A Randomized, Prospective, Comparative Study of the Effectiveness of Prophylactic Entecavir Treatment for HBV Reactivation in Past HBV Infected Patients With Hematopoietic Stem Cell Transplantation
Phase: NA
Conditions: Hepatitis B Reactivation, Hematopoietic Stem Cell Transplantation, Antiviral Drug, HBV
Sponsor: Seoul St. Mary's Hospital

 
 
 
 
A randomized, prospective, comparative study of 
the effectiveness of prophylactic entecavir treatment 
for HBV reactivation in past HBV infected patients 
with hematopoietic stem cell transplantation 
 
 
 
 
 
 
 
 
NCT number: NCT04942886 
Protocol Version: 1.1 
Document date: July 12, 2025 
 
 

1. Protocol summary  
1) Brief Title: Prophylactic Entecavir for HBV Reactivation in Past HBV Infected Patients 
With Hematopoietic Stem Cell Transplantation 
2) Study type: Interventional  
3) Official Title: A randomized, prospective, comparative study of the effectiveness of 
prophylactic entecavir treatment for HBV reactivation in past HBV infected patients with 
hematopoietic stem cell transplantation 
 
2. Sponsors and Collaborators  
1) Responsible Party, by Official Title: Investigator  
2) Investigator Information: Dong-Gun Lee, Professor, Seoul St. Mary’s Hospital,  
Name of the sponsor: Seoul St. Mary’s Hospital, College of Medicine, The Catholic 
University of Korea 
3) Collaborators: Dong-A PharmTech Co., Ltd. 
 
3. Study Description 
1) Brief Summary  
This study is a randomized, prospective, comparative study of the effectiveness of 
prophylactic entecavir treatment for HBV reactivation in past HBV infected patients (HBsAg-, 
HBcIgG+) with allogeneic hematopoietic stem cell transplantation. 
2) Detailed Description  
This study is a randomized, prospective, comparative study of the effectiveness of 
prophylactic entecavir treatment for HBV reactivation in past HBV infected patients (HBsAg-, 
HBcIgG+) with allogeneic hematopoietic stem cell transplantation. 
In this study, patients are randomized into treatment group or delayed treatment group.  
* Stratified randomization (Block randomization within strata) according to the presence of 
HBsAb at baseline was used in this study. 
 

(1) Experimental: Treatment group (n=113)  
The intervention group take entecavir 0.5mg everyday by oral administration for 3 years after 
allogeneic hematopoietic stem cell transplantation. The intervention group visit clinic every 
month and examined liver function test, HBsAg/Ab. HBV DNA level is examined at every 3 
months. 
* oral administration of entecavir is planned to start within 7 days after hematopoietic stem 
cell transplantation.  
(2) No Intervention: delayed treatment group (n=113)  
The delayed treatment group visit clinic every month and examined liver function test, 
HBsAg/Ab. HBV DNA level is examined at every 3 months. If the patient in the delayed 
treatment group shows HBV reactivation (positive HBsAg or HBV DNA ≥10 IU/mL), entecavir 
treatment is started. 
 
4. Conditions  
1) Conditions or Focus of Study: hepatitis B reactivation, hematopoietic stem cell 
transplantation, antiviral drug, HBV 
2) Keywords: hepatitis B reactivation, hematopoietic stem cell transplantation, prophylactic 
antiviral agents, past HBV infection 
 
5. Study design 
1) Primary purpose: Treatment  
2) Study Phase: N/A 
3) Interventional Study Model: Parallel 
4) Number of Arms: 2 
5) Masking: None (Open Label) 
6) Allocation: Randomized  
7) Enrollment-number of participants: 226, anticipated  
8) Schematic study design  

