Efficacy and Safety of TAF in Patients With Suboptimal Response to Other Nucleos(t)Ides

November 15, 2020 updated by: New Discovery LLC

Efficacy and Safety of Tenofovir Alafenamide in Chronic Hepatitis B Patients With Suboptimal Response Following Nucleos(t)Ide Therapy

Both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are potent antiviral agents for hepatitis B virus (HBV) and recommended by the American Association for the Study of Liver Disease (AASLD) as well as the European Association for the Study of Liver (EASL) guidelines for the treatment of nucleos(t)ide therapy induced HBV resistance. However, it is not clear if chronic hepatitis B (CHB) patients with nucleos(t)ide treatment experience without genotypic mutations would be benefit from TAF therapy. Previous studies have observed that suboptimal response (SOR) following antiviral therapy with nucleos(t)ide treatment is associated with an increased risk of subsequent treatment failure and viral resistance. It remains unclear whether switching to TAF is a reasonable approach in patients with SOR to second-line antivirals Lamivudine (LAM)/ Telbivudine (LdT)/ Adefovir Dipivoxil (ADV) and its combinations with other second-line antivirals for 24 weeks, or SOR to the first-line antiviral Entecavir (ETV) or any antiviral combinations containing ETV for 48 weeks. This study is aimed to determine how the aforementioned patients with SOR to nucleos(t)ide treatment respond to TAF monotherapy. The investigator's study will provide evidence base for therapy selection in SOR patients, especially in China where the majority of patients with CHB are treated with nucleos(t)ide therapy.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a prospective, single-arm, multicenter cohort study evaluating the efficacy, safety, and tolerability of TAF monotherapy in in Asian CHB adults with SOR to the nucleos(t)ide therapy by assessing the HBV DNA suppression in 48 weeks. Approximately one hundred adults who received the aforementioned nucleos(t)ide therapy will be prospectively enrolled during the period from December 2019 to June 2021. Subjects will be enrolled by medical clinic in about 10 university centers in different regions in China. Approximately 10-15 consecutive eligible patients will be enrolled from each participating sites. This study will be conducted in accordance with the guidelines of Good Clinical Practices (GCPs) including Institutional Review Board (IRB) approval and consent will be applied. Patient identification (ID) will be de-identified for submitting to the central database for analyses from all study sites. Free TAF treatment will be provided to all enrolled patients for 48 weeks. Patients will be under the local standard of care upon the completion of the current study.

Patients aged 18-80 with CHB infection who had received nucleos(t)ide therapy over 24 weeks of LAM/LdT/ADV or 48 weeks of ETV with medication adherence, but failure to achieve the levels of HBV-DNA below 300 IU/mL will be eligible. Subjects will be excluded if they meet the following criteria: co-infected with HIV or other viral hepatitis; the serum levels of HBV DNA are too low (i.e. about 300 IU/mL) to be analyzed for the genotypic mutation(s); nucleos(t)ide resistant mutants have been detected at screening visit, patient is under a clinical research protocol of phase I-III development; unable to consent or unlikely to complete one year follow up after the enrollment; and other medical condition may affect the ability to participate the study.

Study Type

Interventional

Enrollment (Anticipated)

100

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 Contact

Study Contact Backup

  • Name: Calvin Q Pan, MD
  • Phone Number: (+001) 7188887728
  • Email: Panc01@nyu.edu

Study Locations

  • China
    • Anhui
      • Bengbu, Anhui, China, 233000
        • Recruiting
        • The First affiliated hospital of bengbu medical college
        • Contact:
        • Contact:
        • Principal Investigator:
          • Shousong Zhao, MD
        • Sub-Investigator:
          • Chuanmiao Liu, MD
    • Beijing
      • Beijing, Beijing, China, 100015
        • Recruiting
        • Beijing Ditan Hospital, Capital Medical University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Wen Xie, MD
        • Sub-Investigator:
          • Ting Zhang, MD
    • Chongqing
      • Chongqing, Chongqing, China, 400038
        • Recruiting
        • Southwest Hospital
        • Contact:
          • Yuming Wang, MD
          • Phone Number: (+86) 023-65334998
          • Email: wym417@163.com
        • Contact:
        • Principal Investigator:
          • Yuming Wang, MD
        • Sub-Investigator:
          • Junnan Li, MD
    • Fujian
      • Fuzhou, Fujian, China
        • Recruiting
        • Liver Research Center, The First Affiliated Hospital of Fujian Medical University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Yueyong Zhu, MD
        • Sub-Investigator:
          • Jiaji Jiang, MD
    • Guangdong
      • Guangzhou, Guangdong, China, 510630
        • Recruiting
        • Third Affiliated Hospital of Sun Yat-sen University
        • Contact:
        • Contact:
          • Zhiliang Gao, MD
          • Phone Number: (+86) 18922102588
          • Email: gaozl@21cn.com
        • Principal Investigator:
          • Zhiliang Gao, MD
        • Sub-Investigator:
          • Yubao Zheng, MD
    • Hubei
      • Wuhan, Hubei, China, 430022
        • Recruiting
        • Wuhan Union Hospital, Tongji Medical College (TJMC), Huazhong University of Science and Technology (HUST)
        • Contact:
        • Contact:
        • Principal Investigator:
          • Dongliang Yang, MD
        • Sub-Investigator:
          • Xin Zheng, MD
    • Liaoning
      • Shengyang, Liaoning, China, 110004
        • Recruiting
        • ShengJing Hospital Of China Medical University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Xiaoguang Dou, MD
        • Sub-Investigator:
          • Qiuju Sheng, MD
    • Shaanxi
      • Xi'an, Shaanxi, China, 710004
        • Recruiting
        • Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital
        • Contact:
        • Contact:
          • Shuang-suo Dang, MD
          • Phone Number: (+86) 13992896471
          • Email: dang212@126.com
        • Sub-Investigator:
          • Ya-ping Li, MD
        • Principal Investigator:
          • Shuang-suo Dang, MD
    • Shanghai
      • Jing'an, Shanghai, China, 200040
        • Recruiting
        • Huashan Hospital Fudan University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Wenhong Zhang, MD
        • Sub-Investigator:
          • Yuxian Huang, MD
    • Shijiazhuang
      • Hebei, Shijiazhuang, China, 050035
        • Recruiting
        • The Third Hospital of Hebei Medical University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Cai-Yan Zhao, MD
        • Sub-Investigator:
          • Ya-Dong Wang, MD

