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Hepatitis BPhase 3NCT00737568

Tenofovir Disoproxil Fumarate (Tenofovir DF) Versus Emtricitabine/Tenofovir DF in Subjects Resistant to Lamivudine

A Phase 3 study testing TDF and FTC/TDF in people with Hepatitis B, run by Gilead Sciences at 69 sites in 14 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Hepatitis B
What is being tested?
TDF and FTC/TDF
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
280 participants
Where
69 sitesin 14 countries
Study dates
Sep 2008to Feb 2015
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
Show all 10Show fewer
  • 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

Who cannot join

  • 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
Show all 13Show fewer
  • 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

Trial locations and contacts

69 sites in 14 countries.

69 sites in 14 countries

Poland9 sites

  • Study site

    Bialystok, 15-540

  • Study site

    Bydgoszcz, 85-030

  • Study site

    Chorzów, 41-500

  • Study site

    Krakow, 31-351

  • Study site

    Lodz, 91-347

  • Study site

    Szczecin, 71-455

  • Study site

    Warsaw, 01-201

  • Study site

    Warsaw, 02-507

  • Study site

    Wroclaw, 50-220

Other trials in Poland

Canada8 sites

  • Study site

    Toronto, Ontario, M5G 1X5

  • Study site

    Toronto, Ontario, M5G 2C4

  • Study site

    Toronto, Ontario, M5T 2S8

  • Study site

    Toronto, Ontario, M6H 3M1

  • Study site

    Vancouver, British Columbia, V5Z

  • Study site

    Vancouver, British Columbia, V6AB46

  • Study site

    Vancouver, British Columbia, V6Z 2K5

  • Study site

    Winnepeg, Manitoba, R3E 3P4

Other trials in Canada

Germany8 sites

  • Study site

    Berlin, 13353

  • Study site

    Düsseldorf, 40225

  • Study site

    Essen, 45122

  • Study site

    Frankfurt, 60590

  • Study site

    Hamburg, 20099

  • Study site

    Hanover, 30625

  • Study site

    Stuttgart

  • Study site

    Ulm, Baden-Wurttemberg, 89081

Other trials in Germany

Romania8 sites

  • Study site

    Bucharest, 020125

  • Study site

    Bucharest, 021105

  • Study site

    Bucharest, 022328

  • Study site

    Bucharest, 030303

  • Study site

    Cluj-Napoca, 400158

  • Study site

    Constanța, 900708

  • Study site

    Lasi, Judetul Lasi, 700111

  • Study site

    Timișoara, Timiș County, 300736

Other trials in Romania

Turkey (Türkiye)6 sites

  • Study site

    Ankara, 06100

  • Study site

    Bursa, 16059

  • Study site

    Izmir, 35100

  • Study site

    Samsun, 55139

  • Study site

    Trabzon, 61080

  • Study site

    Üsküdar, 34668

Other trials in Turkey (Türkiye)

Czechia5 sites

  • Study site

    Brno, 625 00

  • Study site

    Pilsen, 304 60

  • Study site

    Prague, 14021

  • Study site

    Prague, 160 00

  • Study site

    Ústí nad Labem, 40001

Other trials in Czechia

Bulgaria4 sites

  • Study site

    Sofia, 1407

  • Study site

    Sofia, 1527

  • Study site

    Sofia, 1606

  • Study site

    Varna, 9010

Other trials in Bulgaria

Hungary4 sites

  • Study site

    Budapest, 1126

  • Study site

    Debrecen, 4032

  • Study site

    Gyula, H5700

  • Study site

    Kasposvar, H7400

Other trials in Hungary

Serbia4 sites

  • Study site

    Belgrade, 11000

  • Study site

    Kragujevac, 34000

  • Study site

    Niš, 18000

  • Study site

    Novi Sad, 21000

Other trials in Serbia

United States3 sites

  • Study site

    Bradenton, Florida, 34205

  • Study site

    Flushing, New York, 11355

  • Study site

    Philadelphia, Pennsylvania, 19107

Other trials in United States

Austria3 sites

  • Study site

    Innsbruck, A-6020

  • Study site

    Vienna, A-1090

  • Study site

    Vienna, A-1130

Other trials in Austria

Greece3 sites

  • Study site

    Larissa, 41110

  • Study site

    Pátrai, 25404

  • Study site

    Thessaloniki, 54642

Other trials in Greece

New Zealand3 sites

  • Study site

    Auckland

  • Study site

    Hamilton

  • Study site

    Wellington, 6035

Other trials in New Zealand

Spain1 site

  • Study site

    Seville, 4103

Other trials in Spain

About this study

Official 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

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.

