Chronic Viral Hepatitis B Without Delta-agentPhase 4IN-US-0202NCT01639092
Tenofovir vs. Tenofovir Plus Entecavir in Entecavir-Resistant Chronic Hepatitis B
A Phase 4 study testing Tenofovir and Entecavir in people with Chronic Viral Hepatitis B Without Delta-agent, run by Asan Medical Center at 1 site in South Korea.
Trial summary
With the availability of potent nucloes(t)ide analogues (NA), such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV), suppression of serum HBV DNA to undetectable levels by polymerase chain reaction (PCR) assays became achievable in most NA treatment-naïve patients. Read more about this study
- Who is it for?
- Ages 20 to 75 years
- Conditions the study is for
- Chronic Viral Hepatitis B Without Delta-agent
- What is being tested?
- Tenofovir and Entecavir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 88 participants
- Where
- 1 siteSouth Korea
- Study dates
- 28 Sep 2012to 29 Mar 2018
- 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 20 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Compensated liver disease (Child-Pugh class A)
- HBsAg positive at least 6 months or more
- HBeAg positive or negative
- Confirmation of resistance mutations to Lamivudine (rtM204V/I and/or rtL180M) and ETV (rtT184 or rtS202 or rtM250) at any time before screening
- Serum HBV DNA ≥ 60 IU/mL despite continued preceding oral antiviral treatment (Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study)
- Patient is ambulatory.
- Patient is willing and able to comply with the study drug regimen and all other study requirements.
- The patient is willing and able to provide written informed consent to participate in the study.
Who cannot join
- Patient previously received TDF for more than 1 week
- Patient had documented resistance mutations to ADV at any time before or at screening
- Patient has a history of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies. In patients with such findings, HCC should be ruled-out prior to randomizing the patient for the present study.
- Patient has received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study.
- Patient has concomitant other chronic viral infection (HCV or HIV)
- Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL
Show all 17Show fewer
- Patient has medical condition that requires concurrent use of systemic prednisolone or other immunosuppressive agent (including chemotherapeutic agent)
- Patient is currently abusing alcohol (more than 40 g/day) or illicit drugs, or has a history of alcohol abuse or illicit substance abuse within the preceding two years.
- Patient is pregnant or breastfeeding or willing to be pregnant
- Patient has one or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, congestive heart failure or other severe cardiopulmonary disease, etc.).
- A history of treated malignancy (other than hepatocellular carcinoma) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years.
- Clinical signs of decompensated liver disease as indicated by any one of the following:
- serum bilirubin > 3 mg/dL
- prothrombin time > 6 seconds prolonged or INR >1.5
- serum albumin < 2.8 g/dL
- History of ascites, variceal hemorrhage, or hepatic encephalopathy
- Child-Pugh score ≥7
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Multicenter Randomized Controlled Open-label Trial of Tenofovir vs. Tenofovir Plus Entecavir in Chronic Hepatitis B Patients With Genotypic Resistance to Entecavir and Partial Virologic Response to Ongoing Treatment
With the availability of potent nucloes(t)ide analogues (NA), such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV), suppression of serum HBV DNA to undetectable levels by polymerase chain reaction (PCR) assays became achievable in most NA treatment-naïve patients. Until recently, however, many patients commenced antiviral treatment with inferior NAs prior to the availability of TDF or ETV, such as lamivudine (LAM) which has a low genetic barrier to resistance.
ETV resistance increase up to 51% of patients after 5 years of ETV treatment in lamivudine-refractory patients. Resistance to ETV appears to occur through a two-hit mechanism with initial selection of M204V/I mutation followed by amino acid substitutions at rtT184, rtS202, or rtM250.
Read more
In vitro studies showed that ETV-resistant mutations are susceptible to TDF, but there are little clinical data on the efficacy of TDF monotherapy in patients with ETV-resistance.
On the other hand, there was a retrospective cohort study reporting that, with the combination of TDF and ETV, most of patients became HBV DNA undetectable after median 6 months of treatment. Probability of reaching complete HBV DNA suppression was not decreased in patients with ADV or ETV-resistance.
Thus, there is no consistent treatment recommendation for patients with ETV-resistance.
In this clinical trial, the investigators will clarify whether tenofovir monotherapy is as effective as tenofovir plus entecavir in inducing complete virologic response in CHB patients with genotypic resistance to ETV and partial virologic response to ongoing treatment.
Read the detailed description
A multi-center randomized active-controlled open-label trial
- Patients will be randomly assigned 1:1 to receive tenofovir (300 mg/day) or tenofovir (300 mg/day) plus entecavir (1 mg/day) for 48 weeks.
- Because over 98% of Korean patients with CHB have HBV genotype C, HBV genotype will not determined or be regarded as a stratification factor.
