Chronic HepatitisPhase 4NCT01833611
Entecavir for Chronic Hepatitis B Patients With Persistently Normal ALT
A Phase 4 study testing Entecavir in people with Chronic Hepatitis, run by National Cheng-Kung University Hospital at 4 sites in Taiwan.
Trial summary
Entecavir (ETV) has shown superior ability to suppress hepatitis B virus (HBV) replication, histology improvement as well as low rate of emergence of resistant mutants. Out of range of clinical recommendations for treatment of chronic hepatitis B (CHB), chronic HBV carriers with persistently normal ALT and viral load… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Chronic Hepatitis
- What is being tested?
- Entecavir
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 130 participants
- Where
- 4 sitesTaiwan
- Study dates
- Sep 2008to May 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
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 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male and female subjects aged between 18 and 65 year-old with history of chronic hepatitis B virus infection;
- Detectable HBsAg at screening and for at least 24 weeks prior to screening or detectable HBsAg for < 24 week and negative for IgM core antibody and confirmation of chronic hepatitis on liver biopsy;
- ALT should be within normal range in recent one year and at least twice, which are at least 3 month apart;
- Normal ALT at screening;
- Screening HBV DNA of more than 10^5 copies/mL by Roche AmplicorTM PCR assay performed by the central laboratory;
- Evidence of chronic hepatitis on liver biopsy (Knodell HAI Score >= 4) performed ≤ 52 weeks prior to randomization;
- All women of childbearing potential must have a negative serum or urine pregnancy test.
Who cannot join
- Coinfection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis D virus (HDV);
- Other forms of liver disease e.g., alcoholic, autoimmune, biliary disease;
- Patients with evidence of decompensation of liver disease;
- Therapy with interferon, thymosin alpha or antiviral agents with activity against hepatitis B (e.g., adefovir, famciclovir, lamivudine, and telbivudine) within 24 weeks of randomization into this study;
- More than 12 weeks of prior therapy with nucleoside or nucleotide analogue antiviral agents with activity against hepatitis B (e.g., adefovir, famciclovir lamivudine, and telbivudine);
- Prior therapy with entecavir;
Show all 12Show fewer
- Known history of allergy to nucleoside analogues;
- Hemoglobin < 10.0 g/dL;
- Platelet count < 75,000/mm3;
- Absolute neutrophil count< 1500 cells/mm3;
- Creatinine > 1.5mg/dL (133 μmol/L);
- Anti-nuclear antibody (ANA) titer > l :160 unless attributable to non-hepatic disease.
Trial locations and contacts
4 sites in 1 country.
Taiwan4 sites
Buddhist Dalin Tzu-Chi General Hospital
Chiayi City
Chia-Yi Christian Hospital
Chiayi City
Chang-Gung Memorial Hospital, Kaohsiung
Kaohsiung City
Kaohsiung Medical University Hospital
Kaohsiung City
About this study
Official title: Phase IV Study of the Efficacy of Entecavir in Patients With Chronic Hepatitis B Virus Infection and Persistently Normal Alanine Aminotransferase
Entecavir (ETV) has shown superior ability to suppress hepatitis B virus (HBV) replication, histology improvement as well as low rate of emergence of resistant mutants. Out of range of clinical recommendations for treatment of chronic hepatitis B (CHB), chronic HBV carriers with persistently normal ALT and viral load more than 10^5 copies/mL have progression of liver disease during long-term follow-up. In addition, certain proportions of these patients do have significant inflammation and fibrosis in liver histology. This study will be able to identify who are at risk of liver disease progression and evaluate efficacy of ETV regarding improvement of liver histology during short-term (1-year) and long-term ETV treatment (3-year).
Read the detailed description
TITLE : A Randomized, Double-blind, Placebo-control Study Evaluating the Efficacy of Entecavir in Patients with Chronic Hepatitis B Virus Infection and Persistently Normal Alanine Aminotransferase INDICATION : Chronic hepatitis B virus infection with persistently normal ALT
OBJECTIVES :
Primary objective To evaluate the efficacy of entecavir (ETV) in improving liver histology in patients with chronic hepatitis B virus infection and persistently normal ALT.
