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
CRIS Registration Number |
KCT0003429 |
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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
Board Approval Status | Submitted approval |
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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 Person for Principal Investigator / Scientific Queries | |
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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
Study Site | Multi-center Number of center : 11 - Multi-national} | |
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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
1. Source of Monetary/Material Support | |
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Organization Name | Gilead Sciences Inc |
Organization Type | Others |
Project ID | IN-KR-320-5358 |
6. Sponsor Organization
1. Sponsor Organization | |
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Organization Name | Asan Medical Center |
Organization Type | Medical Institute |
7. Study Summary
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. |
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8. Study Design
Study Type | Interventional Study |
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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
Condition(s)/Problem(s) |
(K00-K93)Diseases of the digestive system
Hepatitis B, Chronic |
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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 <70 if male, <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 <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<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. 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)
Type of Primary Outcome | Efficacy | |
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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
Result Registered | No |
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12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)
Sharing Statement | No |
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