 
⚫ 
Screening period 
Patients will be screened based on the inclusion and exclusion criteria from up to 30 
days prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) until the day 
of transplantation. After receiving a full explanation of the study details, written informed 
consent will be obtained from all participants. 
⚫ 
Randomization period 
Patients will be randomized in a 1:1 ratio to either the treatment group or the delayed 
treatment group between Day 0 and Day 7 following allo-HSCT. Stratified block 
randomization will be used, with stratification based on baseline hepatitis B surface 
antibody (HBsAb) status. 
⚫ 
Treatment period 
Patients in the intervention (treatment) group will receive oral entecavir at a dose of 0.5 
mg once daily for 3 years after allo-HSCT. Dose adjustments will be made as appropriate 
based on renal function. Patients in this group will visit the clinic monthly for follow-up, 
including liver function tests and HBsAg/Ab monitoring. HBV DNA levels will be assessed 
every 3 months. 
Patients in the delayed treatment (control) group will also visit the clinic monthly for liver 
function tests and HBsAg/Ab monitoring, with HBV DNA testing every 3 months. If HBV 
reactivation occurs—defined as HBsAg seroconversion or an HBV DNA level ≥10 
IU/mL—entecavir treatment will be initiated. 
 
6) Randomization  
After obtaining written informed consent, participants will be assigned a screening number. 
Final eligibility will be confirmed after reviewing each participant’s suitability. Eligible subjects 
will then be assigned a randomization number and allocated to a study group based on the 
predefined randomization table, which is managed by an independent third party. 
Randomization will be conducted to ensure the scientific validity of the clinical trial. This 
process maximizes the comparability between the intervention (treatment) group and the 

delayed treatment (control) group while minimizing investigator bias in subject allocation. 
Randomization will be stratified by HBsAb status (negative or positive). Within each HBsAb 
stratum, subjects will be randomized at a 1:1 ratio to either the intervention (treatment) group 
or the delayed treatment (control) group, using a computer-generated scheme in permuted 
blocks of random sizes 2 and 4. Patients will be randomized between Day 0 and Day 7 
following allo-HSCT. 
The randomization sequence was generated by an independent statistician using SAS 
version 9.3 (SAS Institute Inc., Cary, NC, USA) at the Department of Biostatistics, Clinical 
Research Coordinating Center, The Catholic University of Korea, and was produced in 
sequentially numbered opaque sealed envelopes. 
 
7. Arms and Interventions 
1) Arms: 
- Experimental: Treatment group: The intervention group take entecavir 0.5mg everyday 
by oral administration for 3 years after allogeneic hematopoietic stem cell transplantation. 
The intervention group visit clinic every month and examined liver function test, HBsAg/Ab. 
HBV DNA level is examined at every 3 months. 
- No Intervention: delayed treatment group: The delayed treatment group (control 
group) visit clinic every month and examined liver function test, HBsAg/Ab for 3 years after 
allogeneic hematopoietic stem cell transplantation. HBV DNA level is examined at every 3 
months for 3 years after allogenic hematopoietic stem cell transplantation. If the patient in 
the delayed treatment group shows HBV reactivation (positive HBsAg or HBV DNA ≥10 
IU/mL), entecavir treatment is started. 
2) Interventions: 
- Drug: Baracle Tab (entecavir)  
- Other Names: Prophylactic treatment group 
- Description: The intervention group take entecavir 0.5mg everyday by oral administration 
for 3 years after hematopoietic stem cell transplantation. 
 
 

8. Eligibility 
1) Inclusion Criteria: 
⚫ 
Age: 19 – 70 
⚫ 
Patients receiving allogeneic hematopoietic stem cell transplantation 
⚫ 
HBV serologic test: HBsAg (-), anti-HBc IgG (+) before receiving allogeneic 
hematopoietic stem cell transplantation 
⚫ 
ECOG performence: 0-2 
⚫ 
patients with informed consent   
 
