The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00737568




Registration number
NCT00737568
Ethics application status
Date submitted
15/08/2008
Date registered
19/08/2008
Date last updated
11/03/2016

Titles & IDs
Public title
Tenofovir Disoproxil Fumarate (Tenofovir DF) Versus Emtricitabine/Tenofovir DF in Subjects Resistant to Lamivudine
Scientific title
A Phase 3b, Randomized, Double-Blind, Double-Dummy Study Evaluating the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus Emtricitabine Plus Tenofovir DF Fixed-Dose Combination Therapy in Subjects With Chronic Hepatitis B Who Are Resistant to Lamivudine
Secondary ID [1] 0 0
GS-US-174-0121
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatitis B 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - TDF
Treatment: Drugs - FTC/TDF
Treatment: Drugs - TDF Placebo
Treatment: Drugs - FTC/TDF Placebo

Experimental: Tenofovir DF - TDF plus placebo to match FTC/TDF

Experimental: FTC/TDF - FTC/TDF plus placebo to match TDF


Treatment: Drugs: TDF
Tenofovir disoproxil fumarate (tenofovir DF; TDF) 300 mg tablet administered orally once daily

Treatment: Drugs: FTC/TDF
Emtricitabine (FTC)/TDF 200/300 mg fixed-dose combination tablet administered orally once daily

Treatment: Drugs: TDF Placebo
TDF placebo tablet administered orally once daily

Treatment: Drugs: FTC/TDF Placebo
FTC/TDF placebo tablet administered orally once daily

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96
Timepoint [1] 0 0
Week 96
Secondary outcome [1] 0 0
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240
Timepoint [1] 0 0
Weeks 48, 144, 192, and 240
Secondary outcome [2] 0 0
Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240
Timepoint [2] 0 0
Weeks 48, 96, 144, 192, and 240
Secondary outcome [3] 0 0
HBV DNA Level at Weeks 48, 96, 144, 192, and 240
Timepoint [3] 0 0
Weeks 48, 96, 144, 192, and 240
Secondary outcome [4] 0 0
Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240 - Normal ALT was defined as having a value less than or equal to the ULN. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged = 69.
Timepoint [4] 0 0
Weeks 48, 96, 144, 192, and 240
Secondary outcome [5] 0 0
Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240 - The percentage of participants who were HBeAg positive at baseline and who had HBeAg Loss at the given time point was summarized. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative.
Timepoint [5] 0 0
Baseline; Weeks 48, 96, 144, 192, and 240
Secondary outcome [6] 0 0
Percentage of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at Weeks 48, 96, 144, 192, and 240 - The percentage of participants who were HBeAg positive at baseline and who had seroconversion to anti-HBe at the given time point was summarized. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative to positive.
Timepoint [6] 0 0
Baseline; Weeks 48, 96, 144, 192, and 240
Secondary outcome [7] 0 0
Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Weeks 48, 96, 144, 192, and 240 - The percentage of participants with HBsAg Loss at the given time point was summarized. Loss of HBsAg was defined as change of detectable HBsAg from positive to negative.
Timepoint [7] 0 0
Baseline; Weeks 48, 96, 144, 192, and 240
Secondary outcome [8] 0 0
Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Weeks 48, 96, 144, 192, and 240 - The percentage of participants with seroconversion to anti-HBs at the given time point was summarized. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative to positive.
Timepoint [8] 0 0
Baseline; Weeks 48, 96, 144, 192, and 240
Secondary outcome [9] 0 0
Percentage of Participants With Virologic Breakthrough at Weeks 48, 96, 144, 192, and 240 - The percentage of participants with virologic breakthrough at the given time point was summarized. Virologic breakthrough was defined as having two consecutive 1.0 log10 or greater increases in serum HBV DNA from on-treatment nadir, or two consecutive HBV DNA values = 400 copies/mL after being < 400 copies/mL.
Timepoint [9] 0 0
Baseline; Weeks 48, 96, 144, 192, and 240
Secondary outcome [10] 0 0
Percent Change From Baseline in Bone Mineral Density (BMD) of the Spine at Weeks 24, 48, 72, 96, 144, 192, and 240 - BMD is calculated as grams per cubic centimeter (g/cm^2); the mean (SD) percentage change is presented.
Timepoint [10] 0 0
Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
Secondary outcome [11] 0 0
Percent Change From Baseline in BMD of the Hip at Weeks 24, 48, 72, 96, 144, 192, and 240 - BMD is calculated as g/cm^2; the mean (SD) percentage change is presented.
Timepoint [11] 0 0
Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240
Secondary outcome [12] 0 0
Development of Drug-resistant Mutations (DRMs) - The development of DRMs was summarized, either as development of new DRMs or enrichment of existing DRMs.
Timepoint [12] 0 0
Baseline to Week 240

