Real-world Study Optimizing Nucleotide-analogues

Study Overview
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Brief Summary
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The goal of this multicenter, observational, prospective study is to observe and compare different anti-viral treatment strategies in a real-world cohort of patients with CHB managed in routine clinical settings in China. The main questions it aims to answer are: To evaluate the benefits of initiating first-line nucleos(t)ide analogue in patients with chronic HBV infection who are recommended in the updated Chinese Guideline 2022, but not recommended in the Chinese Guideline 2019. To evaluate the Chinese Guideline recommends initiation of treatment, but at least one foreign authoritative guideline (eg. AASLD, EASL) does not recommend the benefit of initiating first-line nucleos(t)ide analogue in patients with chronic HBV infection who initiate treatment. To compare the treatment effect of different alternatives with patients who have partial response after treatment with first-line nucleos(t)ide analogues.

Detailed Description
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REASON is a multicenter, observational, prospective study to explore an optimal anti-viral treatment in a real-world cohort of patients with CHB managed in routine clinical settings in China. The study will enroll treatment-naïve or treatment-experienced patients ≥18 and ≤80 years of age with hepatitis B s antigen positive. The treatment-experienced patients must be treated with monotherapy ETV/TDF/TAF/TMF continuously for a minimum of 48 weeks before enrollment. The treatment of participants will be decided before the screening by doctors based on the situation and patient's intention. When eligible patients are included in this study, no extra intervention will be conducted and only clinical data are collected and observed. Participants will enter different observation groups when they meet the eligibility criteria of each group listed below: Group A：treatment-naive, and meeting the conditions that are recommended to initiate treatment in 2022 Chinese Guideline but not in 2019 Chinese Guideline; Group B：treatment-naive, meeting the conditions that are recommended to initiate treatment in both 2019 and 2022 Chinese guideline, but not in AASLD/EASL guidelines; Group C: treatment-experienced and with partial response. The primary efficacy endpoint was the proportion of patients with HBV DNA less than 20 IU/ml at 48 weeks, 96 weeks, and 144 weeks. Participants in all groups will be stratified by whether they initiate treatment in Group A and B, and by the treatment regimens in Group C. The primary safety outcome is the change from baseline in the Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) at 48 weeks, 96 weeks, and 144 weeks. The secondary outcomes including HBsAg loss, HBsAg seroconversion, HBeAg loss, HBeAg seroconversion, fibrosis regression and progression, and liver-related events, which will be measured at each follow-up visit. The follow-up time course of this study will be 3 years.

Official Title
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A Real-world Study of Optimizing Nucleotide-analogues-based Treatment for Chronic Hepatitis B

