Chronic Hepatitis BPhase 4NCT01594905
Entecavir Plus Tenofovir Combination in Subjects With Multi-drug Resistant Chronic Hepatitis B Virus Infection
A Phase 4 study testing Entecavir + Tenofovir (MDR group) in people with Chronic Hepatitis B, run by Yonsei University.
Trial summary
Entecavir(ETV) plus Tenofovir Disoproxil Fumarate(TDF) combination will show effective antiviral activity and prevent further development of antiviral resistance in hepatitis B e antigen(HBeAg)-positive or -negative Chronic Hepatitis B(CHB) patients who experienced multidrug resistance All subjects will orally take… Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Chronic Hepatitis B
- What is being tested?
- Entecavir + Tenofovir (MDR group)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- No sites listed yet
- Study dates
- Aug 2012to Apr 2014
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- ≥ 20 years of age
- History of HBsAg positive for more than 6 months
- Subject who has a history of genotypic resistance to NAs from two different classes A
- Detectable HBV DNA (≥ 60 IU/mL) while on any rescue treatment regimen for at least 24 weeks
- HBeAg-positive and -negative
- Compensated liver disease (Child-Pugh A)
- Signed written informed consent after being instructed about the objective and procedure of the clinical study
Who cannot join
- Subjects with Alanine Aminotransferase(ALT) > 10xUpper Limit of normal(ULN)
- Co-infected with hepatitis C virus(HCV) or HIV
- Pregnant or lactating woman
- Subject who needs long-term administration of drugs including immunosuppressive agents, agents related to high risk in the hepatic/renal toxicity, agents influencing renal excretion
- History of liver transplantation or planned for liver transplantation
- Subject who was diagnosed malignant tumor and has been receiving chemotherapy
Show all 12Show fewer
- Subject who has hepatocellular carcinoma(HCC) history or who shows potential HCC finding such as suspicious region in the radiologic exam(abdominal US or CT) or serum Alpha Feto Protein(AFP) elevation
- Renal Insufficiency (CLcr < 50ml/min based on Cockcroft-Gault equation considering weight, ages and serum creatinine)
- Patient who has a liver disease other than chronic hepatitis B (e.g. hemochromatosis, Wilson's disease, alcoholic liver disease, nonalcoholic fatty liver disease, alpha 1-antitrypsin deficiency etc.)
- Subject who has a history of hypersensitivity to study drug or its ingredients
- Subject who is involved in other clinical trial within 60 days prior to study entry
- Subject who the investigator deems inappropriate to participate in this study
About this study
Official title: A Multicenter, Open-label, Prospective Study to Evaluate Antiviral Efficacy and Safety of Entecavir Plus Tenofovir Combination in Subjects With Multi-drug Resistant Chronic Hepatitis B Virus Infection
Entecavir(ETV) plus Tenofovir Disoproxil Fumarate(TDF) combination will show effective antiviral activity and prevent further development of antiviral resistance in hepatitis B e antigen(HBeAg)-positive or -negative Chronic Hepatitis B(CHB) patients who experienced multidrug resistance
All subjects will orally take investigational drugs once daily for 48 weeks. All subjects will be assessed at baseline, Week 4, 12, 24, 36 and 48. Evaluations at each visit will include vital signs, physical examinations, laboratory tests and HBV DNA levels. They were also questioned about adverse events and concomitant medications. At baseline and every six months thereafter, serum will be assayed for HBV serology. Genotypic analysis will be performed at baseline and 48 weeks.
Read the detailed description
- It has been one of unsolved issues and unmet needs in CHB management to develop an optimal combination regimen to manage multidrug resistant HBV characterized by selection of variants with two or more classes A of signature genotypic resistant mutations1-3
- Currently adding on Adefovir(ADV) has been generally recommended in Lamivudine(LAM)- or Telbivudine(LdT)-resistant patients but little is known about the optimal management of CHB patients who developed multidrug resistance4
- Recent report has shown that the combination of LAM plus ADV did not suppress HBV DNA effectively in CHB patients with resistance mutations to both drugs. Only 12.2% of these pts achieved virologic response(VR; HBV DNA <60 IU/mL) at 12 months and multivariable analysis showed that LAM+ADV group and the presence of the rtA181V/T mutation were independently associated with a decreased rate of virologic response (HBV DNA <2,000 IU/ml) at 12 months4
- ETV has been demonstrated to be effective in patients with ADV resistance but not in patients with proven YMDD mutation. In contrast, TDF has been shown to be effective in patients with YMDD mutation but not necessarily in all patients with ADV resistance.1-3
- Thus theoretically, the combination of the most potent nucleoside analogue and nucleotide analogue with non-overlapping resistance profiles, such as ETV plus TDF, is expected to be a promising salvage treatment for multidrug resistant HBV but clinical evidence is limited
- Therefore, this study will explore that adequate management of multidrug resistant patients using ETV plus TDF combination may lead to faster and greater viral suppression and prevent further emergence of antiviral resistance
All subjects will orally take investigational drugs once daily for 48 weeks. All subjects will be assessed at baseline, Week 4, 12, 24, 36 and 48. Evaluations at each visit will include vital signs, physical examinations, laboratory tests and HBV DNA levels. They were also questioned about adverse events and concomitant medications. At baseline and every six months thereafter, serum will be assayed for HBV serology. Genotypic analysis will be performed at baseline and 48 weeks.