The primary endpoint is to compare the proportion of subjects in each treatment group who achieve the histologic Endpoint, defined as improvement in the necroinflammatory score (≥ 2 point decrease in Knodell HAI score) and no worsening of fibrosis (≥ 1 point increase in the Knodell fibrosis score), at the Week 52 compared to baseline.
Secondary objectives
To compare the proportion of subjects in each treatment group with the following objectives at week 52, week 104, and week 156, and post-dosing 24 weeks:
- Undetectable HBV DNA by the Roche TaqMan® HBV Test (limit of detection 60 IU/mL); HBV DNA by PCR will also be evaluated as a continuous parameter;
- The reduction of HBV DNA from baseline.
STUDY DESIGN This is a 3-year prospective randomized, double-blind, placebo-control study. Enrolled subjects will be allocated according to HBeAg status (HBeAg-positive and HBeAg-negative), then randomized to ETV or placebo group.
ETV group: 1st year: ETV 0.5mg qd, then open with ETV 0.5mg qd for 2nd, 3rd year Placebo gr: 1st year: placebo, then open with ETV 0.5mg for 2nd, 3rd year
Dose of ETV: 0.5 mg/day Screening period: 6 weeks Timing of liver biopsy: baseline, 52th week, 156th week NUMBER OF PATIENTS 130 (1:1)
STUDY PERIOD NOV 2007 ~ MAY 2011 DRUG ADMINISTRAITON Route: oral Dose: ETV 0.5 mg/day Comparable placebo
STATISTICAL ANALYSIS Sample size determination:
An evaluation of the efficacy of entecavir compared to placebo is planned. A test for superiority of entecavir to placebo will be conducted that has high power to demonstrate superiority if there are larger histologic improvements of clinical importance. Histologic improvement after one year is estimated as 50% of entecavir treatment and 25% of placebo. Thus, a sample size of 47 will be required for 90% of confidence level with 5% of error. Finally, we estimate that it will be appropriate to enroll 65 patients in each arm due to probably patients' withdrawal.
Statistical Analyses The difference in response rates for the Histologic Endpoint (entecavir-placebo) along with its standard error and 95% confidence interval will be computed. Subset analyses defined by prognostic variables [e.g. gender, and HBV DNA level] for the Histologic Endpoint will be performed.
Change from baseline at Week 52 and 156 in Knodell Scores will also be summarized as a continuous parameter. The secondary efficacy variables will also be summarized and compared between the treatment groups.
- Conditions
- Chronic Hepatitis
- Being tested
- Entecavir, placebo
- Medical subject headings
- Hepatitis, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EntecavirDrug
Also called baraclude (generic name)
entecavir 0.5mg qd
placeboDrug
placebo qd
| Study group | Role | What they receive |
|---|---|---|
| ETV group | Experimental | Entecavir 0.5mg at first year; then open with entecavir 0.5mg qd for 2nd, 3rd year Receives: Drug: Entecavir |
| Placebo group | Placebo comparator | Placebo at first year, then opne with entecavir 0.5mg qd for 2nd, 3rd year Receives: Drug: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Improvement of liver histology in patients with chronic hepatitis B virus infection and persistently normal ALT receiving entecavir. Please refer to "Description" section for the definiton of improvement of liver histology
- The ratio of liver histology improvement in two groups.
- Definition of improving liver histology is improvement in the necroinflammatory score (≥ 2 point decrease in Knodell necroinflammation score) and no worsening of fibrosis (≥ 1 point increase in the Knodell fibrosis score) at the week 52 liver biopsy compared to baseline.
Measured: 1 year
Secondary outcomes (2)
Undetectable HBV DNA
- The ratio of undetectable HBV DNA in two groups
- HBV DNA by the Roche TaqMan® HBV Test (limit of detection 60 IU/mL)
Measured: 1 year and 3 year
the reduction of HBV DNA from baseline
- expressed with Log 10 coipes/ml
- HBV DNA by the Roche TaqMan® HBV Test (limit of detection 60 IU/mL)
Measured: 1 year and 3 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Apr 2013 (estimated)
- Study startSep 2008
- Primary completionNov 2014 (estimated)
- Study completionMay 2015 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic HepatitisStudies of the same condition, open and under way.
