Switching From TDF to TAF vs. Maintaining TDF in Chronic Hepatitis B With Resistance to Adefovir or Entecavir.

NCT03241641 | Completed Phase 4

• 1 other identifier: IN-US-320-4390
• Study Type: interventional
• Target: 174
• Locations: 1 country
• Sites: 1

Brief Summary

Treatment of CHB patients with genotypic resistance to NUCs has been problematic due to the lack of data from randomized trials. Recently, two randomized trials comparing the efficacy of TDF monotherapy versus TDF and ETV combination therapy in CHB patients with documented genotypic resistance to adefovir (ADV) or ETV demonstrated TDF monotherapy was not statistically different in viral suppression at week 48 of treatment.1,2 The extension study based on the above two trials merged study subjects from these trials with changing from TDF and ETV combination group to TDF monotherapy to evaluate long-term efficacy and safety of TDF monotherapy for multidrug-resistant patients. At the time of merging of 192 subjects, by intention-to-treat analysis, 66.3% of TDF group and 68.0% of TDF-ETV group had virological response as determined by serum HBV DNA \<15 IU/mL. (in press) Three year long-term follow up study showed that the proportion of virologic suppression increased to 76.8% and 72.2% in TDF-TDF and TDF/TDF-ETV groups, respectively( P=0.46). (in press) TAF, a novel prodrug of tenofovir was developed to have greater stability in plasma than TDF, thereby enabling more efficient delivery of the active metabolite to target cells at a substantially lower dose. The reduced systemic exposure of tenofovir offers the potential for an improved safety profile compared to TDF a benefit that demonstrated in a recent clinical trial in patients with HIV infection. In a recent double-blind randomized phase 3 noninferiority trial with 873 treatment naive patients who were positive for HBeAg, the proportion of patients receiving TAF who had HBV DNA \<29 IU/mL at week 48 was 64%, which was non-inferior to the rate of 67% in patients receiving TDF (P=0.25).3 In the safety profile, TAF group had significantly smaller decrease in BMD than TDF group in the hip and spine, as well as significantly smaller increases in serum creatinine at week 48.3 For treatment naive HBeAg negative patients, a recent study with 425 subjects applied the same methodology and showed noninferiority in efficacy of TAF compared to TDF at week 48.4 Considering noninferiority in efficacy and superior bone and renal safety from TAF, TAF might be considered preferred choice of NUC instead of TDF. However, it is still unknown whether TAF would show similar efficacy and safety profile in patients with multidrug-resistant CHB.

Conditions

Chronic Hepatitis b

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with virologic response

  The proportion of patients who achieve virologic response (serum HBV DNA concentrations below 60 IU/mL)

  At week 48 of treatment

Secondary Outcomes (12)

• Proportion of patients with virologic response

  At week 96 of treatment

• The proportion of patients with HBV DNA less than 15 IU/mL

  At week 48, and 96 of treatment

• The proportion of patients with normal ALT

  At week 24, 48, 72 and 96 of treatment

• The proportion of patients with HBeAg loss or seroconversion

  At week 24, 48, 72 and 96 of treatment

• The proportion of patients with HBsAg loss or seroconversion

  At week 24, 48, 72 and 96 of treatment

Study Arms (2)

Maintaining TAF monotherapy

EXPERIMENTAL

\- Tenofovir AlaFenamide (Vemlidy) Tablet, 25mg, Daily Oral, 96 weeks

Drug: Tenofovir Alafenamide

Switching from TDF to TAF

ACTIVE COMPARATOR

* Tenofovir Disoproxil Fumarate (Viread) Tablet, 300mg, Daily Oral, 48 weeks * Tenofovir AlaFenamide (Vemlidy) Tablet, 25mg, Daily Oral, 48 weeks

Drug: Tenofovir Alafenamide; Drug: Tenofovir Disoproxil Fumarate

Interventions

Tenofovir Alafenamide DRUG

25mg, Daily Oral

Also known as: Vemlidy

Maintaining TAF monotherapy; Switching from TDF to TAF

Tenofovir Disoproxil Fumarate DRUG

300mg, Daily Oral

Also known as: Viread

Switching from TDF to TAF

Eligibility Criteria

• Age: 20 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
• Male or female, 20 to 80 years of age
• Compensated liver disease (Child-Pugh score \< 8)
• HBsAg positive at least 6 months or more
• HBeAg positive or negative
• Confirmation of ETV resistance mutation (rt184, rtS202, or rtM250) at the enrollment of IN-US-174-0202 study, or ADV resistance mutation (rtA181V, rtA181T or rtN236T) at the enrollment of IN-US-174-0205 study
• Completion of the week 240 visit in studies IN-US-174-0202 or 0205 study and maintained on TDF 300 mg QD
• Patient is willing and able to comply with all study requirements

You may not qualify if:

• Co-infection with HCV, HDV, HIV
• Abusing alcohol (more than 40 g/day) or illicit drugs
• Abnormal hematological and biochemical parameters, including:
• \) serum bilirubin \>3 mg/dL 2) prothrombin time (INR) \>1.5 3) serum albumin \<2.8 g/dL 4) ascites, encephalopathy or variceal hemorrhage 5) Child-Pugh score ≥8
• \. Received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study
• \. Medical condition that requires concurrent use of systemic corticosteroid or other immunosuppressive agent
• \. Received solid organ or bone marrow transplant
• \. Known hypersensitivity to study drugs, metabolites, or formulation excipients
• \. Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study or unable to comply with dosing requirements
• \. Use of investigational agents within 3 months of screening, unless allowed by the Sponsor or Investigator
• \. A history of hepatocellular carcinoma (HCC) within 5 years of screening
• \. A history treated malignancy (other than HCC) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years
• \. Participation in another investigational drug trial
• \. Pregnant or breastfeeding or willing to be pregnant