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 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients must be 18-80 years of age.

  • Patients must have documented compensated and stable chronic hepatitis B defined by all of the following:

    • HBsAg persistently positive > 6 months.
    • Clinical history, physical findings, and test results are compatible with compensated chronic hepatitis B
  • Patients must have received nucleos(t)ide therapy consisting of LAM/LdT/ADV and its combinations with other second-line antivirals for 24 weeks, or with the first-line antiviral ETV or any antiviral combinations containing ETV for 48 weeks with medication adherence.
  • Although having undergone therapy, patients have had failure to achieve the levels of HBV-DNA below 300 IU/mL.
  • Patient is willing and able to comply with the study drug regimen and all other study requirements.
  • Patient must understand the risk, and be willing and able to provide written informed consent to participate in the study.

Exclusion Criteria:

  • Pregnant women, and women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.
  • Males and females of reproductive potential who are not willing to use an effective method of contraception during the study. For males, condoms should be used and for females, a barrier contraception method should be used in combination with one other form of contraception.
  • Unwilling and/or unable to provide written informed consent
  • Patients with CHB but are also co-infected with HIV or other viral hepatitis
  • Patients whose serum levels of HBV DNA are too low (i.e. about 300 IU/mL) to be analyzed for the genotypic mutation(s) at the onset of this trial, i.e. baseline
  • At the screening visit, nucleos(t)ide resistant mutants have been detected in the strain of HBV of the patient
  • The patient is under a clinical research protocol of phase I-III development; unable to consent or unlikely to complete one year follow up after the enrollment; and other medical condition may affect the ability to participate the study.
  • Decompensated liver disease defined as direct (conjugated) bilirubin ≥ 1.2 Upper Limit of Normal (ULN); Prothrombin Time (PT) ≥ 1.2 ULN, platelets ≤ 150,000/mm3, or serum albumin ≤ 3.5 g/dL
  • Prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy) or variceal hemorrhage
  • Serum α-fetoprotein ≥ 50 ng/mL
  • Evidence of hepatocellular carcinoma (HCC)
  • History of significant renal disease (e.g., nephrotic syndrome, renal dysgenesis, polycystic kidney disease, congenital nephrosis, acute tubular necrosis, other renal disease)
  • History of significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochondrosis, multiple bone fractures)
  • Significant cardiovascular, pulmonary or neurological disease
  • Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of orally administered medications
  • History of solid organ or bone marrow transplantation

  • Ongoing therapy with any of the following: Nephrotoxic agents

    • Parenteral aminoglycoside antibiotics (e.g., gentamicin, tobramycin, amikacin)
    • Cidofovir
    • Cisplatin
    • Foscarnet
    • IV amphotericin B
    • IV pentamidine
    • Oral or IV ganciclovir
    • Cyclosporine
    • Tacrolimus
    • IV vancomycin
    • Chronic daily non-steroidal anti-inflammatory drug therapy
    • Competitors of renal excretion (e.g., probenecid) Systemic chemotherapeutic agents
    • Systemic corticosteroids
    • Interleukin-2 (IL-2) and other immunomodulating agents
  • Investigational agents (except with the expressed approval of the lead investigators)

Note: administration of any of the above medications must be discontinued at least 30 days prior to the Baseline Visit and for the duration of the study period.