- More trials run by National Cheng-Kung University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 130 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cheng-Kung University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ting-Tsung Chang, National Cheng-Kung University Hospital
- Investigators
- Ting-Tsung Chang, MD. PhD, Principal investigator, National Cheng-Kung University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01833611
- Sponsor's protocol ID
- ETV HR-96-23
- Status last verified
- Apr 2013
- First submitted
- 27 Apr 2012
- Last updated
- 17 Apr 2013
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Tseng KC, Chen CY, Tsai HW, Chang TT, Chuang WL, Hsu PI, Liu WC, Cheng PN. Efficacy of entecavir in chronic hepatitis B patients with persistently normal alanine aminotransferase: randomized, double-blind, placebo-controlled study. Antivir Ther. 2014;19(8):755-64. doi: 10.3851/IMP2754. Epub 2014 Feb 28.
PubMed 24583931
Study at a glance
From the registry record, last updated by the sponsor on 17 Apr 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase IV Study of the Efficacy of Entecavir in Patients With Chronic Hepatitis B Virus Infection and Persistently Normal Alanine Aminotransferase
- ClinicalTrials.gov ID
- NCT01833611
- Acronym / sponsor ID
- ETV HR-96-23
- Conditions
- Chronic Hepatitis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 130 participants (estimated)
- Lead sponsor
- National Cheng-Kung University HospitalUniversity, hospital or other
- Study start
- Sep 2008
- Primary completion
- Nov 2014 (estimated)
- Study completion
- May 2015 (estimated)
- First posted
- 17 Apr 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Entecavir (ETV) has shown superior ability to suppress hepatitis B virus (HBV) replication, histology improvement as well as low rate of emergence of resistant mutants. Out of range of clinical recommendations for treatment of chronic hepatitis B (CHB), chronic HBV carriers with persistently normal ALT and viral load more than 10^5 copies/mL have progression of liver disease during long-term follow-up. In addition, certain proportions of these patients do have significant inflammation and fibrosis in liver histology. This study will be able to identify who are at risk of liver disease progression and evaluate efficacy of ETV regarding improvement of liver histology during short-term (1-year) and long-term ETV treatment (3-year).
Detailed description
TITLE : A Randomized, Double-blind, Placebo-control Study Evaluating the Efficacy of Entecavir in Patients with Chronic Hepatitis B Virus Infection and Persistently Normal Alanine Aminotransferase INDICATION : Chronic hepatitis B virus infection with persistently normal ALT
OBJECTIVES :
Primary objective To evaluate the efficacy of entecavir (ETV) in improving liver histology in patients with chronic hepatitis B virus infection and persistently normal ALT.
The primary endpoint is to compare the proportion of subjects in each treatment group who achieve the histologic Endpoint, defined as improvement in the necroinflammatory score (≥ 2 point decrease in Knodell HAI score) and no worsening of fibrosis (≥ 1 point increase in the Knodell fibrosis score), at the Week 52 compared to baseline.
Secondary objectives
To compare the proportion of subjects in each treatment group with the following objectives at week 52, week 104, and week 156, and post-dosing 24 weeks:
- Undetectable HBV DNA by the Roche TaqMan® HBV Test (limit of detection 60 IU/mL); HBV DNA by PCR will also be evaluated as a continuous parameter;
- The reduction of HBV DNA from baseline.
STUDY DESIGN This is a 3-year prospective randomized, double-blind, placebo-control study. Enrolled subjects will be allocated according to HBeAg status (HBeAg-positive and HBeAg-negative), then randomized to ETV or placebo group.
ETV group: 1st year: ETV 0.5mg qd, then open with ETV 0.5mg qd for 2nd, 3rd year Placebo gr: 1st year: placebo, then open with ETV 0.5mg for 2nd, 3rd year
Dose of ETV: 0.5 mg/day Screening period: 6 weeks Timing of liver biopsy: baseline, 52th week, 156th week NUMBER OF PATIENTS 130 (1:1)
STUDY PERIOD NOV 2007 ~ MAY 2011 DRUG ADMINISTRAITON Route: oral Dose: ETV 0.5 mg/day Comparable placebo
STATISTICAL ANALYSIS Sample size determination:
An evaluation of the efficacy of entecavir compared to placebo is planned. A test for superiority of entecavir to placebo will be conducted that has high power to demonstrate superiority if there are larger histologic improvements of clinical importance. Histologic improvement after one year is estimated as 50% of entecavir treatment and 25% of placebo. Thus, a sample size of 47 will be required for 90% of confidence level with 5% of error. Finally, we estimate that it will be appropriate to enroll 65 patients in each arm due to probably patients' withdrawal.
