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

• ClinicalTrials.gov Identifier: NCT03241641
• Recruitment Status: Completed
• First Posted: August 7, 2017
• Last Update Posted: March 29, 2021
• Sponsor: Young-Suk Lim
• Collaborators: Samsung Medical Center; Korea University Guro Hospital; Konkuk University Medical Center; Seoul National University Hospital
• Information provided by (Responsible Party): Young-Suk Lim, Asan Medical Center

Tracking Information

• First Submitted Date: August 3, 2017
• First Posted Date: August 7, 2017
• Last Update Posted Date: March 29, 2021
• Actual Study Start Date: October 26, 2017
• Actual Primary Completion Date: March 25, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 3, 2017)

Proportion of patients with virologic response [ Time Frame: At week 48 of treatment ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 3, 2017)

• Proportion of patients with virologic response [ Time Frame: At week 96 of treatment ]
  The proportion of patients who achieve virologic response (serum HBV DNA concentrations below 60 IU/mL)
• The proportion of patients with HBV DNA less than 15 IU/mL [ Time Frame: At week 48, and 96 of treatment ]
  The proportion of patients with HBV DNA less than 15 IU/mL
• The proportion of patients with normal ALT [ Time Frame: At week 24, 48, 72 and 96 of treatment ]
  The proportion of patients with normal ALT
• The proportion of patients with HBeAg loss or seroconversion [ Time Frame: At week 24, 48, 72 and 96 of treatment ]
  The proportion of patients with HBeAg loss or seroconversion
• The proportion of patients with HBsAg loss or seroconversion [ Time Frame: At week 24, 48, 72 and 96 of treatment ]
  The proportion of patients with HBsAg loss or seroconversion
• The incidence of virologic breakthrough [ Time Frame: At week 48, and 96 of treatment ]
  Virologic breakthrough is defined as the increases in HBV DNA levels ≥1 log10IU/mL from nadir on two consecutive tests during continued treatment
• The proportion of patients with resistance mutations to Entecavir or Adefovir or Tenofovir [ Time Frame: At week 48, and 96 of treatment ]
  The proportion of patients with resistance mutations to Entecavir or Adefovir or Tenofovir
• Percentage change from baseline in hip and spine bone mineral density (BMD) [ Time Frame: At week 24, 48, 72 and 96 of treatment ]
  Percentage change from baseline in hip and spine bone mineral density (BMD)
• Percentage change from baseline in urine beta2-microglobulin [ Time Frame: At week 24, 48, 72 and 96 of treatment ]
  Percentage change from baseline in urine beta2-microglobulin
• Percentage change from baseline in urine protein to creatinine ratio [ Time Frame: At week 24, 48, 72 and 96 of treatment ]
  Percentage change from baseline in urine protein to creatinine ratio
• Percentage change from baseline in urine albumin to creatinine ratio [ Time Frame: At week 24, 48, 72 and 96 of treatment ]
  Percentage change from baseline in urine albumin to creatinine ratio
• Percentage change from baseline in serum creatinine [ Time Frame: At week 24, 48, 72 and 96 of treatment ]
  Percentage change from baseline in serum creatinine

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Switching From TDF to TAF vs. Maintaining TDF in Chronic Hepatitis B With Resistance to Adefovir or Entecavir.
• Official Title: Switching From Tenofovir Disoproxil Fumarate(TDF) to Tenofovir AlaFenamide(TAF) vs. Maintaining TDF Monotherapy in Chronic Hepatitis B Patients With Genotypic Resistance to Adefovir or Entecavir

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.

Detailed Description

Study objectives The objective of this study is to evaluate whether efficacy, safety, and tolerability (including bone and renal outcomes) were non-inferior in patients switched to a tenofovir alafenamide (TAF), compared with patients who remained on tenofovir disoproxil fumarate (TDF).

Study procedures This is a randomized, active-controlled, open-label, multicenter study to evaluate safety and non-inferior efficacy of switching from TDF 300 mg QD to TAF 25 mg QD for 48 weeks in chronic hepatitis B patients who have genotypic resistance to Adefovir/Entecavir.

174 subjects who complete the previous IN-US-174-0202/0205 studies will be randomized in a 1:1 ratio (A:B) to receive either TAF 25 mg QD or TDF 300 mg QD Case group: approximately 87 subjects administered TAF 25 mg QD Control group: approximately 87 subjects administered TDF 300 mg QD

The primary analysis will occur at Week 48 with the primary efficacy endpoint being newly achievement and maintenance of virologic response (HBV DNA <60 IU/mL at Week 48).

The duration of maintaining both arms is 48 weeks. All subjects who complete 48 weeks of treatment are eligible for participation in the open label TAF 25 mg extension period for an additional 48 weeks (through Week 96)

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Hepatitis b

Intervention

• Drug: Tenofovir Alafenamide
  25mg, Daily Oral
  Other Name: Vemlidy
• Drug: Tenofovir Disoproxil Fumarate
  300mg, Daily Oral
  Other Name: Viread

Study Arms

• Experimental: Maintaining TAF monotherapy
  - Tenofovir AlaFenamide (Vemlidy) Tablet, 25mg, Daily Oral, 96 weeks
  Intervention: Drug: Tenofovir Alafenamide
• Active Comparator: Switching from TDF to TAF
  • Tenofovir Disoproxil Fumarate (Viread) Tablet, 300mg, Daily Oral, 48 weeks
  • Tenofovir AlaFenamide (Vemlidy) Tablet, 25mg, Daily Oral, 48 weeks
  Interventions:

  • Drug: Tenofovir Alafenamide
  • Drug: Tenofovir Disoproxil Fumarate

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: Lancet Gastroenterol Hepatol. 2016 Nov;1(3):e2.
• 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. Erratum In: Lancet Gastroenterol Hepatol. 2016 Nov;1(3):e2.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 3, 2017): 174
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: March 25, 2021
• Actual Primary Completion Date: March 25, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:All of below

1. Patient must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
2. Male or female, 20 to 80 years of age
3. Compensated liver disease (Child-Pugh score < 8)
4. HBsAg positive at least 6 months or more
5. HBeAg positive or negative
6. 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
7. Completion of the week 240 visit in studies IN-US-174-0202 or 0205 study and maintained on TDF 300 mg QD
8. Patient is willing and able to comply with all study requirements

Exclusion Criteria: Any of below

1. Co-infection with HCV, HDV, HIV
2. Abusing alcohol (more than 40 g/day) or illicit drugs
3. Abnormal hematological and biochemical parameters, including:

1) 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

4. Received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study

5. Medical condition that requires concurrent use of systemic corticosteroid or other immunosuppressive agent

6. Received solid organ or bone marrow transplant

7. Known hypersensitivity to study drugs, metabolites, or formulation excipients

8. 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

9. Use of investigational agents within 3 months of screening, unless allowed by the Sponsor or Investigator

10. A history of hepatocellular carcinoma (HCC) within 5 years of screening

11. 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

12. Participation in another investigational drug trial

13. Pregnant or breastfeeding or willing to be pregnant

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Korea, Republic of

Administrative Information

• NCT Number: NCT03241641
• Other Study ID Numbers: IN-US-320-4390
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Young-Suk Lim, Asan Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Young-Suk Lim
• Original Study Sponsor: Same as current

Collaborators

• Samsung Medical Center
• Korea University Guro Hospital
• Konkuk University Medical Center
• Seoul National University Hospital

Investigators

• Principal Investigator: Young-Suk Lim, M.D.,Ph D.; Asan Medical Center

• PRS Account: Asan Medical Center
• Verification Date: March 2021