- Patients' treatment information before randomization will be retrospectively collected.(DNA change, HBeAg status, HBsAg titre, ALT, and treatment duration. etc)
- Patients will be screened within 4 weeks before randomization to determine study eligibility.
- Being tested
- Tenofovir, Entecavir
- Keywords
- Resistance of Entecavir
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TenofovirDrug
Also called Viread
Tenofovir 300mg Daily Oral
TenofovirDrug
Also called Viread
Tenofovir 300mg Daily Oral
EntecavirDrug
Also called Baraclude
Entecavir 1 mg daily Oral
| Study group | Role | What they receive |
|---|---|---|
| Tenofovir monotherapy | Experimental | Tenofovir 300 mg/day orally Receives: Drug: Tenofovir |
| Tenofovir plus Entecavir combination | Active comparator | Tenofovir 300 mg/day orally and Entecavir 1 mg/day orally Receives: Drug: Tenofovir; Drug: Entecavir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients with complete virologic response
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
Measured: at week 48 of treatment
Secondary outcomes (6)
Changes in serum HBV DNA levels
Changes in serum HBV DNA levels during 48 weeks of treatment
Measured: at week 48, 96, 144, and 240 of treatment
Proportion of patients with normal ALT
Measured: at week 48, 96, 144, and 240 of treatment
Proportion of patients with HBe-Ag loss or seroconversion
Measured: at week 48, 96, 144, and 240 of treatment
Proportion of patients with resistance mutations to Entecavir or Tenofovir
The proportion of patients with resistance mutations to Entecavir or Tenofovir at week 48
Measured: at week 48, 96, 144, and 240 of treatment
Proportion of patients with virologic breakthrough
Virologic breakthrough is defined as the increase in serum HBV DNA by >1 log10 (10-fold) above nadir after achieving virologic response as determined by at least 2 consecutive measurements of at least 2 weeks apart, during continued treatment
Measured: at week 48, 96, 144, and 240 of treatment
Proportion of patients with complete virologic response
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
Measured: at week 48, 96, 144, and 240 of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jul 2012 (estimated)
- Study start28 Sep 2012
- Primary completion29 Mar 2018
- Study completion29 Mar 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Chronic Viral Hepatitis B Without Delta-agentStudies of the same condition, open and under way.
- More trials run by Asan Medical CenterThe 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
- None (open label)
- Enrolment
- 88 participants (actual)
Sponsor and investigators
- Lead sponsor
- Asan Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Samsung Medical Center, Konkuk University Medical Center, Korea University Guro Hospital, Seoul National University Hospital
- Responsible party
- Principal investigator, Young-Suk Lim, Asan Medical Center
- Investigators
- Young-Suk Lim, M.D.,Ph.D., Principal investigator, Asan Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01639092
- Sponsor's protocol ID
- AMC2012-1215
- Acronym
- IN-US-0202
- Status last verified
- May 2018
- First submitted
- 10 Jul 2012
- Last updated
- 9 May 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Lim YS, Byun KS, Yoo BC, Kwon SY, Kim YJ, An J, Lee HC, Lee YS. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial. Gut. 2016 May;65(5):852-60. doi: 10.1136/gutjnl-2014-308353. Epub 2015 Jan 16.
PubMed 25596179Lim YS, Gwak GY, Choi J, Lee YS, Byun KS, Kim YJ, Yoo BC, Kwon SY, Lee HC. Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial. J Hepatol. 2019 Jul;71(1):35-44. doi: 10.1016/j.jhep.2019.02.021. Epub 2019 Mar 13.
PubMed 30876946
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter Randomized Controlled Open-label Trial of Tenofovir vs. Tenofovir Plus Entecavir in Chronic Hepatitis B Patients With Genotypic Resistance to Entecavir and Partial Virologic Response to Ongoing Treatment
- ClinicalTrials.gov ID
- NCT01639092
- Acronym / sponsor ID
- IN-US-0202 / AMC2012-1215
- Keywords
- Resistance of Entecavir
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 88 participants (actual)
- Lead sponsor
- Asan Medical CenterUniversity, hospital or other
- Collaborators
- Samsung Medical Center, Konkuk University Medical Center, Korea University Guro Hospital, Seoul National University Hospital
- Study start
- 28 Sep 2012 (actual)
- Primary completion
- 29 Mar 2018 (actual)
- Study completion
- 29 Mar 2018 (actual)
- First posted
- 12 Jul 2012 (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.
With the availability of potent nucloes(t)ide analogues (NA), such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV), suppression of serum HBV DNA to undetectable levels by polymerase chain reaction (PCR) assays became achievable in most NA treatment-naïve patients. Until recently, however, many patients commenced antiviral treatment with inferior NAs prior to the availability of TDF or ETV, such as lamivudine (LAM) which has a low genetic barrier to resistance.