Eligibility
Key inclusion criteria
Inclusion Criteria

- Chronic HBV infection, defined as positive serum HBsAg for at least 6 months

- 18 through 75 years of age, inclusive

- HBV DNA = 10^3 IU/mL

- Receiving treatment with lamivudine with confirmation of HBV reverse transcriptase
mutation(s) known to confer resistance to lamivudine (rtM204I/V with or without
rtL180M) by central laboratory assessment prior to randomization; adefovir dipivoxil
treatment of = 48 weeks at the time of screening (inclusive of combination adefovir
dipivoxil + lamivudine at entry) was allowed

- Willing and able to provide written informed consent

- Negative serum pregnancy test (for females of childbearing potential only)

- Calculated creatinine clearance = 50 mL/min

- Hemoglobin = 10 g/dL

- Neutrophils = 1000 /mm^3

- No prior oral HBV therapy with approved nucleotide and/or nucleoside therapy or other
investigational agents for HBV infection other than lamivudine or adefovir dipivoxil
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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

- Alanine aminotransferase (ALT) = 10 × the upper limit of the normal range (ULN)

- Decompensated liver disease

- Interferon or pegylated interferon therapy within 6 months of the screening visit

- Alpha fetoprotein > 50 ng/mL

- Evidence of hepatocellular carcinoma

- Coinfection with hepatitis C virus, HIV, or hepatitis D virus

- Significant renal, cardiovascular, pulmonary, or neurological disease

- Received solid organ or bone marrow transplantation

- Receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational
agents, nephrotoxic agents, or agents susceptible of modifying renal excretion

- Proximal tubulopathy

- Known hypersensitivity to the study drugs, the metabolites or formulation excipients