- Conditions
- Chronic Hepatitis B
- Being tested
- Entecavir + Tenofovir (MDR group)
- Keywords
- To explore, adequate management, CHB, Multidrug resistance
- Medical subject headings
- Hepatitis B, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Entecavir + Tenofovir (MDR group)Drug
Also called Entecavir 1.0mg - Braclude, Tenofovir 300mg - Viread
Entecavir 1.0mg + Tenofovir 300mg
| Study group | Role | What they receive |
|---|---|---|
| Entecavir 1.0mg + Tenofovir 300mg | Experimental | All subjects will orally take investigational drugs once daily for 48 weeks. Receives: Drug: Entecavir + Tenofovir (MDR group) |
What is being measured
The primary outcome is the main question the study is designed to answer.
The proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) by real-time PCR at Week 48
To evaluate the proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) by real-time Polymerase chain reaction(PCR) at Week 48 after Entecavir plus Tenofovir combination therapy
Measured: at Week 48
Secondary outcomes (1)
Virologic, serologic, biochemical efficacy and safety profile, as measured by the incidence of clinical adverse events and laboratory abnormalities including renal marker
To evaluate virologic, serologic and biochemical response and safety of Entecavir plus Tenofovir combination therapy for 48 weeks
Measured: Week 4, 12, 24, 36, and 48
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2012 (estimated)
- Study startAug 2012
- Primary completionApr 2014 (estimated)
- Study completionApr 2014 (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 Hepatitis BStudies of the same condition, open and under way.
- More trials run by Yonsei UniversityThe 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 90 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yonsei University
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb, Seoul St. Mary's Hospital, The Catholic University of Korea
- Responsible party
- Principal investigator, Sang Hoon Ahn, Yonsei University
- Investigators
- Sang Hoon Ahn, MD, PhD, Principal investigator, Yonsei University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01594905
- Sponsor's protocol ID
- AI463-273
- Status last verified
- Jan 2014
- First submitted
- 7 May 2012
- Last updated
- 31 Jan 2014
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Park JY, Kim CW, Bae SH, Jung KS, Kim HY, Yoon SK, Han KH, Ahn SH. Entecavir plus tenofovir combination therapy in patients with multidrug-resistant chronic hepatitis B: results of a multicentre, prospective study. Liver Int. 2016 Aug;36(8):1108-15. doi: 10.1111/liv.13059. Epub 2016 Feb 7.
PubMed 26781724
Study at a glance
From the registry record, last updated by the sponsor on 31 Jan 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Open-label, Prospective Study to Evaluate Antiviral Efficacy and Safety of Entecavir Plus Tenofovir Combination in Subjects With Multi-drug Resistant Chronic Hepatitis B Virus Infection
- ClinicalTrials.gov ID
- NCT01594905
- Acronym / sponsor ID
- AI463-273
- Conditions
- Chronic Hepatitis B
- Keywords
- To explore, adequate management, CHB, Multidrug resistance
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 90 participants (estimated)
- Lead sponsor
- Yonsei UniversityUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb, Seoul St. Mary's Hospital, The Catholic University of Korea
- Study start
- Aug 2012
- Primary completion
- Apr 2014 (estimated)
- Study completion
- Apr 2014 (estimated)
- First posted
- 9 May 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.
Entecavir(ETV) plus Tenofovir Disoproxil Fumarate(TDF) combination will show effective antiviral activity and prevent further development of antiviral resistance in hepatitis B e antigen(HBeAg)-positive or -negative Chronic Hepatitis B(CHB) patients who experienced multidrug resistance
All subjects will orally take investigational drugs once daily for 48 weeks. All subjects will be assessed at baseline, Week 4, 12, 24, 36 and 48. Evaluations at each visit will include vital signs, physical examinations, laboratory tests and HBV DNA levels. They were also questioned about adverse events and concomitant medications. At baseline and every six months thereafter, serum will be assayed for HBV serology. Genotypic analysis will be performed at baseline and 48 weeks.
