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

March 25, 2021 updated by: Young-Suk Lim

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

174

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 78 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Maintaining TAF monotherapy
- Tenofovir AlaFenamide (Vemlidy) Tablet, 25mg, Daily Oral, 96 weeks
Drug: Tenofovir Alafenamide
25mg, Daily Oral
Other Names:
  • Vemlidy
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
Drug: Tenofovir Alafenamide
25mg, Daily Oral
Other Names:
  • Vemlidy
Drug: Tenofovir Disoproxil Fumarate
300mg, Daily Oral
Other Names:
  • Viread

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
At week 48 of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
At week 96 of treatment
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
At week 48, and 96 of treatment
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
At week 24, 48, 72 and 96 of treatment
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
At week 24, 48, 72 and 96 of treatment
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
At week 24, 48, 72 and 96 of treatment
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
At week 48, and 96 of 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
At week 48, and 96 of treatment
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)
At week 24, 48, 72 and 96 of treatment
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
At week 24, 48, 72 and 96 of treatment
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
At week 24, 48, 72 and 96 of treatment
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
At week 24, 48, 72 and 96 of treatment
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
At week 24, 48, 72 and 96 of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Young-Suk Lim

Collaborators

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

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 26, 2017

Primary Completion (Actual)

March 25, 2021

Study Completion (Actual)

March 25, 2021

Study Registration Dates

First Submitted

August 3, 2017

First Submitted That Met QC Criteria

August 3, 2017

First Posted (Actual)

August 7, 2017

Study Record Updates

Last Update Posted (Actual)

March 29, 2021

Last Update Submitted That Met QC Criteria

March 25, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IN-US-320-4390

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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