Chronic Hepatitis B
Conditions
Brief summary
This study explores the efficacy, safety and tolerability of tenofovir DF (TDF) 300 mg once daily monotherapy versus the combination of emtricitabine 200 mg plus tenofovir DF 300 mg (FTC/TDF) once daily in subjects currently being treated with adefovir dipivoxil (Hepsera) for chronic hepatitis B who have persistent viral replication (detectable hepatitis B virus deoxyribonucleic acid \[HBV DNA\]). Subjects with confirmed (within 4 weeks) plasma HBV DNA ≥ 400 copies/mL during double blind treatment at Week 24 or any time thereafter have the option of receiving 12 weeks of open-label FTC/TDF which may be continued through the end of the 168-week treatment period if there is a virologic response (HBV DNA \< 400 copies/mL). Alternatively, subjects with confirmed HBV DNA \< 400 copies/mL at or any time after Week 24 of double-blind treatment may continue blinded therapy up to Week 168 at the discretion of the investigator. If, in the investigator's opinion, it is felt that continued blinded treatment beyond 24 weeks in subjects with confirmed HBV DNA ≥ 400 copies/mL is not beneficial, the subject may discontinue the study and begin commercially available HBV therapy rather than initiate open-label FTC/TDF.
Interventions
DRUGtenofovir DF
300 mg tablet, once daily (QD)
DRUGemtricitabine /tenofovir DF
emtricitabine 200 mg/tenofovir DF 300 mg once daily (combination tablet)
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
Inclusion criteria
* 18 through 69 years of age, inclusive * Chronic HBV infection, defined as positive serum HBsAg for at least 6 months * Active chronic HBV infection with all the following: 1. Currently treated with adefovir dipivoxil 10 mg QD (for at least 24 weeks but not more than 96 weeks) 2. HBeAg positive or negative at screening 3. Plasma HBV DNA \>/= 1000 copies/mL at screening (irrespective of HBeAg status) 4. Serum ALT less than 10 times the upper limit of normal (ULN) 5. Calculated creatinine clearance of at least 70 mL/min using the Cockcroft-Gault formula 6. Hemoglobin at least 8 g/dL 7. Neutrophils at least 1,000 /mm3 * Nucleoside naive except for lamivudine (\>/= 12 weeks of therapy) * Negative serum beta human chorionic gonadotropin * Compliant with adefovir dipivoxil * Willing and able to provide written informed consent
Exclusion criteria
* Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study * Male or females of reproductive potential who are unwilling to use an effective method of contraceptive while enrolled in the study. For males, condoms should be used and for females, a barrier contraception method should be used * Decompensated liver disease defined as conjugated bilirubin greater than 1.5 times ULN, prothrombin time (PT) greater than 1.5 times ULN, platelets less than 75,000/mm3, serum albumin less than 3.0 g/dL, or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, variceal hemorrhage) * Prior use of tenofovir DF or entecavir * Received treatment with interferon or pegylated interferon within 6 months of the screening visit * Evidence of hepatocellular carcinoma (HCC); for example, alpha-fetoprotein greater than 50 ng/mL or by any other standard of care measure. * Co-infection with HCV (based on serology), human immunodeficiency virus (HIV), or hepatitis delta virus (HDV) * Significant renal, cardiovascular, pulmonary, or neurological disease. * Received solid organ or bone marrow transplantation. * Is currently receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents capable of modifying renal excretion * Has proximal tubulopathy * Known hypersensitivity to the study drugs (tenofovir DF or emtricitabine/tenofovir DF), the metabolites (tenofovir or emtricitabine) or formulation excipients
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48 | 48 weeks |
| Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48 | 48 Weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Normal ALT at Week 48 | 48 Weeks | ULN for males = 43 U/L; 34 U/L for females |
| Percentage of Participants With Normalized ALT at Week 48 | 48 Weeks | Subjects with elevated ALT at baseline that return to normal by Week 48. |