Conditions
Hepatitis B
Being tested
TDF, FTC/TDF, TDF Placebo, FTC/TDF Placebo
Keywords
Tenofovir DF, Emtricitabine, Chronic hepatitis B, Combination therapy
Medical subject headings
Hepatitis B, Hepatitis B, Chronic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TDFDrug

    Also called Viread®

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

  • FTC/TDFDrug

    Also called Truvada®

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

  • TDF PlaceboDrug

    TDF placebo tablet administered orally once daily

  • FTC/TDF PlaceboDrug

    FTC/TDF placebo tablet administered orally once daily

Study groups in NCT00737568
Study groupRoleWhat they receive
Tenofovir DFExperimentalTDF plus placebo to match FTC/TDF
Receives: Drug: TDF; Drug: FTC/TDF Placebo
FTC/TDFExperimentalFTC/TDF plus placebo to match TDF
Receives: Drug: FTC/TDF; Drug: TDF Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

    Measured: Week 96

Secondary outcomes (12)

  1. Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240

    Measured: Weeks 48, 144, 192, and 240

  2. Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240

    Measured: Weeks 48, 96, 144, 192, and 240

  3. HBV DNA Level at Weeks 48, 96, 144, 192, and 240

    Measured: Weeks 48, 96, 144, 192, and 240

  4. 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.

    Measured: Weeks 48, 96, 144, 192, and 240

  5. 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.

    Measured: Baseline; Weeks 48, 96, 144, 192, and 240

  6. 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.

    Measured: Baseline; Weeks 48, 96, 144, 192, and 240

  7. 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.

    Measured: Baseline; Weeks 48, 96, 144, 192, and 240

  8. 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.

    Measured: Baseline; Weeks 48, 96, 144, 192, and 240

  9. 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.

    Measured: Baseline; Weeks 48, 96, 144, 192, and 240

  10. 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.

    Measured: Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240

  11. 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.

    Measured: Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240

  12. Development of Drug-resistant Mutations (DRMs)

    The development of DRMs was summarized, either as development of new DRMs or enrichment of existing DRMs.

    Measured: Baseline to Week 240

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Aug 2008 (estimated)
  2. Study startSep 2008
  3. Primary completionNov 2011
  4. Study completionFeb 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
280 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00737568
Sponsor's protocol ID
GS-US-174-0121
Status last verified
Feb 2016
First submitted
15 Aug 2008
Last updated
11 Mar 2016
Data monitoring committee
Yes

Publications

  • Corsa AC, Liu Y, Flaherty JF, Mitchell B, Fung SK, Gane E, Miller MD, Kitrinos KM. No resistance to tenofovir disoproxil fumarate through 96 weeks of treatment in patients with lamivudine-resistant chronic hepatitis B. Clin Gastroenterol Hepatol. 2014 Dec;12(12):2106-12.e1. doi: 10.1016/j.cgh.2014.05.024. Epub 2014 Jun 11.

    PubMed 24929235

  • Liu Y, Fung S, Gane EJ, Dinh P, Flaherty JF, Svarovskaia ES, Miller MD, Kitrinos KM. Evaluation of HBV DNA decay kinetics in patients containing both rtM204V/I mutant and wild-type HBV subpopulations during tenofovir DF (TDF) monotherapy or combination therapy with emtricitabine (FTC)/TDF. J Med Virol. 2014 Sep;86(9):1473-81. doi: 10.1002/jmv.23982. Epub 2014 May 23.

    PubMed 24861361

  • Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, Gurel S, Caruntu FA, Flaherty JF, Massetto B, Dinh P, Corsa A, Subramanian GM, McHutchison JG, Husa P, Gane E. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2014 Apr;146(4):980-8. doi: 10.1053/j.gastro.2013.12.028. Epub 2013 Dec 22.

    PubMed 24368224

  • Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, Gurel S, Caruntu FA, Flaherty JF, Massetto B, Kim K, Kitrinos KM, Subramanian GM, McHutchison JG, Yee LJ, Elkhashab M, Berg T, Sporea I, Yurdaydin C, Husa P, Jablkowski MS, Gane E. Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study. J Hepatol. 2017 Jan;66(1):11-18. doi: 10.1016/j.jhep.2016.08.008. Epub 2016 Aug 18.

    PubMed 27545497

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing TDF and FTC/TDF in people with Hepatitis B, run by Gilead Sciences at 69 sites in 14 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 69 sites in Poland, Canada, Germany, Romania, Turkey (Türkiye) and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Apr 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96 (time frame: Week 96). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00737568, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Mar 2016.

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