Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

NCT01546116 | Completed Phase 4 DMC

• 1 other identifier: ALTER_114093
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 9

Brief 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.
• 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.

Conditions

Chronic Hepatitis B

Keywords

adefovir; lamivudine; entecavir resistance

Outcome Measures

Primary Outcomes (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.

  at week 52

Secondary Outcomes (6)

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

  at week 52

• ALT normalization

  at week 52

• HBeAg loss

  at week 52

• HBeAg to anti- HBe seroconversion

  at week 52

• Development of adefovir resistance

  at week 52

Study Arms (1)

Adefovir and lamivudine combination

EXPERIMENTAL

Drug: ADEFOVIR, LAMIVUDINE

Interventions

ADEFOVIR, LAMIVUDINE DRUG

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

Also known as: Adefovir (Hepasera), Lamivudine (Zeffix)

Adefovir and lamivudine combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• 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) -

Sponsors & Collaborators

• Korea University: lead
• GlaxoSmithKline: collaborator

Study Sites (9)

Chungbuk National University Hospital

Cheongju-si, Chngcheongbuk-do, South Korea

Location

Yonsei University Wonju Christian Hospital

Wŏnju, Gangwon-do, South Korea

Location

Korea University Ansan Hospital

Ansan, Gyeonggi-do, South Korea

Location

Hallym University, Sacred Heart Hospital

Anyang-si, Gyeonggi-do, South Korea

Location

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

Euijeongbu, Gyeonggi-do, South Korea

Location

Gachon University Gil Medical Center

Incheon, South Korea

Location

Inha University Hospital

Incheon, South Korea

Location

Hallym University, Gangnam Sacred Heart Hospital

Seoul, South Korea

Location

Korea University Anam Hospital

Seoul, South Korea

Location

Related Publications (8)

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

  PMID: 9392700 BACKGROUND

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

  PMID: 19714720 BACKGROUND

• 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.

  PMID: 19280622 BACKGROUND

• 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.

  PMID: 16941700 BACKGROUND

• 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.

  PMID: 17983801 BACKGROUND

• 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.

  PMID: 17256746 BACKGROUND

• 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.

  PMID: 17239478 RESULT

• 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.

  PMID: 17935165 RESULT

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

adefovir; Lamivudine

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

Study Officials

• HYUNG JOON YIM, M.D., Ph.D.

  Korea University Ansan Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: December 22, 2011
• First Posted: March 7, 2012
• Study Start: February 1, 2010
• Primary Completion: February 1, 2012
• Study Completion: February 1, 2014
• Last Updated: February 17, 2014

Record last verified: 2014-02

Locations

KR (9)