  • Known hypersensitivity to the study drugs, the metabolites or formulation excipients
  • Any other condition (including alcohol or substance abuse) or prior therapy that, in the opinion of the Investigators, would make the subject unsuitable for the study or unable to comply with dosing requirements

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Single Arm Intervention Group
All approximately 100 patients experienced previous suboptimal response to other direct acting antivirals. Patients must have received nucleos(t)ide therapy consisting of LAM/LdT/ADV and its combinations with other second-line antivirals for 24 weeks, or with the first-line antiviral ETV or any antiviral combinations containing ETV for 48 weeks with medication adherence. All patients in this study are in the same arm.
Drug: Tenofovir Alafenamide 25 MG
All patients will receive Tenofovir Alafenamide, 25mg PO, to treat chronic hepatitis B and their previous suboptimal response over the study duration of 48 weeks. Patients will be followed every 12 weeks for medication adherence, medication refill, and follow up as per standard of care.
Other Names:
  • Vemlidy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
this study seeks to evaluate the efficacy of TAF in Asian CHB adults with a proven SOR to previous nucleo(t)side therapy by assessing the percentage of patients who achieve HBV DNA viral suppression over a time span of 48 weeks.
Time Frame: 48 weeks
In this study, HBV DNA viral suppression is defined as a HBV DNA level <20 IU/mL, and previous nucleo(t)side therapy is defined as treatments including LAM, LdT, ADV, and ETV before switching to TAF. The parameters for SOR will be set as patients who exhibit a 1 log10 IU/mL decrease in HBV DNA with medication adherence, but still present with an HBV DNA level of >300 IU/mL and has no detectable genotype mutation(s) when treated with the second-line antivirals LAM/LdT/ADV and its combinations with other second-line antivirals for 24 weeks, or treated with the first-line antiviral ETV or any antiviral combinations containing ETV for 48 weeks.
48 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Treatment-Emergent Adverse Events in Patients as stratified by the CTCAE v 5.0
Time Frame: At 12, 24, 36, and 48 weeks
Assess the percentage of Asian CHB adults with SOR to nucleos(t)ide therapy who have adverse events during the study, graded by the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0
At 12, 24, 36, and 48 weeks
Percentage of Patients Who Discontinue the Therapy Due to Issues with Tolerability
Time Frame: At 12, 24, 36, and 48 weeks
To evaluate the frequency of treatment discontinuation in patients who can not tolerate TAF therapy
At 12, 24, 36, and 48 weeks
Percentage of patients with Alanine transferase (ALT) levels within the normal limit
Time Frame: 48 weeks
To calculate the percentage of patients at the end of 48 weeks whose ALT (U/L) levels stay within the normal limit in response to TAF therapy in Asian adults with CHB infection who are SOR to nucleos(t)ide therapy.
48 weeks
Percentage of patients with Aspartamine transferase (AST) levels within the normal limit
Time Frame: 48 weeks
To calculate the percentage of patients at the end of 48 weeks whose AST (U/L) levels stay within the normal limit in response to TAF therapy in Asian adults with CHB infection who are SOR to nucleos(t)ide therapy.
48 weeks
Percentage of patients who experience loss/seroconversion of HBsAg and/or HBeAg during the study.
Time Frame: 48 weeks
Assess the percentage of patients who loss/seroconversion of HBsAg or/and HBeAg during the study. Loss is defined by a test showing a negative HBsAg/HBeAg result at the end of the trial, given a positive respective test result at baseline. A seroconversion is defined as a test showing a negative HBsAg and a positive HBsAb result, or a negative HBeAg and a positive HBeAb result at the end of the trial, given a positive HBsAg/HBeAg test result at baseline.
48 weeks
Percentage of patients with detectable drug resistance mutations
Time Frame: 48 weeks
To evaluate the incidence of drug resistance and drug resistance mutations in 48 weeks of TAF treatment if patients have HBV DNA levels >300 IU/mL. Drug resistance by population sequencing and genotyping will be done for these patients.
48 weeks
Percentage of patients who have skipped TAF treatment during the study
Time Frame: 48 weeks.
Assess the medication compliance on patients and compare the two sub-groups of patients who will be stratified by the levels of HBV DNA using the cut of of 20 IU/mL at 48 weeks.
48 weeks.

Collaborators and Investigators

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

Sponsor

New Discovery LLC

Collaborators

Beijing Ditan Hospital

Investigators

  • Principal Investigator: Calvin Q Pan, MD, NYU Langone Health
  • Study Director: Wen Xie, MD, Capital Medical University

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 (Anticipated)

May 1, 2021

Primary Completion (Anticipated)

September 30, 2023

Study Completion (Anticipated)

September 30, 2023

Study Registration Dates

First Submitted

December 6, 2019

First Submitted That Met QC Criteria

December 14, 2019

First Posted (Actual)

December 17, 2019

Study Record Updates

Last Update Posted (Actual)

November 17, 2020

Last Update Submitted That Met QC Criteria

November 15, 2020

Last Verified

December 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IN-CN-320-5556

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

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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