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A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the Effectiveness of TENofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B Patients beyond Treatment IndicaTIONs by Current Guidelines

Status Approved

  • First Submitted Date

    2018/11/28

  • Registered Date

    2019/01/16

  • Last Updated Date

    2023/11/24

CRIS Required

WHO ICTRP (International Clinical Trial Registry Platform) Required

  • 1. Background

    Background - CRIS Registration Number, Unique Protocol ID, Public/Brief Title, Scientific Title, Acronym, MFDS Regulated Study, IND/IDE Protocol, Registered at Other Registry, Name of Registry/Registration Number
    CRIS
    Registration Number
    KCT0003429
    Unique Protocol ID IN-KR-320-5358
    Public/Brief Title A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the Effectiveness of TENofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B Patients beyond Treatment IndicaTIONs by Current Guidelines
    Scientific Title A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the Effectiveness of TENofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B Patients beyond Treatment IndicaTIONs by Current Guidelines
    Acronym ATTENTION
    MFDS Regulated Study No
    IND/IDE Protocol No
    Registered at Other Registry Yes
    Name of Registry / Registration Number ClinicalTrials.gov-NCT03753074
    Healthcare Benefit Approval Status Submitted approval
  • 2. Institutional Review Board / Ethics Committee

    Institutional Review Board Information
    Board Approval Status Submitted approval
    Board Approval Number 20181369
    Approval Date 2018-11-08
    Institutional Review Board Name Asan Medical Center Institutional Board
    Institutional Review Board Address 88, Olympic-ro 43-gil, Songpa-gu, Seoul
    Institutional Review Board Telephone 02-3010-7166
    Data Monitoring Committee Yes
    Data and Safety Monitoring Board
  • 3. Contact Details

    Contact Details Information - Contact Person for Principal Investigator / Scientific Queries, Contact Person for Public Queries, Contact Person for Updating Information의 Name, Title, Email, Telephone, Cellular Phone, Affiliation, Address
    Contact Person for Principal Investigator / Scientific Queries
    Name Young-Suk Lim
    Title Professor
    Telephone +82-2-3010-5933
    Affiliation Asan Medical Center
    Address 88, OLYMPIC-RO 43-GIL, SONGPA-GU, SEOUL 05505, KOREA
    Contact Person for Public Queries
    Name Hyangki Lee
    Title Project Manager
    Telephone +82-2-3010-7369
    Affiliation Asan Medical Center
    Address 88, OLYMPIC-RO 43-GIL, SONGPA-GU, SEOUL 05505, KOREA
    Contact Person for Updating Information
    Name Hyangki Lee
    Title Project Manager
    Telephone +82-2-3010-8663
    Affiliation Asan Medical Center
    Address 88, OLYMPIC-RO 43-GIL, SONGPA-GU, SEOUL 05505, KOREA
  • 4. Status

    Status Information - Study Site, Overall Recruitment Status, Date of First Enrollment, Status of First Enrollment, Target Number of Participant, Primary Completion Date, Recruitment Status by Participating Study Site, Name of Study Site, Recruitment Status, Date of First Enrollment, Status of First Enrollemnt
    Study Site Multi-center Number of center : 11 - Multi-national}
    Overall Recruitment Status Recruiting
    Date of First Enrollment 2019-02-18 Actual
    Target Number of Participant 780
    Primary Completion Date 2031-09-30 , Anticipated
    Study Completion Date 2031-12-31 , Anticipated
    Recruitment Status by Participating Study Site 1
    Name of Study Asan Medical Center
    Recruitment Status Recruiting
    Date of First Enrollment 2019-02-18 ,
    Recruitment Status by Participating Study Site 2
    Name of Study Samsung Medical Center
    Recruitment Status Recruiting
    Date of First Enrollment 2019-04-26 ,
    Recruitment Status by Participating Study Site 3
    Name of Study Kyung Hee University Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2019-05-29 ,
    Recruitment Status by Participating Study Site 4
    Name of Study Chung-Ang Univerisity Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2019-06-17 ,
    Recruitment Status by Participating Study Site 5
    Name of Study Seoul National University Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2019-04-18 ,
    Recruitment Status by Participating Study Site 6
    Name of Study Ulsan Univeristy Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2019-11-04 ,
    Recruitment Status by Participating Study Site 7
    Name of Study Konkuk University Medical Center
    Recruitment Status Recruiting
    Date of First Enrollment 2021-07-02 ,
    Recruitment Status by Participating Study Site 8
    Name of Study Kyungpook National University Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2021-05-31 ,
    Recruitment Status by Participating Study Site 9
    Name of Study Koera University Guro Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2021-06-11 ,
    Recruitment Status by Participating Study Site 10
    Name of Study The Catholic University of Korea, Seoul St. Mary's Hospital
    Recruitment Status Withdrawn Withdrawn Reason : 환자 등록이 매우 저조할 것으로 예상하여, 주관 기관과 협의 하에 조기 종료하기로 결정함.
    Date of First Enrollment 2023-12-31 ,
    Recruitment Status by Participating Study Site 11
    Name of Study Seoul National University Bundang Hospital
    Recruitment Status Recruiting
    Date of First Enrollment 2022-06-13 ,
  • 5. Source of Monetary / Material Support

    Source of Monetary / Material Support Information - Organization Name, Organization Type, Project ID
    1. Source of Monetary/Material Support
    Organization Name Gilead Sciences Inc
    Organization Type Others
    Project ID IN-KR-320-5358
  • 6. Sponsor Organization

    Sponsor Organization Information - Organization Name, Organization Type
    1. Sponsor Organization
    Organization Name Asan Medical Center
    Organization Type Medical Institute
  • 7. Study Summary

    Study Summary Information
    Lay Summary
    The natural course of chronic hepatitis B (CHB) is generally divided into several phases by hepatitis B e antigen (HBeAg) status, serum HBV DNA levels, and alanine aminotransferase (ALT) activity. Phases of CHB include immune-tolerant (IT), immune-active (IA), inactive carrier, and HBeAg-negative hepatitis.
    Traditionally, IT phase has been considered not treating with antiviral therapy from the belief that IT phase has a silent histological activity and the risk of disease progression in this phase is low. However, recent studies suggested that the histological activity and HBV-specific immune responses do occur in the IT phase and are comparable with those occurring in the IA phase. Moreover, the process of hepatocarcinogenesis could be already undergoing in these patients. Recently, our research group conducted a large-scale of historical cohort study evaluating the risk of hepatocellular carcinoma (HCC) and death/transplantation in patients with IT phase. Our study showed untreated IT-phase patients were associated with significantly higher risks of HCC and death/transplantation than the IA-phase patients treated with nucleos(t)ide analogues. In particular, the risks of HCC and death/transplantation were further increased among patients in the mildly active phase (ALT levels, 1-2x upper limit of normal).
    
    Primary objective is To investigate whether TAF(Tenofovir Alafenamide) treatment reduce clinical events (HCC, death, liver decompensation, portal hypertensive complications, and liver transplantation) in CHB patients beyond treatment indications by current guidelines.
    
    Study procedure: 780 subjects will be randomized in a 1:1 ratio (A:B) either to receive TAF((Tenofovir Alafenamide)) 25 mg QD or to receive best supportive care after stratification according to the HBeAg status. The study duration is 12 years.  During treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows:
    
    Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female)
    40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months.
    
    • Treatment Arm A(Tenofovir Alafenamide): 390 subjects administered TAF 25 mg once daily 
    • Treatment Arm B(Best supportive care): 390 subjects received best supportive care
    The primary analysis will occur at Year 4. the primary endpoint is the occurrence of composite events during follow-up observation. 
  • 8. Study Design

    Study Design Information - Study Type, Study Purpose, Phase, Intervention Model, Blinding/Masking, Blinded Subject, Allocation, Intervention Type, Intervention Description, Number of Arms, Arm Label, Target Number of Participant, Arm Type, Arm Description
    Study Type Interventional Study
    Study Purpose
    Treatment
    Phase Phase4
    Intervention Model Parallel  
    Blinding/Masking Open
    Allocation RCT
    Intervention Type Drug  
    Intervention Description
    780 subjects will be randomized in a 1:1 ratio (A:B) either to receive TAF((Tenofovir Alafenamide)) 25 mg QD oral or to receive best supportive care after stratification according to the HBeAg status. The study duration is 12 years. During treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows:
    
    Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female)
    40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months.
    • Treatment Arm A(Tenofovir Alafenamide): 390 subjects administered TAF 25 mg oral once daily 
    • Treatment Arm B(Best supportive care): 390 subjects received best supportive care
    The primary analysis will occur at Year 4. the primary endpoint is the occurrence of composite events during follow-up observation. 
    Number of Arms 2
    Arm 1

    Arm Label

    Treatment Arm A(Tenofovir Alafenamide)

    Target Number of Participant

    390

    Arm Type

    Experimental

    Arm Description

    390 subjects administered TAF 25 mg once oral daily 
    Arm 2

    Arm Label

    Treatment Arm B(Best supportive care)

    Target Number of Participant

    390

    Arm Type

    No intervention

    Arm Description

    390 subjects received best supportive care but during treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows:
    
    -Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female)
    -40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months.
  • 9. Subject Eligibility

    Subject Eligibility Information
    Condition(s)/Problem(s)    (K00-K93)Diseases of the digestive system 

    Hepatitis B, Chronic
    Rare Disease No
    Inclusion Criteria

    Gender

    Both

    Age

    40Year~80Year

    Description

    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, 40 to 80 years of age 
    3. Positive for HBsAg or HBV DNA for at least 6 months or more 
    4. HBeAg positive or negative 
    5. No evidence of liver cirrhosis (platelet count ≥100,000/mm3) 
    6. serum HBV DNA ≥ 4 log10 IU/mL and ≤ 8 log10 IU/mL 
    7. Serum ALT level &lt;70 if male, &lt;50 if female 
    8. Estimated creatinine clearance ≥ 30 ml/min based on serum creatinine as measured at the screening evaluation 
    9. Patient is willing and able to comply with all study requirements
    Exclusion Criteria
    1. Co-infection with HCV, HDV, HIV (Confirmed by nucleic acid tests) 
    2. Abusing alcohol (more than 60 g/day) or illicit drugs 
    3. Patients with history of hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage) 
    4-1) Evidence of cirrhosis, including any of follows:
     - Platelet count &lt;100,000/mm3 
     - Esophagogastric varices on endoscopy 
     - Evidence of clinically significant portal hypertension
     - Fibroscan ≥ 12.0 kPa (If the test was done in 6 months before the time of screening.) and confirmed to have liver cirrhosis by an investigator
    4-2) 40≤ALT levels&lt;70 IU/L (males) or 40≤ ALT levels&lt;50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months.
    5. Received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study
    6. Medical condition that requires concurrent use of systemic corticosteroid or other immunosuppressive agents
    7. Received solid organ or bone marrow transplant
    8. Known hypersensitivity to study drugs, metabolites, or formulation excipients
    9. 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
    10. Use of investigational agents within 6 months of screening, unless allowed by the Sponsor or Investigator
    11. Any malignant tumor in the preceding five years. However, a history of 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. Participating in other clinical trials to administer medication. However, it is possible to participate if it is not an antiviral agent or immunosuppressant related clinical trial.
    13. Pregnant or breastfeeding or willing to be pregnant
    Healthy Volunteers No
  • 10. Outcome Measure(s)

    Outcome Measure(s) Information - Type of Primary Outcome, Primary Outcome, Outcome, Timepoint, Secondary Outcome, Outcome, Timepoint
    Type of Primary Outcome Efficacy
    Primary Outcome(s) 1
    Outcome
    Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation[Child-Pugh score 7], portal hypertensive complications, and HCC)
    Timepoint
    At year 4
    Secondary Outcome(s) 1
    Outcome
    Cumulative and annual  incidence rate of portal hypertensive complications[ascites, Esophagogastric varices]
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 2
    Outcome
    Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation[Child-Pugh score 7], portal hypertensive complications, and HCC)
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 3
    Outcome
    Cumulative incidence rate of HCC(hepatocellular carcinoma)
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 4
    Outcome
    All-cause mortality
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 5
    Outcome
    Cumulative incidence rate of liver transplantation
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 6
    Outcome
    Cumulative  incidence rate of liver decompensation
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 7
    Outcome
    Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B(Best supportive care) subjects
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 8
    Outcome
    Cumulative  incidence rate of virologic response defined as HBV(Hepatitis B virus) DNA less than 15 IU/mL
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 9
    Outcome
    Cumulative incidence rate of ALT(alanine aminotransferase) normalization if baseline ALT is elevated 
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 10
    Outcome
    Cumulative incidence rat of HBeAg(hepatitis B e antigen) seroclearance and seroconversion among HBeAg-positive patients
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 11
    Outcome
    Change of fibroscan
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 12
    Outcome
    Change of APRI index (Aspartate aminotransferase (AST)-to-Platelet Ratio index)
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 13
    Outcome
    Change of FIB-4 (Fibrosis-4)
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 14
    Outcome
    Cumulative incidence rate of HCC among HBeAg-positive patients or HBeAg-Negative patients
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 15
    Outcome
    All cause-mortality among HBeAg-positive patients or HBeAg-Negative patients
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 16
    Outcome
    Cumulative incidence rate of liver decompensation[Child-Pugh score 7] among HBeAg-positive patients or HBeAg-Negative patients
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 17
    Outcome
    Cumulative incidence rate of portal hypertensive complications[ascites, Esophagogastric varices]among HBeAg-positive patients or HBeAg-Negative patients
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 18
    Outcome
    Cumulative incidence rate of liver transplantation among HBeAg-positive patients or HBeAg-Negative patients
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 19
    Outcome
    Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (<40 U/L) at the time of enrollmen
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 20
    Outcome
    Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical  events within 6 months of enrollment
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 21
    Outcome
    Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical  events within 12 months of enrollment
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 22
    Outcome
    Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 6 months of enrollment
    Timepoint
    At year 4, 8 and 12
    Secondary Outcome(s) 23
    Outcome
    Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 12 months of enrollment
    Timepoint
    At year 4, 8 and 12
  • 11. Study Results and Publication

    Study Results and Publication Information - Result Registered, Final Enrollment Number, Number of Publication, Publications, Results Upload, Date of Posting Results, Protocol URL or File Upload, Brief Summary
    Result Registered No
  • 12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)

    Sharing of Study Data Information - Sharing Statement, Time of Sharing, Way of Sharing
    Sharing Statement No
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