Detailed description
- It has been one of unsolved issues and unmet needs in CHB management to develop an optimal combination regimen to manage multidrug resistant HBV characterized by selection of variants with two or more classes A of signature genotypic resistant mutations1-3
- Currently adding on Adefovir(ADV) has been generally recommended in Lamivudine(LAM)- or Telbivudine(LdT)-resistant patients but little is known about the optimal management of CHB patients who developed multidrug resistance4
- Recent report has shown that the combination of LAM plus ADV did not suppress HBV DNA effectively in CHB patients with resistance mutations to both drugs. Only 12.2% of these pts achieved virologic response(VR; HBV DNA <60 IU/mL) at 12 months and multivariable analysis showed that LAM+ADV group and the presence of the rtA181V/T mutation were independently associated with a decreased rate of virologic response (HBV DNA <2,000 IU/ml) at 12 months4
- ETV has been demonstrated to be effective in patients with ADV resistance but not in patients with proven YMDD mutation. In contrast, TDF has been shown to be effective in patients with YMDD mutation but not necessarily in all patients with ADV resistance.1-3
- Thus theoretically, the combination of the most potent nucleoside analogue and nucleotide analogue with non-overlapping resistance profiles, such as ETV plus TDF, is expected to be a promising salvage treatment for multidrug resistant HBV but clinical evidence is limited
- Therefore, this study will explore that adequate management of multidrug resistant patients using ETV plus TDF combination may lead to faster and greater viral suppression and prevent further emergence of antiviral resistance
All subjects will orally take investigational drugs once daily for 48 weeks. All subjects will be assessed at baseline, Week 4, 12, 24, 36 and 48. Evaluations at each visit will include vital signs, physical examinations, laboratory tests and HBV DNA levels. They were also questioned about adverse events and concomitant medications. At baseline and every six months thereafter, serum will be assayed for HBV serology. Genotypic analysis will be performed at baseline and 48 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Entecavir 1.0mg + Tenofovir 300mg | Experimental | Drug: Entecavir + Tenofovir (MDR group)All subjects will orally take investigational drugs once daily for 48 weeks. |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- ≥ 20 years of age
- History of HBsAg positive for more than 6 months
- Subject who has a history of genotypic resistance to NAs from two different classes A
- Detectable HBV DNA (≥ 60 IU/mL) while on any rescue treatment regimen for at least 24 weeks
- HBeAg-positive and -negative
Key exclusion criteria (12 listed)
- Subjects with Alanine Aminotransferase(ALT) > 10xUpper Limit of normal(ULN)
- Co-infected with hepatitis C virus(HCV) or HIV
- Pregnant or lactating woman
- Subject who needs long-term administration of drugs including immunosuppressive agents, agents related to high risk in the hepatic/renal toxicity, agents influencing renal excretion
- History of liver transplantation or planned for liver transplantation
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 |
|---|---|---|
| Entecavir + Tenofovir (MDR group)Also: Entecavir 1.0mg - Braclude, Tenofovir 300mg - VireadEntecavir 1.0mg + Tenofovir 300mg | Drug | Entecavir 1.0mg + Tenofovir 300mg |
Primary outcome
The proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) by real-time PCR at Week 48
Time frame: at Week 48
To evaluate the proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) by real-time Polymerase chain reaction(PCR) at Week 48 after Entecavir plus Tenofovir combination therapy
1 secondary outcome
Virologic, serologic, biochemical efficacy and safety profile, as measured by the incidence of clinical adverse events and laboratory abnormalities including renal marker
Time frame: Week 4, 12, 24, 36, and 48
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2014.
- Derived from this study: PubMed 26781724Park JY, Kim CW, Bae SH, Jung KS, Kim HY, Yoon SK, Han KH, Ahn SH. Entecavir plus tenofovir combination therapy in patients with multidrug-resistant chronic hepatitis B: results of a multicentre, prospective study. Liver Int. 2016 Aug;36(8):1108-15. doi: 10.1111/liv.13059. Epub 2016 Feb 7.
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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.
Sang Hoon Ahn, MD, PhD principal investigator
Yonsei University
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Entecavir + Tenofovir (MDR group) in people with Chronic Hepatitis B, run by Yonsei University.
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 31 Jan 2014. Status can change between updates, so confirm with the study contact before making plans.
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?
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?
The proportion of subjects who achieve virologic response(HBV DNA < 60 IU/mL, approximately 300 copies/mL) by real-time PCR at Week 48 (time frame: at Week 48). 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 NCT01594905, 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 31 Jan 2014.