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Florida
Country [2] 0 0
United States of America
State/province [2] 0 0
New York
Country [3] 0 0
United States of America
State/province [3] 0 0
Pennsylvania
Country [4] 0 0
Austria
State/province [4] 0 0
Innsbruck
Country [5] 0 0
Austria
State/province [5] 0 0
Wien
Country [6] 0 0
Bulgaria
State/province [6] 0 0
Sofia
Country [7] 0 0
Bulgaria
State/province [7] 0 0
Varna
Country [8] 0 0
Canada
State/province [8] 0 0
British Columbia
Country [9] 0 0
Canada
State/province [9] 0 0
Manitoba
Country [10] 0 0
Canada
State/province [10] 0 0
Ontario
Country [11] 0 0
Czech Republic
State/province [11] 0 0
Brno
Country [12] 0 0
Czech Republic
State/province [12] 0 0
Plzen
Country [13] 0 0
Czech Republic
State/province [13] 0 0
Prague
Country [14] 0 0
Czech Republic
State/province [14] 0 0
Praha 4
Country [15] 0 0
Czech Republic
State/province [15] 0 0
Usti Nad Labem
Country [16] 0 0
Germany
State/province [16] 0 0
Baden-Wuerttemberg
Country [17] 0 0
Germany
State/province [17] 0 0
Berlin
Country [18] 0 0
Germany
State/province [18] 0 0
Duesseldorf
Country [19] 0 0
Germany
State/province [19] 0 0
Essen
Country [20] 0 0
Germany
State/province [20] 0 0
Frankfurt
Country [21] 0 0
Germany
State/province [21] 0 0
Hamburg
Country [22] 0 0
Germany
State/province [22] 0 0
Hannover
Country [23] 0 0
Germany
State/province [23] 0 0
Stuttgart
Country [24] 0 0
Greece
State/province [24] 0 0
Larissa
Country [25] 0 0
Greece
State/province [25] 0 0
Patras
Country [26] 0 0
Greece
State/province [26] 0 0
Thessaloniki
Country [27] 0 0
Hungary
State/province [27] 0 0
Budapest
Country [28] 0 0
Hungary
State/province [28] 0 0
Debrecen
Country [29] 0 0
Hungary
State/province [29] 0 0
Gyula
Country [30] 0 0
Hungary
State/province [30] 0 0
Kasposvar
Country [31] 0 0
New Zealand
State/province [31] 0 0
Auckland
Country [32] 0 0
New Zealand
State/province [32] 0 0
Hamilton
Country [33] 0 0
New Zealand
State/province [33] 0 0
Wellington
Country [34] 0 0
Poland
State/province [34] 0 0
Bialystok
Country [35] 0 0
Poland
State/province [35] 0 0
Bydgoszcz
Country [36] 0 0
Poland
State/province [36] 0 0
Chorzow
Country [37] 0 0
Poland
State/province [37] 0 0
Krakow
Country [38] 0 0
Poland
State/province [38] 0 0
Lodz
Country [39] 0 0
Poland
State/province [39] 0 0
Szczecin
Country [40] 0 0
Poland
State/province [40] 0 0
Warszawa
Country [41] 0 0
Poland
State/province [41] 0 0
Wroclaw
Country [42] 0 0
Romania
State/province [42] 0 0
Judetul lasi
Country [43] 0 0
Romania
State/province [43] 0 0
Judetul Timis
Country [44] 0 0
Romania
State/province [44] 0 0
Bucharest
Country [45] 0 0
Romania
State/province [45] 0 0
Bucuresti
Country [46] 0 0
Romania
State/province [46] 0 0
Cluj-Napoca
Country [47] 0 0
Romania
State/province [47] 0 0
Constanta
Country [48] 0 0
Serbia
State/province [48] 0 0
Belgrade
Country [49] 0 0
Serbia
State/province [49] 0 0
Kragujevac
Country [50] 0 0
Serbia
State/province [50] 0 0
Nis
Country [51] 0 0
Serbia
State/province [51] 0 0
Novi Sad
Country [52] 0 0
Spain
State/province [52] 0 0
Sevilla
Country [53] 0 0
Turkey
State/province [53] 0 0
Ankara
Country [54] 0 0
Turkey
State/province [54] 0 0
Bursa
Country [55] 0 0
Turkey
State/province [55] 0 0
Izmir
Country [56] 0 0
Turkey
State/province [56] 0 0
Samsun
Country [57] 0 0
Turkey
State/province [57] 0 0
Trabzon
Country [58] 0 0
Turkey
State/province [58] 0 0
Uskudar

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The aim of therapy for the treatment of chronic hepatitis B virus (HBV) is to maintain
suppression of viral replication to prevent the emergence of complications, which requires
long-term therapy. Durable suppression of viral replication is achieved in the treatment of
chronic viral diseases by preventing of the emergence of drug-resistant mutations. The
clinical guidelines for the management of lamivudine resistant patients are variable. Some
recommend switching to another agent without cross-resistance, while others recommend adding
on another agent without cross-resistance. Limited clinical data exists to demonstrate
whether tenofovir disoproxil fumarate (tenofovir DF; TDF) is an effective monotherapy for
lamivudine resistant patients or if it should be used as part of a combination therapy
regimen.

This study is designed to evaluate the effectiveness, safety, and tolerability of tenofovir
DF monotherapy versus emtricitabine (FTC)/tenofovir DF combination therapy in participants
with chronic HBV with lamivudine resistance (presence of the rtM204I/V mutation with or
without the rtL180M mutation) over a 240-week period. Participants in this study must be
receiving lamivudine treatment at the time of enrollment.
Trial website
https://clinicaltrials.gov/show/NCT00737568
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
John Flaherty, PharmD
Address 0 0
Gilead Sciences
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications