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

Sponsor

Young-Suk Lim (Other)

Overall Status

Completed

CT.gov ID

NCT03241641

Collaborator

Samsung Medical Center (Other), Korea University Guro Hospital (Other), Konkuk University Medical Center (Other), Seoul National University Hospital (Other)

174

Enrollment

Location

Arms

40.9

Actual Duration (Months)

4.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis b	Drug: Tenofovir Alafenamide Drug: Tenofovir Disoproxil Fumarate	Phase 4

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 Design

Study Type:

Interventional

Actual Enrollment :

174 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 26, 2017

Actual Primary Completion Date :

Mar 25, 2021

Actual Study Completion Date :

Mar 25, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Proportion of patients with virologic response [At week 48 of treatment]
The proportion of patients who achieve virologic response (serum HBV DNA concentrations below 60 IU/mL)

Secondary Outcome Measures

Proportion of patients with virologic response [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 [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 [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 [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 [At week 24, 48, 72 and 96 of treatment]
The proportion of patients with HBsAg loss or seroconversion
The incidence of virologic breakthrough [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 [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) [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 [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 [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 [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 [At week 24, 48, 72 and 96 of treatment]
Percentage change from baseline in serum creatinine

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:All of below

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

Exclusion Criteria: Any of below

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