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

Study Overview
=================
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.

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

Conditions
-----------------
Hepatitis B Virus (HBV)

Intervention / Treatment
-----------------
* Drug: Tenofovir disoproxil fumarate (TDF)
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir disoproxil fumarate (TDF)<br> | Drug: Tenofovir disoproxil fumarate (TDF)<br>* TDF administered as a 300-mg tablet once daily<br>* Other names: Viread®;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* TDF placebo tablet once daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 96, 144, and 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | Weeks 48, 96, 144, and 192 | 
| Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Weeks 48, 72, 96, 144, and 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | 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 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | Weeks 48, 72, 96, 144, and 192 | 
| Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 72, 96, 144, and 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | 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 | Data were summarized by treatment and age group (grouped by baseline age for analysis), using the M = F. | Baseline; Weeks 48, 72, 96, 144, and 192 | 
| Percentage of Participants With HBsAg Seroconversion at Weeks 48, 72, 96, 144, and 192 | HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive. Data were summarized by treatment and age group (grouped by baseline age for analysis), using the M = F. | Baseline; Weeks 48, 72, 96, 144, and 192 | 
| Percentage of Participants With at Least a 6% Decrease From Baseline in Spine BMD at Weeks 48, 96, 144, and 192 | The percentage of participants reported is the cumulative incidence from baseline to the respective time point. Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Weeks 48, 96, 144, and 192 | 
| Percentage of Participants With at Least a 6% Decrease From Baseline in Whole Body BMD at Weeks 48, 72, 96, 144, and 192 | The percentage of participants reported is the cumulative incidence from baseline to the respective time point. Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Weeks 48, 72, 96, 144, and 192 | 
| Percent Change From Baseline in Spine Bone Mineral Density (BMD) at Week 48 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 48 | 
| Percent Change From Baseline in Spine BMD at Week 72 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 72 | 
| Percent Change From Baseline in Spine BMD at Week 96 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 96 | 
| Percent Change From Baseline in Spine BMD at Week 144 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 144 | 
| Percent Change From Baseline in Spine BMD at Week 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 192 | 
| Percent Change From Baseline in Whole Body BMD at Week 48 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 48 | 
| Percent Change From Baseline in Whole Body BMD at Week 72 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 72 | 
| Percent Change From Baseline in Whole Body BMD at Week 96 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 96 | 
| Percent Change From Baseline in Whole Body BMD at Week 144 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 144 | 
| Percent Change From Baseline in Whole Body BMD at Week 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 192 | 
| Change From Baseline in Z-score for Spine BMD at Week 48 | 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. Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 48 | 
| Change From Baseline in Z-score for Spine BMD at Week 72 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 72 | 
| Change From Baseline in Z-score for Spine BMD at Week 96 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 96 | 
| Change From Baseline in Z-score for Spine BMD at Week 144 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 144 | 
| Change From Baseline in Z-score for Spine BMD at Week 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 192 | 
| Change From Baseline in Z-score for Whole Body BMD at Week 48 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 48 | 
| Change From Baseline in Z-score for Whole Body BMD at Week 72 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 72 | 
| Change From Baseline in Z-score for Whole Body BMD at Week 96 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 96 | 
| Change From Baseline in Z-score for Whole Body BMD at Week 144 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 144 | 
| Change From Baseline in Z-score for Whole Body BMD at Week 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis). | Baseline; Week 192 | 
| Number of Participants With Changes in Drug-Resistant Mutations During the Study | The number of participants with changes in drug-resistant mutations during the study was summarized. | Baseline through Week 192 | 
| Percentage of Participants Who Were HBeAg-Positive at Baseline and Who Had HBeAg Loss at Weeks 48, 72, 96, 144, and 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | Baseline; Weeks 48, 72, 96, 144, and 192 | 
| Percentage of Participants Who Were HBeAg-Positive at Baseline and Who Had HBeAg Seroconversion at Weeks 48, 72, 96, 144, and 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | Baseline; Weeks 48, 72, 96, 144, and 192 | 
| 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 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | Baseline; Weeks 48, 72, 96, 144, and 192 | 
| Percentage of Participants With Abnormal ALT at Baseline Who Had Normalized ALT at Weeks 48, 72, 96, 144, and 192 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | Baseline; Weeks 48, 72, 96, 144, and 192 | 
| 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 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | Baseline; Weeks 48, 72, 96, 144, and 192 | 
| 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 | Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. | Baseline; Weeks 48, 72, 96, 144, and 192 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
tenofovir, adolescents, chronic hepatitis B