Statistical Analyses The difference in response rates for the Histologic Endpoint (entecavir-placebo) along with its standard error and 95% confidence interval will be computed. Subset analyses defined by prognostic variables [e.g. gender, and HBV DNA level] for the Histologic Endpoint will be performed.
Change from baseline at Week 52 and 156 in Knodell Scores will also be summarized as a continuous parameter. The secondary efficacy variables will also be summarized and compared between the treatment groups.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ETV group | Experimental | Drug: EntecavirEntecavir 0.5mg at first year; then open with entecavir 0.5mg qd for 2nd, 3rd year |
| Placebo group | Placebo comparator | Drug: placeboPlacebo at first year, then opne with entecavir 0.5mg qd for 2nd, 3rd year |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Male and female subjects aged between 18 and 65 year-old with history of chronic hepatitis B virus infection;
- Detectable HBsAg at screening and for at least 24 weeks prior to screening or detectable HBsAg for < 24 week and negative for IgM core antibody and confirmation of chronic hepatitis on liver biopsy;
- ALT should be within normal range in recent one year and at least twice, which are at least 3 month apart;
- Normal ALT at screening;
- Screening HBV DNA of more than 10^5 copies/mL by Roche AmplicorTM PCR assay performed by the central laboratory;
Key exclusion criteria (12 listed)
- Coinfection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis D virus (HDV);
- Other forms of liver disease e.g., alcoholic, autoimmune, biliary disease;
- Patients with evidence of decompensation of liver disease;
- Therapy with interferon, thymosin alpha or antiviral agents with activity against hepatitis B (e.g., adefovir, famciclovir, lamivudine, and telbivudine) within 24 weeks of randomization into this study;
- More than 12 weeks of prior therapy with nucleoside or nucleotide analogue antiviral agents with activity against hepatitis B (e.g., adefovir, famciclovir lamivudine, and telbivudine);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EntecavirAlso: baraclude (generic name)entecavir 0.5mg qd | Drug | ETV group |
| placeboplacebo qd | Drug | Placebo group |
Primary outcome
Improvement of liver histology in patients with chronic hepatitis B virus infection and persistently normal ALT receiving entecavir. Please refer to "Description" section for the definiton of improvement of liver histology
Time frame: 1 year
1. The ratio of liver histology improvement in two groups. 2. Definition of improving liver histology is improvement in the necroinflammatory score (≥ 2 point decrease in Knodell necroinflammation score) and no worsening of fibrosis (≥ 1 point increase in the Knodell fibrosis score) at the week 52 liver biopsy compared to baseline.
2 secondary outcomes
Undetectable HBV DNA
Time frame: 1 year and 3 year
the reduction of HBV DNA from baseline
Time frame: 1 year and 3 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Apr 2013.
- Derived from this study: PubMed 24583931Tseng KC, Chen CY, Tsai HW, Chang TT, Chuang WL, Hsu PI, Liu WC, Cheng PN. Efficacy of entecavir in chronic hepatitis B patients with persistently normal alanine aminotransferase: randomized, double-blind, placebo-controlled study. Antivir Ther. 2014;19(8):755-64. doi: 10.3851/IMP2754. Epub 2014 Feb 28.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ting-Tsung Chang, MD. PhD principal investigator
National Cheng-Kung University Hospital
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Entecavir in people with Chronic Hepatitis, run by National Cheng-Kung University Hospital at 4 sites in Taiwan.
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 7 inclusion and 12 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: status not confirmed, as of the sponsor's last update on 17 Apr 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Taiwan. 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. Some participants in this study may receive a placebo. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
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?
Improvement of liver histology in patients with chronic hepatitis B virus infection and persistently normal ALT receiving entecavir. Please refer to "Description" section for the definiton of improvement of liver histology (time frame: 1 year). 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 NCT01833611, which also lists 1 linked publication.
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 17 Apr 2013.