| Hepatitis B Early Antigen (HBeAg) Loss at Week 48 | 48 Weeks | Defined as having negative serum HBeAg for subjects with positive HBeAg at baseline. |
| HBeAg Seroconversion at Week 48 | 48 Weeks | Defined as having negative serum HBeAg and positive serum antibody to HBeAg \[anti-HBe\] for subjects with positive serum HBeAg at baseline. |
| HBsAg Loss at Week 48 | 48 Weeks | Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline. |
| Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 48 | 48 Weeks | Defined as having negative serum HBsAg and positive serum antibody to HBsAg \[anti-HBs\] for subject with positive serum HBsAg at baseline. |
| Change From Baseline in log10 Plasma HBV DNA Levels at Week 168 | 168 weeks | — |
| Change From Baseline in log10 Plasma HBV DNA Levels at Week 48 | 48 Weeks | — |
| Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168 | 168 weeks | — |
| Percentage of Participants With Normal ALT at Week 168 | 168 weeks | ULN for males = 43 U/L; ULN for females = 34 U/L |
| Percentage of Participants With Normalized ALT at Week 168 | 168 weeks | Subjects with elevated ALT at baseline that return to normal by Week 48. |
| Hepatitis B Early Antigen (HBeAg) Loss at Week 168 | 168 weeks | Defined as having negative serum HBeAg for subjecst with positive HBeAg at baseline. |
| Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 168 | 168 weeks | Defined as having negative serum BHsAg and positive serum antibody to HBsAg (anti-HBs) for subject with positive serum BHsAg at baseline. |
| HBsAg Loss at Week 168 | 168 weeks | Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline. |
| Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 168 | 168 weeks | P-values were from a Cochran-Mantel-Haenszel test, controlling for baseline HBeAg status and prior lamivudine use. |
| Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 168 | 168 weeks | — |
| Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 48 | 48 Weeks | — |
Countries
France, Germany, Spain, United States
Participant flow
Recruitment details
A total of 106 subjects were randomized (105 of which were subsequently treated) across 28 study centers in the US, Germany, France and Spain between 24 April 2006 and 07 March 2007.
Participants by arm
| Arm | Count |
|---|---|
| Tenofovir DF tenofovir DF 300 mg QD | 53 |
| Emtricitibine/Tenofovir DF emtricitabine 200 mg / tenofovir DF 300 mg QD (combination tablet) | 52 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Baseline Through Week 48 | Lost to Follow-up | 0 | 1 |
| Baseline Through Week 48 | Physician Decision | 1 | 0 |
| Baseline Through Week 48 | Withdrawal by Subject | 0 | 1 |
| Week 48 Through Week 168 | Adverse Event | 1 | 0 |
| Week 48 Through Week 168 | Death | 0 | 1 |
| Week 48 Through Week 168 | Lack of Efficacy | 2 | 2 |
| Week 48 Through Week 168 | Lost to Follow-up | 0 | 1 |
| Week 48 Through Week 168 | Physician Decision | 1 | 0 |
| Week 48 Through Week 168 | Seroconversion | 1 | 0 |
| Week 48 Through Week 168 | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Tenofovir DF | Emtricitibine/Tenofovir DF | Total |
|---|---|---|---|
| Age Continuous | 40 years STANDARD_DEVIATION 11.4 | 39 years STANDARD_DEVIATION 10.4 | 39 years STANDARD_DEVIATION 10.9 |
| Baseline HBV DNA | 6.06 log10 copies/mL STANDARD_DEVIATION 1.43 | 5.87 log10 copies/mL STANDARD_DEVIATION 1.779 | 5.97 log10 copies/mL STANDARD_DEVIATION 1.607 |
| Previous Lamivudine Experience No | 23 participants | 21 participants | 44 participants |
| Previous Lamivudine Experience Yes | 30 participants | 31 participants | 61 participants |
| Race/Ethnicity, Customized Asian | 26 Participants | 18 Participants | 44 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 8 Participants | 10 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 23 Participants | 21 Participants | 44 Participants |
| Sex: Female, Male Female | 15 Participants | 10 Participants | 25 Participants |
| Sex: Female, Male Male | 38 Participants | 42 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 49 / — | 42 / — |