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: ETV/TAF/TDF/TMF/IFN
* Drug: ETV/TAF/TDF/TMF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CHB defined as positive hepatitis B surface antigen at least 6 months, or HBV-related histological changes within 1 year if HBsAg positive less than 6 months. Age between 18-80 years. Patient who reads and signs informed consent. Meet any conditions of the group listed below Group A-naïve and meeting the conditions that are recommended to initiate treatment in 2022 Chinese Guideline, but not in 2019 Chinese Guideline (observe-plan to treat or control-plan to follow-up) : A. HBV DNA positive, ALT is continuously upper limit of normal (male 30 U/L, female 19 U/L) B. HBeAg positive, HBV DNA≤2×10^7 IU/ml; HBeAg negative, HBV DNA≥2×10^3 IU/ml C. Meet any of the conditions listed below Age>30 years, and have a family history of cirrhosis or HCC, TE indicates no significant fibrosis; Family history of cirrhosis or HCC, and ≤30 years, TE indicates no significant fibrosis; TE indicates significant fibrosis, and ≤30 years, without family history of cirrhosis or HCC Group B-naïve and meeting the conditions that are recommended to initiate treatment in both 2019 and 2022 Chinese Guidelines, but not in EASL or AASLD guideline (observe-plan to treat or control-plan to follow-up) : A. Without cirrhosis, HBV DNA≤2000 IU/ml, ALT>1 ULN； B. Without cirrhosis, HBV DNA>2000 IU/ml, 1 ULN<ALT≤2 ULN； C. Without cirrhosis, normal ALT, >30 years, have a family history of cirrhosis or HCC, or TE indicates significant fibrosis; D. Without cirrhosis, HBV DNA 20-2000 IU/ml Group C-experienced and partial response (1. switch another first-line NA; 2. add-on another first-line NA; 3. switch another first-line NA and add-on peginterferon alpha; 4. continue the original plan) Treatment experienced patient who has received a first-line nucleos(t)ide analogue(NA) monotherapy for at least 48 weeks, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, tenofovir amibufenamide, and has partial response. They plan to continue or change the therapy Exclusion Criteria: Have poor compliance; Received contraindicated concomitant drugs (subjects receiving prohibited drugs will need at least 30 days of washing out period) and known hypersensitivity reactions to the study drug, metabolites, or formulated excipients; Any other clinical symptoms or previous treatment that the investigator considers that the individual subject is not suitable for this study or cannot comply with the administration requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Recommend to initiate treatment in 2022 Chinese Guideline, but not in 2019 Chinese Guideline<br>Untreated population who does not be recommended to initiate treatment in 2022 Chinese Guideline, but not in 2019 Chinese Guideline. The initate treatment is to receive a first-line nucleos(t)ide analogue, i.e., entecavir, tenofovir disoproxil, or tenofovir alafenamide, tenofovir amibufenamide | Drug: ETV/TAF/TDF/TMF<br>* peginterferon alpha or nucleos(t)ide alone are decided by patients' doctors according to their conditions, instead of extra interventions brought by the study<br>|
| Recommend to initiate treatment in 2019 and 2022 Chinese Guideline, but not in AASLD/EASL guidelines<br>Untreated population will receive a first-line nucleos(t)ide analogue , i.e., entecavir, tenofovir disoproxil, or tenofovir alafenamide, tenofovir amibufenamide, and the population should meet the conditions that are recommended to initiate treatment in 2019 and 2022 Chinese guideline, but not in AASLD/EASL guidelines | Drug: ETV/TAF/TDF/TMF<br>* peginterferon alpha or nucleos(t)ide alone are decided by patients' doctors according to their conditions, instead of extra interventions brought by the study<br>|
| Treatment experienced and with partial response<br>Treatment experienced population who has received a first-line nucleos(t)ide analogue(NA) as monotherapy at least 48 weeks, i.e., entecavir, tenofovir disoproxil, or tenofovir alafenamide, tenofovir amibufenamide, and has partial response to NA. They will continue the original therpay or plans to change the therapy (e.g. switch another first-line NA, add-on another first-line NA, switch another first-line NA and add-on peginterferon alpha) | Drug: ETV/TAF/TDF/TMF/IFN<br>* peginterferon alpha or nucleos(t)ide alone are decided by patients' doctors according to their conditions, instead of extra interventions brought by the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with HBV DNA <20 IU/ml | The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at each follow-up time point, as determined by high-sensitivity PCR | Week 48 | 
| The proportion of patients with HBV DNA <20 IU/ml | The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at each follow-up time point, as determined by high-sensitivity PCR | Week 96 | 
| The proportion of patients with HBV DNA <20 IU/ml | The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at each follow-up time point, as determined by high-sensitivity PCR | Week 144 | 
| Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) | Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) at each follow-up time point | Baseline | 
| Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) | Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) at each follow-up time point | Week 48 | 
| Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) | Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) at each follow-up time point | Week 96 | 
| Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) | Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) at each follow-up time point | Week 144 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with Normal Alanine Aminotransferase (ALT) | Proportion of participants with Normal Alanine Aminotransferase (ALT) at each follow-up time point | Week 48, Week 96 and Week 144 | 
| Proportion of participants with Hepatitis B s Antigen (HBsAg) Loss | Proportion of participants with Hepatitis B s Antigen (HBsAg) Loss at each follow-up time point | Week 48, Week 96 and Week 144 | 
| Proportion of participants with Hepatitis B s Antigen (HBeAg) Loss | Proportion of participants with Hepatitis B s Antigen (HBeAg) Loss at each follow-up time point | Week 48, Week 96 and Week 144 | 
| Proportion of participants with seroconversion to Hepatitis B s Antigen (HBsAg) | Proportion of participants with seroconversion to Hepatitis B s Antigen (HBsAg) at each follow-up time point | Week 48, Week 96 and Week 144 | 
| Proportion of participants with seroconversion to Hepatitis B e Antigen (HBeAg) | Proportion of participants with seroconversion to Hepatitis B e Antigen (HBeAg) at each follow-up time point | Week 48, Week 96 and Week 144 | 
| Proportion of participants with fibrosis regression and progression | Proportion of participants with fibrosis regression and progression at each follow-up time point | Week 48, Week 96 and Week 144 | 
| Rate of liver-related events | Rate of liver-related events (HCC, decompensation cirrhosis, death) at each follow-up time point | Week 48, Week 96 and Week 144 |