2) Exclusion Criteria: 
⚫ 
HBV DNA (+, ≥10 IU/mL) at the time of screening 
⚫ 
Receiving hematopoietic stem cell transplantation from donor with HBsAg+ 
⚫ 
Combined other chronic liver disease (severe alcoholics, autoimmune hepatitis, chronic 
hepatitis C etc.) 
⚫ 
HIV (+) 
⚫ 
Previous antiviral therapy history for chronic hepatitis B 
⚫ 
Other concomitant malignancy 
⚫ 
Combined autoimmune disease (rheumatic arthritis, SLE etc) 
⚫ 
CTP class B, C 
⚫ 
Decompensated complications (ascites, hepatic encephalopathy etc.) 
⚫ 
Active tuberculosis 
⚫ 
Patients with lymphoma  
⚫ 
Patients receiving autologous hematopoietic stem cell transplantation 
 
9. Study population  
1) Sample size estimation 
At the initiation of the study in 2021, the planned sample size was 82 patients per group for 
both the treatment (intervention) and delayed treatment (control) groups. This estimation 
was based on an assumed incidence of hepatitis B virus (HBV) reactivation of 5% in the 
treatment group and 20% in the delayed treatment group.  
The required sample size, calculated to be a minimum of 75 patients per group, was 
determined using a two-sample Z-test with unpooled variance, with a two-sided significance 

level (α) of 0.05 and a statistical power of 80%. After accounting for an anticipated 10% 
withdrawal rate, the final target sample size was set at 164 patients (82 per group). 
By June 2023, approximately two years after study initiation, a total of 110 patients had been 
enrolled (55 in each group). Among these, 17 patients (15%) had withdrawn from the study. 
In addition, 21 patients (19%) had died due to causes including infections and relapse of 
hematologic malignancy—events defined as competing risks. 
Given the higher-than-expected rates of withdrawal and competing events, the sample size 
was recalculated based on the following revised assumptions: 
The study is designed to detect the event of interest, with cumulative incidence proportions 
of 0.01 in the treatment group and 0.05 in the control group (a hazard ratio of 0.1951) at 3 
year of follow-up period for each patient, with competing risks having cumulative incidence 
proportions of 0.2 in both groups at this time, and accounts for a 0.15 proportion of subjects 
lost to follow-up. The comparison will be made using a two-sided, two-sample logrank test 
accounting for competing risks with a Type I error rate (α) of 0.05 and 80% power. Using 
these updated parameters and the PASS version 12 software (NCSS, LLC), the 
recalculated total sample size was 226 patients, with 113 patients allocated to each group. 
 

10. Outcome Measures  
1) Primary Outcome measure 
1. Comparison of the rate of HBV reactivation between the treatment and delayed treatment 
groups. 
Description: Comparing the rate of HBV reactivation between the treatment and delayed 
treatment groups during 3 years after hematopoietic stem cell transplantation * Definition of 
HBV reactivation: HBsAg ≥ 1.0 S/CO or HBV DNA ≥ 10 IU/mL 
Time Frame: The primary outcome is evaluated during 3 years after hematopoietic stem cell 
transplantation 
2) Secondary Outcome measure 
2. Comparison of the rate of active hepatitis with HBV reactivation between the treatment 
and delayed treatment groups. 
Description: Comparing the rate of active hepatitis with HBV reactivation between the 
treatment and delayed treatment groups. * Definition of active hepatitis: ALT >= 2 times of 
upper normal limit 
Time Frame: The secondary outcomes are evaluated during 3 years after hematopoietic 
stem cell transplantation. 
3. Comparison of the rate of hepatic failure related to HBV reactivation between the 
treatment and delayed treatment groups. 
Description: Comparing the rate of hepatic failure between the treatment and delayed 
treatment groups. 
Time Frame: The secondary outcomes are evaluated during 3 years after hematopoietic 
stem cell transplantation. 
4. Comparison of the rate of survival related to HBV reactivation between the treatment and 
delayed treatment groups. 
Description: Comparing the rate of survival related to HBV reactivation between the 
treatment and delayed treatment groups. 
Time Frame: The secondary outcomes are evaluated during 3 years after hematopoietic 
stem cell transplantation. 
 