| serious Total, serious adverse events | 6 / — | 10 / — |
Outcome results
Primary
Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48
Time frame: 48 weeks
Population: Randomized and Treated (RAT) subjects at Week 48 - Non-Completers=Failure (ie, includes subjects who switched to open-label FTC/TDF at or after Week 24)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48 | 75.5 percentage of participants |
| Emtricitibine/Tenofovir DF | Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48 | 69.2 percentage of participants |
p-value: 0.544Cochran-Mantel-Haenszel
Primary
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48
Time frame: 48 Weeks
Population: RAT Analysis Set Non-Completers=Failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48 | 81.1 percentage of participants |
| Emtricitibine/Tenofovir DF | Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48 | 80.8 percentage of participants |
p-value: 0.988Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 168
Time frame: 168 weeks
Population: Non-completers = failure analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir DF | Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 168 | -26.8 U/mL | Standard Deviation 60.23 |
| Emtricitibine/Tenofovir DF | Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 168 | -54.5 U/mL | Standard Deviation 141.63 |
p-value: 0.999van Elteren
Secondary
Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 48
Time frame: 48 Weeks
Population: RAT Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir DF | Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 48 | -21.6 U/mL | Standard Deviation 54.53 |
| Emtricitibine/Tenofovir DF | Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 48 | -41.4 U/mL | Standard Deviation 151.67 |
p-value: 0.712van Elteren
Secondary
Change From Baseline in log10 Plasma HBV DNA Levels at Week 168
Time frame: 168 weeks
Population: Non-completers = failure analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir DF | Change From Baseline in log10 Plasma HBV DNA Levels at Week 168 | -3.79 log10 copies/mL | Standard Deviation 1.305 |
| Emtricitibine/Tenofovir DF | Change From Baseline in log10 Plasma HBV DNA Levels at Week 168 | -3.48 log10 copies/mL | Standard Deviation 1.629 |
p-value: 0.103van Elteren
Secondary
Change From Baseline in log10 Plasma HBV DNA Levels at Week 48
Time frame: 48 Weeks
Population: RAT Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tenofovir DF | Change From Baseline in log10 Plasma HBV DNA Levels at Week 48 | -3.58 log10 copies/mL | Standard Deviation 1.29 |
| Emtricitibine/Tenofovir DF | Change From Baseline in log10 Plasma HBV DNA Levels at Week 48 | -3.34 log10 copies/mL | Standard Deviation 1.753 |
p-value: 0.208van Elteren
Secondary
HBeAg Seroconversion at Week 48
Defined as having negative serum HBeAg and positive serum antibody to HBeAg \[anti-HBe\] for subjects with positive serum HBeAg at baseline.
Time frame: 48 Weeks
Population: RAT Analysis Set with Positive Baseline HBeAg. Non-Completers=Failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | HBeAg Seroconversion at Week 48 | 2 participants |
| Emtricitibine/Tenofovir DF | HBeAg Seroconversion at Week 48 | 3 participants |
p-value: 0.655Cochran-Mantel-Haenszel
Secondary
HBsAg Loss at Week 168
Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline.
Time frame: 168 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | HBsAg Loss at Week 168 | 1 Participants |
| Emtricitibine/Tenofovir DF | HBsAg Loss at Week 168 | 0 Participants |
p-value: 0.254Cochran-Mantel-Haenszel
Secondary
HBsAg Loss at Week 48
Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline.
Time frame: 48 Weeks
Population: RAT Analysis Set Non-Completers=Failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | HBsAg Loss at Week 48 | 1 participants |
| Emtricitibine/Tenofovir DF | HBsAg Loss at Week 48 | 0 participants |
p-value: 0.401Cochran-Mantel-Haenszel
Secondary
Hepatitis B Early Antigen (HBeAg) Loss at Week 168
Defined as having negative serum HBeAg for subjecst with positive HBeAg at baseline.
