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Chronic Hepatitis BPhase 4ALTERNCT01546116

Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

A Phase 4 study testing ADEFOVIR, LAMIVUDINE in people with Chronic Hepatitis B, run by Korea University at 9 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

Entecavir has been one of the option for treatment of lamivudine resistant chronic hepatitis B (CHB). In case of entecavir resistance, adefovir could be used. However, sequential monotherapy may result in multidrug resistance. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Hepatitis B
What is being tested?
ADEFOVIR, LAMIVUDINE
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
9 sitesSouth Korea
Study dates
Feb 2010to Feb 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 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Chronic hepatitis B patients (positive HBsAg > 6 months)
  • Age > 18 year old
  • History of treatment with entecavir more than 6 months
  • Proven entecavir resistant mutation (rtT184S/A/I/L/G/C/M, rtS202G/C/I, or rtM250I/V)
  • HBV DNA level> 2000 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 14Show fewer
  • Serum AFP >100 ng/mL
  • History of treatment with interferon-alfa, thymosin-alfa 1, or nucleos(t)ide analogue other than entecavir in 6 months of screening
  • History of adefovir resistance (detection of rtA181T/Vor rtN236T at screening or in the past)
  • 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

9 sites in 1 country.

9 sites in 1 country

South Korea9 sites

  • Korea University Ansan Hospital

    Ansan, Gyeonggi-do

  • Hallym University, Sacred Heart Hospital

    Anyang-si, Gyeonggi-do

  • Chungbuk National University Hospital

    Cheongju-si, Chngcheongbuk-do

  • The Catholic University of Korea, Euijeongbu Saint Mary's Hospital

    Euijeongbu, Gyeonggi-do

  • Gachon University Gil Medical Center

    Incheon

  • Inha University Hospital

    Incheon

  • Hallym University, Gangnam Sacred Heart Hospital

    Seoul

  • Korea University Anam Hospital

    Seoul

  • Yonsei University Wonju Christian Hospital

    Wŏnju, Gangwon-do

Other trials in South Korea

About this study

Official title: Efficacy of Adefovir and Lamivudine Combination Therapy in Patients With Entecavir Resistance

  • Entecavir has been one of the option for treatment of lamivudine resistant chronic hepatitis B (CHB).
  • In case of entecavir resistance, adefovir could be used. However, sequential monotherapy may result in multidrug resistance.
  • It is thought that adefovir and lamivudine combination therapy reduce the risk of adefovir resistance, thereby continued therapy will lead to suppression of hepatitis B virus (HBV) DNA to be undetectable in patients with entecavir resistance.
  • This study aim to evaluate the efficacy of adefovir and lamivudine combination therapy in CHB patients with entecavir resistance.
Read the detailed description

Entecavir is a potent antiviral agent for the treatment of chronic hepatitis B (CHB). However, the incidence of entecavir resistance increases over 50% at 5th year in lamivudine-refractory CHB patients. Considering cross resistance profile, adefovir is a good option for managing entecavir resistance. However adefovir monotherapy may lead to adefovir resistance, because entecavir resistant hepatitis B virus (HBV) retain lamivudine resistance. Previously, combination of adefovir and lamivudine was reported to be effective in a patient with entecavir resistance, but only as a case report form. No further data are available on this combination therapy in a sufficient number of patients. It is thought that adefovir and lamivudine combination therapy reduce the risk of adefovir resistance, thereby continued combination treatment will result in suppression of HBV DNA to be undetectable in patients with entecavir resistance.

The aim of this study is to evaluate the efficacy of adefovir and lamivudine combination therapy in CHB patients with entecavir resistance.

Being tested
ADEFOVIR, LAMIVUDINE
Keywords
adefovir, lamivudine, entecavir 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.

  • ADEFOVIR, LAMIVUDINEDrug

    Also called Adefovir (Hepasera), Lamivudine (Zeffix)

    Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week

Study groups in NCT01546116
Study groupRoleWhat they receive
Adefovir and lamivudine combinationExperimentalNot described
Receives: Drug: ADEFOVIR, LAMIVUDINE

What is being measured

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

  1. Degree of HBV DNA reduction from baseline

    Degree of HBV DNA reduction from baseline during 52 week-period of adefovir and lamivudine combination therapy will be assessed.

    Measured: at week 52

Secondary outcomes (6)

  1. HBV DNA undetectability by PCR (<60 IU/mL)

    Measured: at week 52

  2. ALT normalization

    Measured: at week 52

  3. HBeAg loss

    Measured: at week 52

  4. HBeAg to anti- HBe seroconversion

    Measured: at week 52

  5. Development of adefovir resistance

    Measured: at week 52

  6. Virologic breakthrough

    virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).

    Measured: at week 52

Timeline

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

  1. First posted7 Mar 2012 (estimated)
  2. Study startFeb 2010
  3. Primary completionFeb 2012
  4. Study completionFeb 2014

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01546116
Sponsor's protocol ID
ALTER_114093
Acronym
ALTER
Status last verified
Feb 2014
First submitted
22 Dec 2011
Last updated
17 Feb 2014
Results posted
No
Data monitoring committee
Yes

Publications

  • Lee WM. Hepatitis B virus infection. N Engl J Med. 1997 Dec 11;337(24):1733-45. doi: 10.1056/NEJM199712113372406. No abstract available.

    PubMed 9392700

  • Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2. doi: 10.1002/hep.23190. No abstract available.

    PubMed 19714720

  • Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB, Colonno RJ. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. 2009 May;49(5):1503-14. doi: 10.1002/hep.22841.

    PubMed 19280622

  • Yim HJ, Hussain M, Liu Y, Wong SN, Fung SK, Lok AS. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology. 2006 Sep;44(3):703-12. doi: 10.1002/hep.21290.

    PubMed 16941700

  • Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007 Nov;133(5):1445-51. doi: 10.1053/j.gastro.2007.08.079. Epub 2007 Sep 2.

    PubMed 17983801

  • 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

  • Villet S, Ollivet A, Pichoud C, Barraud L, Villeneuve JP, Trepo C, Zoulim F. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol. 2007 Mar;46(3):531-8. doi: 10.1016/j.jhep.2006.11.016. Epub 2006 Dec 18.

    PubMed 17239478

  • Yatsuji H, Hiraga N, Mori N, Hatakeyama T, Tsuge M, Imamura M, Takahashi S, Fujimoto Y, Ochi H, Abe H, Maekawa T, Suzuki F, Kumada H, Chayama K. Successful treatment of an entecavir-resistant hepatitis B virus variant. J Med Virol. 2007 Dec;79(12):1811-7. doi: 10.1002/jmv.20981.

    PubMed 17935165

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing ADEFOVIR, LAMIVUDINE in people with Chronic Hepatitis B, run by Korea University at 9 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 7 inclusion and 14 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 17 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 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?

Degree of HBV DNA reduction from baseline (time frame: at week 52). 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 NCT01546116, which also lists 8 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 17 Feb 2014.

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