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Chronic Hepatitis BPhase 4NCT00531167

Adding Adefovir Dipivoxil Versus Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B

A Phase 4 study testing combination of lamivudine+adefovir vs entecavir in people with Chronic Hepatitis B, run by Korea University at 2 sites in South Korea.

Completed

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

Official record
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Trial summary

Antiviral resistance mutations limit the efficacy of therapy for chronic hepatitis B. At year 2, resistance to adefovir may occur as high as 25% in patients with history of lamivudine resistance. Resistance to entecavir is reported to be 10% in lamivudine refractory patients during the same period. Read more about this study

Who is it for?
Ages 16 to 75 years
Conditions the study is for
Chronic Hepatitis B
What is being tested?
combination of lamivudine+adefovir vs entecavir
Could I receive a placebo?
No, everyone receives an active treatment
How many people
219 participants
Where
2 sitesSouth Korea
Study dates
Apr 2007to Oct 2012
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 16 to 75 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Chronic hepatitis B patients (positive HBsAg > 6 months)
  • Age > 16 year old
  • Serum alanine aminotransferase (ALT) >1.5 x ULN
  • History of treatment with lamivudine more than 6 months
  • Proven lamivudine resistant mutation
  • HBV DNA level> 20000 IU/mL
  • Compensated liver disease (Child-Pugh-Turcotte score over 7; prothrombin time prolonged more than 3 sec above ULN or INR over 1.5; serum albumin >3 g/dL; total bilirubin <2.5 mg/dL; No history of variceal bleeding, ascites, or hepatic encephalopathy)
  • Patients willing to give informed consent

Who cannot join

  • Out of inclusion criteria
  • Any one of following
  • Serum phosphorus level under 2.4 mg/dL
  • Serum creatinine level over 1.5 mg/dL or creatinine clearance <50 mL/min
  • Absolute neutrophil count lower than 1000 cell/mL
  • Hb level under 10 g/dL (male), under 9 g/dL (female)
Show all 13Show fewer
  • Serum AFP >100 ng/mL
  • History of treatment with interferon-a, thymosin-alfa 1, or nucleos(t)ide analogue other than lamivudine in 6 months of screening
  • Recipient of organ transplantation
  • Positive antibody test to HIV, HCV or HDV
  • Pregnant or breast feeding women
  • Patients with hepatocellular carcinoma or uncontrolled malignant disease
  • Habitual alcohol drinker (>140 g/week for men, >70 g/week for women)

Trial locations and contacts

2 sites in 1 country.

South Korea2 sites

  • Korea University Ansan Hospital

    Ansan, Gyeonggi-do

  • Korea University Anam Hospital

    Seoul

Other trials in South Korea

About this study

Official title: Prospective Randomized Study for the Comparison of Adding Adefovir Dipivoxil and Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B

Antiviral resistance mutations limit the efficacy of therapy for chronic hepatitis B. At year 2, resistance to adefovir may occur as high as 25% in patients with history of lamivudine resistance. Resistance to entecavir is reported to be 10% in lamivudine refractory patients during the same period. However, combination of lamivudine and adefovir decreased the adefovir resistance rate as low as 0% in the recent studies. By overcoming the antiviral resistance, the efficacy of therapy will be maximized. This study is intended to compare the efficacy of two strategies, combination of lamivudine and adefovir vs. entecavir monotherapy in patients with lamivudine resistance.

Read the detailed description

Recently, published data showed combination of lamivudine and adefovir lead to PCR negativity (<1000 copies/mL) up to 80% in the treatment of lamivudine-resistant chronic hepatitis B at year 2 [Rapti et al. Hepatology 2007 Feb;45(2):307-13.]. Other studies also showed 76% and 69% PCR negativity in mostly HBeAg negative subjects [Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1:556A-557A, Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1:693A-694A].

In the study for the treatment of lamivudine-resistant chronic hepatitis B patients which included HBeAg positive subjects more predominantly, entecavir monotherapy showed 34% of PCR negativity (<300 copies/mL) at year 2 [Tenney DJ, et al. Antimicrob Agents Chemother. 2007 Mar;51(3):902-11].

Although it is assumed that combination of lamivudine and adefovir would be more effective than entecavir monotherapy for lamivudine resistant patients, we cannot verify the assumption, because there is no data directly comparing these two strategies until now.

The aim of this study is to determine the most effective therapy for the patients with lamivudine resistant chronic hepatitis B. We will compare the PCR negativity (<60 IU/ml) of HBV DNA at year 2 in patients receiving 'the combination of lamivudine and adefovir' and 'entecavir monotherapy'.

Since we are planning to include lamivudine-resistant chronic hepatitis B patients regardless of HBeAg status, we assumed the PCR negativity (<300 copies/mL or <60 IU/mL) in adefovir-lamivudine combination and entecavir monotherapy group as 55% and 34%, respectively, considering HBeAg status and lower detection limit of PCR.

The result of this study will be able to clearly demonstrate the superiority of combination therapy with lamivudine and adefovir to entecavir monotherapy, which provide us the guide to rescue therapy for patients with lamivudine resistant HBV.

Being tested
combination of lamivudine+adefovir vs entecavir
Keywords
lamivudine resistant mutations, rescue therapy
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.

  • combination of lamivudine+adefovir vs entecavirDrug

    Also called Zeffix, Hepsera, Baraclude

    Lamivudine 100 mg/day, Adefovir 10 mg/day, Entecavir 0.5 mg/day

Study groups in NCT00531167
Study groupRoleWhat they receive
AExperimentalcombination therapy
Receives: Drug: combination of lamivudine+adefovir vs entecavir
BActive comparatorentecavir
Receives: Drug: combination of lamivudine+adefovir vs entecavir

What is being measured

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

  1. PCR negativity (<60 IU/ml) of HBV DNA

    Measured: At the end of year 2 (since starting rescue therapy for lamivudine resistance)

Secondary outcomes (1)

  1. 1. PCR negativity (<60 IU/ml) of HBV DNA at year 1 (interim analysis) 2. Degrees of HBV DNA reduction 3. ALT normalization 4. HBeAg seroconversion 5. Development of resistant mutation 6. Virologic breakthrough 7. Biochemical breakthrough

    Measured: At the end of year 2 except interim analysis

Timeline

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

  1. First posted18 Sep 2007 (estimated)
  2. Study startApr 2007
  3. Primary completionApr 2011
  4. Study completionOct 2012

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 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
219 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00531167
Sponsor's protocol ID
CRT 111098
Status last verified
Oct 2012
First submitted
17 Sep 2007
Last updated
22 Oct 2012
Results posted
No
Data monitoring committee
Yes

Publications

  • Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. doi: 10.1002/hep.21513. No abstract available.

    PubMed 17256718

  • Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology. 2007 Feb;45(2):307-13. doi: 10.1002/hep.21534.

    PubMed 17256746

  • Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ. Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007 Mar;51(3):902-11. doi: 10.1128/AAC.00833-06. Epub 2006 Dec 18.

    PubMed 17178796

  • Peters MG, Hann Hw Hw, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray Df Df, Sullivan M, Kleber K, Ebrahimi R, Xiong S, Brosgart CL. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004 Jan;126(1):91-101. doi: 10.1053/j.gastro.2003.10.051.

    PubMed 14699491

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing combination of lamivudine+adefovir vs entecavir in people with Chronic Hepatitis B, run by Korea University at 2 sites 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 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 22 Oct 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites 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?

PCR negativity (<60 IU/ml) of HBV DNA (time frame: At the end of year 2 (since starting rescue therapy for lamivudine resistance)). 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 NCT00531167, 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 22 Oct 2012.

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