11. Statistical analysis  
Information collected from subjects of the present clinical trial are analyzed in two forms: ITT 
(Intention-To-Treatment) and PP (Per-Protocol) 
1) ITT analysis group 
The ITT population is defined as all randomized patients at the time of receiving allo-HSCT, 
regardless of their adherence with the entry criteria, regardless of treatment they actually 
received, and regardless of subsequent withdrawal from treatment or deviation from the 
protocol. Only some specific reasons that might cause an exclusion of a patient from the ITT 
population: 
- 
No treatment was applied at all  
- 
No data are available after randomization 
2) PP analysis group 
The PP population is the subset of ITT population consisting of all patients who receive and 
retain the treatment or follow up with test according to the study protocol for 3 years in the 
treatment group and the delayed treatment group, respectively. Some specific reasons that 
might cause an exclusion of a patient from the PP population: 
- 
Violation of entry criteria including inclusion and exclusion criteria 
- 
Withdrawal of consent 
- 
Death 
- 
B cell depletion therapy or re-transplantation following relapse of hematologic disease 
causing previous allo-HSCT 
- 
Poor compliance: Discontinuation of test or drugs for 180 days or longer 
In the cases of withdrawal of consent and poor compliance, their data can be used for 
statistical analyses until events occur. 
3) Missing data handling 
- 
Missing variables will not be imputed for planned analyses, except where otherwise 
specified. 
4) Analysis 
- 
The primary endpoint will be analyzed Fine and Gray competing risk survival model to 
estimate the subdistribution hazard ratio (SHR) and to calculate the cumulative 
incidence function (CIF). 

- 
Competing risks include death, B cell depletion therapy, and due to relapse of the 
underlying hematologic disease that led to the initial allo-HSCT.  
5) Primary and secondary endpoint analysis 
- 
The primary endpoint will be analyzed using cumulative incidence function (CIF), as 
described above. 
- 
Subgroup analyses of the primary endpoint will be conducted based on the following 
variables: presence of HBsAb, age, sex, underlying hematologic disease, donor type 
(related vs. unrelated), and ABO mismatch. 
- 
The primary analysis population for both the primary and secondary endpoints will be 
the intention-to-treat (ITT) population. A subsequent analysis of the primary endpoint 
will also be performed in the per-protocol (PP) population. 
- 
Sensitivity analyses will be conducted based on the time of enrollment, including 
comparisons between patients enrolled during vs. after the COVID-19 pandemic 
period and before vs. after the South Korean medical crisis.  
6) Additional analysis 
- 
Baseline characteristics of the patients were presented as mean ± standard deviation 
or median (range) for quantitative variables and as counts (%) for categorical 
variables, whichever was appropriate.  
- 
Comparisons between the two groups were performed using a Student’s t-test or 
Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s 
exact test for categorical variables, as appropriate. 
- 
An interim analysis of the primary and secondary outcomes will be conducted when 
approximately 90% of the target sample size has been enrolled and half of the planned 
follow-up period (1.5 years) has been completed.  
 
12. Informed consent 
Investigator and research coordinator should provide a copy of the informed consent form or 
any other documents shared with the subject to the subject or representative. If there are 
any changes to the consent form or shared documents during clinical trial, the investigator or 
coordinator should provide a copy of the revised form or document to the subject or his/her 
representative. 
 

13. Follow-up treatment of subjects after clinical trial 
After finishing clinical trial, 3 years following allogenic stem cell transplantation, the subjects 
are treated with standard treatment. It includes routine laboratory examinations, including 
liver function test, HBsAg, and HBsAb. 
After completing the clinical trial—three years following allo-HSCT—participants will receive 
standard post-transplant care. This includes routine laboratory monitoring such as liver 
function tests, HBsAg, and HBsAb assessments, in accordance with institutional guidelines 
for long-term follow-up.