarized.	Baseline to Week 48	No
Secondary	Number of Participants With Changes in Drug-resistant Mutations at Week 72	The number of participants with changes in drug-resistant mutations from baseline at Week 72 was summarized.	Baseline to Week 72	No