Clinical trial NCT01597934: Antiviral Efficacy of Switching to ETV Plus TDF
Official title: A Randomized, Multicenter, Prospective Study to Compare Antiviral Efficacy and Safety of Switching to ETV Plus TDF Versus Maintaining LAM/LDT Plus ADF Combination in CHC With PVR to LAM/LDF Plus ADF Combination Rescue Therapy for YMDD Mutation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Chronic Hepatitis B
Keywords: Chronic hepatitis B
Partial virologic response
YMDD mutation
Lead sponsor: Yonsei University
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: Seoul St. Mary's Hospital
name: The Catholic University of Korea
name: Soonchunhyang University Hospital
name: Pusan National University Hospital
name: Kyungpook National University Hospital
name: Hallym University Medical Center
name: Chonbuk National University Hospital
First posted: 2012-05-15
Enrollment: 104
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Switching to Entecavir(ETV) plus Tenofovir Disoproxil Fumarate(TDF) combination will result in faster and greater antiviral activity and lower rates of resistance emergence over maintaining Lamivudine(LAM)/Telbivudine(LdT)+Adefovir(ADV) combination in partial responders to LAM/LdT+ADV rescue therapy.

Earlier switching to combination with the most potent regimen will be more effective to achieve virologic response(VR) and prevent further resistance emergence.

All subjects will orally take assigned drugs once daily for 48 weeks. All subjects will be assessed at baseline and every three months thereafter. Evaluations at each visit will include vital signs, physical examinations, laboratory tests, HBV DNA levels and adverse events. 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: 1. As TDF has not been approved yet in Korea, current KASL practice guideline generally recommends to add ADV in LAM-resistant or LdT-resistant patients.
2. However, several local literatures reported a substantial proportion of patients treated with LAM plus ADV combination therapy showed a persistently inadequate or partial virologic response('VR') and YMDDm still maintained in spite of under rescue combination therapy.
3. Due to the unavailability of TDF in Korea, ETV plus ADV combination has being considered a better salvage therapy with non-overlapping cross-resistance profiles in pts who fail to LAM plus ADV rescue therapy and local report demonstrated that the rate of VR was significantly higher with ETV+ADV switching group than LAM+ADV continuation group in partial responder to LAM plus ADV combination rescue therapy for LAM resistance.
4. Hence, more earlier combination therapy with the most potent Nucleoside and Nucleotide analogue would be a promising salvage treatment for previous NA treatment failures but comparative prospective trials are limited.
5. Therefore, this study will investigate the greater effectiveness and safety of switching to the most potent combination versus maintaining LAM(or LdT) plus ADV and also compare the rate of VR based on the HBV DNA cut-off level at switching - more than and less than 20,000 IU/mL.

All subjects will orally take assigned drugs once daily for 48 weeks. All subjects will be assessed at baseline and every three months thereafter. Evaluations at each visit will include vital signs, physical examinations, laboratory tests, HBV DNA levels and adverse events. At baseline and every six months thereafter, serum will be assayed for HBV serology. Genotypic analysis will be performed at baseline and 48 weeks.

Eligibility criteria: Inclusion Criteria:

1. ≥ 20 years of age
2. History of HBsAg positive for more than 6 months
3. History of genotypic resistance to LAM or LdT (YMDDm)
4. Partial responder (HBV DNA ≥ 60 IU/mL) currently receiving antiviral combination rescue therapy for at least 24 weeks of treatment with LAM+ADV or LdT+ADV
5. Hepatitis B e Antigen(HBeAg)-positive and -negative
6. Compensated liver disease (Child-Pugh A)
7. Signed written informed consent after being instructed about the objective and procedure of the clinical study

Exclusion Criteria:

1. History of genotypic resistance to ADV
2. Most previous treatment of other than LAM+ADV and LdT+ADV
3. Subjects with Alanine Aminotransferase(ALT) \> 10xUpper Limit of normal(ULN)
4. Co-infected with hepatitis C virus(HCV) or HIV
5. Pregnant or lactating woman
6. 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
7. History of liver transplantation or planned for liver transplantation
8. Subject who was diagnosed malignant tumor and has been receiving chemotherapy
9. Subject who has HCC history or who shows potential hepatocellular carcinoma (HCC) finding such as suspicious region in the radiologic exam(abdominal US or CT) or serum Alpha Feto Protein(AFP) elevation
10. Renal Insufficiency (CLcr \< 50ml/min based on Cockcroft-Gault equation considering weight, ages and serum creatinine)
11. Subject 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.)
12. Subject who has a history of hypersensitivity to study drug or its ingredients
13. Subject who is involved in other clinical trial within 60 days prior to study entry
14. Subject who the investigator deems inappropriate to participate in this study

Primary outcomes:
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
timeFrame: at Week 48
Secondary outcomes:
measure: Virologic efficacy
timeFrame: Week 12, 24, 36, and 48
measure: serologic efficacy
timeFrame: Week 12, 24, 36, and 48
measure: biochemical efficacy
timeFrame: Week 12, 24, 36, and 48
measure: Safety issue
timeFrame: Week 12, 24, 36, and 48
Other outcomes:
Locations:
Study officials:
affiliation: Yonsei University
name: Sang Hoon Ahn, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Woo HY, Park JY, Bae SH, Kim CW, Jang JY, Tak WY, Kim DJ, Kim IH, Heo J, Ahn SH. Entecavir+tenofovir vs. lamivudine/telbivudine+adefovir in chronic hepatitis B patients with prior suboptimal response. Clin Mol Hepatol. 2020 Jul;26(3):352-363. doi: 10.3350/cmh.2019.0044n. Epub 2020 May 28.