Real-world Study Optimizing Nucleotide-analogues

Official title

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

Overview

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: 1. 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. 2. 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. 3. 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

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.

Interventions

• Drug ETV/TAF/TDF/TMF/IFN
  peginterferon alpha or nucleos(t)ide alone are decided by patients' doctors according to their conditions, instead of extra interventions brought by the study
• Drug ETV/TAF/TDF/TMF
  peginterferon alpha or nucleos(t)ide alone are decided by patients' doctors according to their conditions, instead of extra interventions brought by the study

Primary outcome measures

• The proportion of patients with HBV DNA <20 IU/ml [Time frame: Week 48]
• The proportion of patients with HBV DNA <20 IU/ml [Time frame: Week 96]
• The proportion of patients with HBV DNA <20 IU/ml [Time frame: Week 144]
• Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) [Time frame: Baseline]
• Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) [Time frame: Week 48]
• Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) [Time frame: Week 96]
• Change from baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG) [Time frame: Week 144]

Secondary outcome measures (7)

• Proportion of participants with Normal Alanine Aminotransferase (ALT) [Time frame: Week 48, Week 96 and Week 144]
• Proportion of participants with Hepatitis B s Antigen (HBsAg) Loss [Time frame: Week 48, Week 96 and Week 144]
• Proportion of participants with Hepatitis B s Antigen (HBeAg) Loss [Time frame: Week 48, Week 96 and Week 144]
• Proportion of participants with seroconversion to Hepatitis B s Antigen (HBsAg) [Time frame: Week 48, Week 96 and Week 144]
• Proportion of participants with seroconversion to Hepatitis B e Antigen (HBeAg) [Time frame: Week 48, Week 96 and Week 144]
• Proportion of participants with fibrosis regression and progression [Time frame: Week 48, Week 96 and Week 144]
• Rate of liver-related events [Time frame: Week 48, Week 96 and Week 144]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

China · 44 centers

• Anhui Provincial Hospital — Hefei
• The First Affiliated Hospital of Anhui Medical University — Hefei
• Beijing YouAn Hospita — Beijing
• Peking University First Hospital — Beijing
• Peking University People's Hospital — Beijing
• The Second Affiliated Hospital of Chongqing Medical University — Chongqing
• the Southwest Hospital of AMU — Chongqing
• First Affiliated Hospital of Fujian Medical University — Fuzhou
• … and 36 more centers

Publications

• Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018 Jun;3(6):383-403. doi: 10.1016/S2468-1253(18)30056-6. Epub 2018 Mar 27. PMID 29599078
• Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. [The guidelines of prevention and treatment for chronic hepatitis B (2019 version)]. Zhonghua Gan Zang Bing Za Zhi. 2019 Dec 20;27(12):938-961. doi: 10.3760/cma.j.issn.1007-3418.2019.12.007. Chinese. PMID 31941257
• European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18. PMID 28427875
• Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. No abstract available. PMID 29405329
• Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut. 2015 Dec;64(12):1972-84. doi: 10.1136/gutjnl-2015-309809. Epub 2015 Jun 5. PMID 26048673
• Agarwal K, Brunetto M, Seto WK, Lim YS, Fung S, Marcellin P, Ahn SH, Izumi N, Chuang WL, Bae H, Sharma M, Janssen HLA, Pan CQ, Celen MK, Furusyo N, Shalimar D, Yoon KT, Trinh H, Flaherty JF, Gaggar A, Lau AH, Cathcart AL, Lin L, Bhardwaj N, Suri V, Mani Subramanian G, Gane EJ, Buti M, Chan HLY; GS-US-320-0110; GS-US-320-0108 Investigators. 96 weeks treatment of tenofovir alafenamide vs. tenofovir PMID 29756595
• Chinese Society of Infectious Disease Chinese Society of Hepatology; Chinese Medical Association. [The expert consensus on clinical cure (functional cure) of chronic hepatitis B]. Zhonghua Gan Zang Bing Za Zhi. 2019 Aug 20;27(8):594-603. doi: 10.3760/cma.j.issn.1007-3418.2019.08.003. Chinese. PMID 31594076
• Zhang L, Fan ZF, Liu DW, Zhou MG, Wang ZQ, Li M. [Trend analysis on the disease burden related to cirrhosis and other chronic liver diseases caused by hepatitis B, in China, from 1990 to 2016]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 10;41(2):173-177. doi: 10.3760/cma.j.issn.0254-6450.2020.02.007. Chinese. PMID 32164125

Identifiers

NCT: NCT05937178 · REASON

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