Sponsors & Collaborators

• Young-Suk Lim: lead
• Samsung Medical Center: collaborator
• Korea University Guro Hospital: collaborator
• Konkuk University Medical Center: collaborator
• Seoul National University Hospital: collaborator

Study Sites (1)

Asan Medical Center

Seoul, 05505, South Korea

Location

Related Publications (14)

• Chae HB, Kim JH, Kim JK, Yim HJ. Current status of liver diseases in Korea: hepatitis B. Korean J Hepatol. 2009 Dec;15 Suppl 6:S13-24. doi: 10.3350/kjhep.2009.15.S6.S13.

  PMID: 20037275 RESULT

• Kim SR, Kudo M, Hino O, Han KH, Chung YH, Lee HS; Organizing Committee of Japan-Korea Liver Symposium. Epidemiology of hepatocellular carcinoma in Japan and Korea. A review. Oncology. 2008;75 Suppl 1:13-6. doi: 10.1159/000173419. Epub 2008 Dec 17.

  PMID: 19092267 RESULT

• Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004 Oct 7;351(15):1521-31. doi: 10.1056/NEJMoa033364.

  PMID: 15470215 RESULT

• Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006 Jan 4;295(1):65-73. doi: 10.1001/jama.295.1.65.

  PMID: 16391218 RESULT

• Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006 Mar;130(3):678-86. doi: 10.1053/j.gastro.2005.11.016.

  PMID: 16530509 RESULT

• Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HS, Carrilho FJ, Poordad F, Halota W, Horsmans Y, Tsai N, Zhang H, Tenney DJ, Tamez R, Iloeje U. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010 Feb;51(2):422-30. doi: 10.1002/hep.23327.

  PMID: 20049753 RESULT

• Snow-Lampart A, Chappell B, Curtis M, Zhu Y, Myrick F, Schawalder J, Kitrinos K, Svarovskaia ES, Miller MD, Sorbel J, Heathcote J, Marcellin P, Borroto-Esoda K. No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus. Hepatology. 2011 Mar;53(3):763-73. doi: 10.1002/hep.24078. Epub 2010 Dec 22.

  PMID: 21374657 RESULT

• Zoulim F, Durantel D, Deny P. Management and prevention of drug resistance in chronic hepatitis B. Liver Int. 2009 Jan;29 Suppl 1:108-15. doi: 10.1111/j.1478-3231.2008.01939.x.

  PMID: 19207973 RESULT

• Bartholomeusz A, Locarnini SA. Antiviral drug resistance: clinical consequences and molecular aspects. Semin Liver Dis. 2006 May;26(2):162-70. doi: 10.1055/s-2006-939758.

  PMID: 16673294 RESULT

• Lim YS, Yoo BC, Byun KS, Kwon SY, Kim YJ, An J, Lee HC, Lee YS. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial. Gut. 2016 Jun;65(6):1042-51. doi: 10.1136/gutjnl-2014-308435. Epub 2015 Mar 23.

  PMID: 25800784 RESULT

• Lim YS, Byun KS, Yoo BC, Kwon SY, Kim YJ, An J, Lee HC, Lee YS. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial. Gut. 2016 May;65(5):852-60. doi: 10.1136/gutjnl-2014-308353. Epub 2015 Jan 16.

  PMID: 25596179 RESULT

• Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, Hui AJ, Janssen HL, Chowdhury A, Tsang TY, Mehta R, Gane E, Flaherty JF, Massetto B, Gaggar A, Kitrinos KM, Lin L, Subramanian GM, McHutchison JG, Lim YS, Acharya SK, Agarwal K; GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):185-195. doi: 10.1016/S2468-1253(16)30024-3. Epub 2016 Sep 22.

  PMID: 28404091 RESULT

• Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, Hui AJ, Lim YS, Mehta R, Janssen HL, Acharya SK, Flaherty JF, Massetto B, Cathcart AL, Kim K, Gaggar A, Subramanian GM, McHutchison JG, Pan CQ, Brunetto M, Izumi N, Marcellin P; GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):196-206. doi: 10.1016/S2468-1253(16)30107-8. Epub 2016 Sep 22.

  PMID: 28404092 RESULT

• Byun KS, Choi J, Kim JH, Lee YS, Lee HC, Kim YJ, Yoo BC, Kwon SY, Gwak GY, Lim YS. Tenofovir Alafenamide for Drug-Resistant Hepatitis B: A Randomized Trial for Switching From Tenofovir Disoproxil Fumarate. Clin Gastroenterol Hepatol. 2022 Feb;20(2):427-437.e5. doi: 10.1016/j.cgh.2021.04.045. Epub 2021 May 4.

  PMID: 33962041 DERIVED

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

tenofovir alafenamide; Tenofovir

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)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Young-Suk Lim, M.D.,Ph D.

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 3, 2017
• First Posted: August 7, 2017
• Study Start: October 26, 2017
• Primary Completion: March 25, 2021
• Study Completion: March 25, 2021
• Last Updated: March 29, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)