The Effect of Entecavir Consolidation on Post-TDF Treatment Durability

Clinical relapse occurred much earlier and tended to be more severe after cessation of TDF than ETV. The follow-up interval and intensity would be different between ETV and TDF after discontinuation of therapy. Whether switch therapy from TDF to ETV can modify the pattern of relapse is interesting but unclear. Our hypothesis is that entecavir consolidation on post-TDF treatment patients reduce and delay the clinical relapse effectively. Hence in this proof of concept study we would like to evaluate the effect of 6 months and 12 months of entecavir consolidation on post-TDF treatment durability.

Study Overview

• Status: Unknown
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: 0.5mg Baraclude(entecavir); Drug: 0.5mg Baraclude(entecavir)

Detailed Description

Long term nucleoside/nucleotide analogues (NAs) treatment is required in the treatment of chronic hepatitis B (CHB). According to current treatment guidelines from APASL 2015, NAs treatment can be stopped if, after HBsAg loss following either anti-HBs seroconversion or at least 12 months of a post-HBsAg clearance consolidation period or after treatment for at least 2 years with undetectable HBV DNA documented on three separate occasions, 6 months apart. In Taiwan, the National Health Insurance system only reimburse 3 years NAs for CHB patients. Previous study from Jeng et al. suggested that the 1-year rate of clinical relapse (HBV DNA>2,000 IU/mL plus ALT>2X ULN) after cessation of entecavir(ETV) therapy by APASL stopping rule (treatment >2 years, HBV DNA undetectable >1 year) in HBeAg-negative chronic hepatitis B(CHB) patients was 45%, of which 25.6% occurred within 6 months. Recently, another study from Jeng et al showed that 34 HBeAg(-) patients who stopped TDF therapy by APASL stopping rule were followed-up every 1-3 months for >6 months. Of these 34 patients, mean age was 51.8 years, 82.4% were males and 14(41.2%) were cirrhotic. The 1-year cumulative clinical relapse rate was 46%, of which 93.3% occurred within 6 months, and 13.3% developed decompensation. Clinical relapse occurred much earlier and tended to be more severe after cessation of TDF than ETV. The follow-up interval and intensity would be different between ETV and TDF after discontinuation of therapy. Whether switch therapy from TDF to ETV can modify the pattern of relapse is interesting but unclear. Our hypothesis is that entecavir consolidation on post-TDF treatment patients reduce and delay the clinical relapse effectively. Hence in this proof of concept study we would like to evaluate the effect of 6 months and 12 months of entecavir consolidation on post-TDF treatment durability.

• Study Type: Interventional
• Enrollment (Anticipated): 156
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• >20 yrs old.
• No history of Lamivudine or telbivudine resistance.
• HBsAg positive for more than 6 months.
• HBeAg (-).
• HBeAg-negative CHB under TDF treatment for mora than 2 years and fulfilled APASL 2012 guideline's stopping rule: HBeAg (-): undetectable HBV DNA on 3 separate occasions at least 6 months apart.

Exclusion Criteria:

• Lamivudine/telbivudine resistance.
• HBeAg (+).
• HIV, HCV co-infection.
• Under immunosuppressant treatment (including steroid and biologics).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm 1; 0.5mg Entecavir QD for 6 months after cessation of TDF and clinical observation for up to 6 months after the end of study follow-up.	Drug: 0.5mg Baraclude(entecavir); 0.5mg Baraclude (entecavir) QD for 6 months after cessation of TDF.; Drug: 0.5mg Baraclude(entecavir); 0.5mg Baraclude (entecavir) QD for 12 month after cessation of TDF.
ACTIVE_COMPARATOR: Arm 2; 0.5mg Entecavir QD for 12 months after cessation of TDF and clinical observation for up to 6 months after the end of study follow-up.	Drug: 0.5mg Baraclude(entecavir); 0.5mg Baraclude (entecavir) QD for 6 months after cessation of TDF.; Drug: 0.5mg Baraclude(entecavir); 0.5mg Baraclude (entecavir) QD for 12 month after cessation of TDF.
NO_INTERVENTION: Arm 3; No consolidation arm and observation only and clinical observation for up to 6 months after the end of study follow-up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical relapse rate.	Clinical relapse rate (HBV DNA>2000 IU/ml and ALT> 2x ULN) within 6 months after cessation of TDF or ETV consolidation treatment (up to 6 or 12 months on post-TDF therapy).	Up to 24 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of ATL flare	Severity of ATL flare (ALT>5X and 10X) within 6 months after cessation of TDF or ETV consolidation treatment (up to 6 or 12 months on post-TDF therapy).	Up to 24 months.
Liver decompensation incidence	Liver decompensation incidence (Total bilirubin > 2mg/dl and/or PT prolongation> 3 sec) within 6 months after cessation of TDF or ETV consolidation treatment (up to 6 or 12 months on post-TDF therapy).	Up to 24 months.
Renal function changes	Renal function changes based on eGFR (monitor per 3m) within 6 months after cessation of TDF or ETV consolidation treatment (up to 6 or 12 months on post-TDF therapy).	Up to 24 months.

Collaborators and Investigators

• Sponsor: Taipei Veterans General Hospital, Taiwan
• Collaborators: China Medical University Hospital; Chang Gung Memorial Hospital; Changhua Christian Hospital

Publications and helpful links

General Publications

• Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016 Jan;10(1):1-98. doi: 10.1007/s12072-015-9675-4. Epub 2015 Nov 13.
• Jeng WJ, Sheen IS, Chen YC, Hsu CW, Chien RN, Chu CM, Liaw YF. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology. 2013 Dec;58(6):1888-96. doi: 10.1002/hep.26549. Epub 2013 Oct 17.
• Jeng WJ, Chen YC, Sheen IS, Lin CL, Hu TH, Chien RN, Liaw YF. Clinical Relapse After Cessation of Tenofovir Therapy in Hepatitis B e Antigen-Negative Patients. Clin Gastroenterol Hepatol. 2016 Dec;14(12):1813-1820.e1. doi: 10.1016/j.cgh.2016.07.002. Epub 2016 Jul 9.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): November 1, 2017
• Primary Completion (ANTICIPATED): July 1, 2019
• Study Completion (ANTICIPATED): April 30, 2022

Study Registration Dates

• First Submitted: October 5, 2017
• First Submitted That Met QC Criteria: October 11, 2017
• First Posted (ACTUAL): October 13, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 17, 2017
• Last Update Submitted That Met QC Criteria: October 14, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Hepatitis, Chronic; Hepatitis; Hepatitis B; Hepatitis B, Chronic; Anti-Infective Agents; Antiviral Agents; Entecavir
• Other Study ID Numbers: AI463-527

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No