ETV resistance increase up to 51% of patients after 5 years of ETV treatment in lamivudine-refractory patients. Resistance to ETV appears to occur through a two-hit mechanism with initial selection of M204V/I mutation followed by amino acid substitutions at rtT184, rtS202, or rtM250.
In vitro studies showed that ETV-resistant mutations are susceptible to TDF, but there are little clinical data on the efficacy of TDF monotherapy in patients with ETV-resistance.
On the other hand, there was a retrospective cohort study reporting that, with the combination of TDF and ETV, most of patients became HBV DNA undetectable after median 6 months of treatment. Probability of reaching complete HBV DNA suppression was not decreased in patients with ADV or ETV-resistance.
Thus, there is no consistent treatment recommendation for patients with ETV-resistance.
In this clinical trial, the investigators will clarify whether tenofovir monotherapy is as effective as tenofovir plus entecavir in inducing complete virologic response in CHB patients with genotypic resistance to ETV and partial virologic response to ongoing treatment.
Detailed description
A multi-center randomized active-controlled open-label trial
- Patients will be randomly assigned 1:1 to receive tenofovir (300 mg/day) or tenofovir (300 mg/day) plus entecavir (1 mg/day) for 48 weeks.
- Because over 98% of Korean patients with CHB have HBV genotype C, HBV genotype will not determined or be regarded as a stratification factor.
- Patients' treatment information before randomization will be retrospectively collected.(DNA change, HBeAg status, HBsAg titre, ALT, and treatment duration. etc)
- Patients will be screened within 4 weeks before randomization to determine study eligibility.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tenofovir monotherapy | Experimental | Drug: TenofovirTenofovir 300 mg/day orally |
| Tenofovir plus Entecavir combination | Active comparator | Drug: Tenofovir, Drug: EntecavirTenofovir 300 mg/day orally and Entecavir 1 mg/day orally |
Who may qualify
- Ages
- 20 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Compensated liver disease (Child-Pugh class A)
- HBsAg positive at least 6 months or more
- HBeAg positive or negative
- Confirmation of resistance mutations to Lamivudine (rtM204V/I and/or rtL180M) and ETV (rtT184 or rtS202 or rtM250) at any time before screening
- Serum HBV DNA ≥ 60 IU/mL despite continued preceding oral antiviral treatment (Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study)
Key exclusion criteria (17 listed)
- Patient previously received TDF for more than 1 week
- Patient had documented resistance mutations to ADV at any time before or at screening
- Patient has a history of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies. In patients with such findings, HCC should be ruled-out prior to randomizing the patient for the present study.
- Patient has received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study.
- Patient has concomitant other chronic viral infection (HCV or HIV)
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 |
|---|---|---|
| TenofovirAlso: VireadTenofovir 300mg Daily Oral | Drug | Tenofovir monotherapy |
| TenofovirAlso: VireadTenofovir 300mg Daily Oral | Drug | Tenofovir plus Entecavir combination |
| EntecavirAlso: BaracludeEntecavir 1 mg daily Oral | Drug | Tenofovir plus Entecavir combination |
Primary outcome
Proportion of patients with complete virologic response
Time frame: at week 48 of treatment
The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
6 secondary outcomes
Changes in serum HBV DNA levels
Time frame: at week 48, 96, 144, and 240 of treatment
Proportion of patients with normal ALT
Time frame: at week 48, 96, 144, and 240 of treatment
Proportion of patients with HBe-Ag loss or seroconversion
Time frame: at week 48, 96, 144, and 240 of treatment
Proportion of patients with resistance mutations to Entecavir or Tenofovir
Time frame: at week 48, 96, 144, and 240 of treatment
Proportion of patients with virologic breakthrough
Time frame: at week 48, 96, 144, and 240 of treatment
Proportion of patients with complete virologic response
Time frame: at week 48, 96, 144, and 240 of treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 May 2018.
- Results publication: PubMed 25596179Lim YS, Byun KS, Yoo BC, Kwon SY, Kim YJ, An J, Lee HC, Lee YS. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial. Gut. 2016 May;65(5):852-60. doi: 10.1136/gutjnl-2014-308353. Epub 2015 Jan 16.
- Derived from this study: PubMed 30876946Lim YS, Gwak GY, Choi J, Lee YS, Byun KS, Kim YJ, Yoo BC, Kwon SY, Lee HC. Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial. J Hepatol. 2019 Jul;71(1):35-44. doi: 10.1016/j.jhep.2019.02.021. Epub 2019 Mar 13.
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.
Young-Suk Lim, M.D.,Ph.D. principal investigator
Asan Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tenofovir and Entecavir in people with Chronic Viral Hepatitis B Without Delta-agent, run by Asan Medical Center at 1 site in South Korea.
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 8 inclusion and 17 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 9 May 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. 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 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Proportion of patients with complete virologic response (time frame: at week 48 of treatment). 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 NCT01639092, which also lists 2 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 9 May 2018.