Time frame: 168 weeks
Population: Non-completer = Failure Analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Hepatitis B Early Antigen (HBeAg) Loss at Week 168 | 21.6 Percent of Participants |
| Emtricitibine/Tenofovir DF | Hepatitis B Early Antigen (HBeAg) Loss at Week 168 | 24.3 Percent of Participants |
p-value: 0.703Cochran-Mantel-Haenszel
Secondary
Hepatitis B Early Antigen (HBeAg) Loss at Week 48
Defined as having negative serum HBeAg for subjects with positive HBeAg at baseline.
Time frame: 48 Weeks
Population: RAT Analysis Set with Positive HBeAg at Baseline. Non-Completers=Failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Hepatitis B Early Antigen (HBeAg) Loss at Week 48 | 3 participants |
| Emtricitibine/Tenofovir DF | Hepatitis B Early Antigen (HBeAg) Loss at Week 48 | 3 participants |
p-value: 0.952Cochran-Mantel-Haenszel
Secondary
Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 168
Defined as having negative serum BHsAg and positive serum antibody to HBsAg (anti-HBs) for subject with positive serum BHsAg at baseline.
Time frame: 168 weeks
Population: Non-completer = Failure Analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 168 | 1 Participants |
| Emtricitibine/Tenofovir DF | Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 168 | 0 Participants |
p-value: 0.254Cochran-Mantel-Haenszel
Secondary
Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 48
Defined as having negative serum HBsAg and positive serum antibody to HBsAg \[anti-HBs\] for subject with positive serum HBsAg at baseline.
Time frame: 48 Weeks
Population: RAT Analysis Set Non-Completers=Failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 48 | 1 participants |
| Emtricitibine/Tenofovir DF | Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 48 | 0 participants |
p-value: 0.401Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Normal ALT at Week 168
ULN for males = 43 U/L; ULN for females = 34 U/L
Time frame: 168 weeks
Population: Non-completers = failure analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Percentage of Participants With Normal ALT at Week 168 | 74.0 Percent of Participants |
| Emtricitibine/Tenofovir DF | Percentage of Participants With Normal ALT at Week 168 | 74.0 Percent of Participants |
p-value: 0.936Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Normal ALT at Week 48
ULN for males = 43 U/L; 34 U/L for females
Time frame: 48 Weeks
Population: RAT Analysis Set Non-Completers=Failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Percentage of Participants With Normal ALT at Week 48 | 66.7 percentage of participants |
| Emtricitibine/Tenofovir DF | Percentage of Participants With Normal ALT at Week 48 | 73.1 percentage of participants |
p-value: 0.423Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Normalized ALT at Week 168
Subjects with elevated ALT at baseline that return to normal by Week 48.
Time frame: 168 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Percentage of Participants With Normalized ALT at Week 168 | 68.0 Percent of Participants |
| Emtricitibine/Tenofovir DF | Percentage of Participants With Normalized ALT at Week 168 | 70.8 Percent of Participants |
p-value: 0.784Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Normalized ALT at Week 48
Subjects with elevated ALT at baseline that return to normal by Week 48.
Time frame: 48 Weeks
Population: RAT Analysis Set - subjects with ALT above ULN at baseline. Non-Completers=Failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Percentage of Participants With Normalized ALT at Week 48 | 40.7 percentage of participants |
| Emtricitibine/Tenofovir DF | Percentage of Participants With Normalized ALT at Week 48 | 61.5 percentage of participants |
p-value: 0.109Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 168
P-values were from a Cochran-Mantel-Haenszel test, controlling for baseline HBeAg status and prior lamivudine use.
Time frame: 168 weeks
Population: Non-completers = failure analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 168 | 80.4 Percent of Participants |
| Emtricitibine/Tenofovir DF | Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 168 | 78.0 Percent of Participants |
p-value: 0.878Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168
Time frame: 168 weeks
Population: Non-completers = failure analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenofovir DF | Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168 | 82.4 Percent of Participants |
| Emtricitibine/Tenofovir DF | Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168 | 84.0 Percent of Participants |
p-value: 0.781Cochran-Mantel-Haenszel