Real-world Study Optimizing Nucleotide-analogues

Hepatitis B, Chronic Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05937178
• Other study ID #: REASON
• Status: Recruiting
• Start date: January 31, 2023
• Est. completion date: January 31, 2029

Study information

• Verified date: July 2023
• Source: Huashan Hospital
• Contact: Wenghong Zhang, MD
• Phone: 13801844344
• Email: zhangwenhong[@]fudan.edu.cn
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20000
• Est. completion date: January 31, 2029
• Est. primary completion date: January 31, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

1. Age>30 years, and have a family history of cirrhosis or HCC, TE indicates no significant fibrosis;

2. Family history of cirrhosis or HCC, and =30 years, TE indicates no significant fibrosis;

3. 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

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis B
• Hepatitis B, Chronic

Intervention

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
• 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

Locations

Country	Name	City	State
China	Beijing YouAn Hospita	Beijing	Beijing
China	Peking University First Hospital	Beijing	Beijing
China	Peking University People's Hospital	Beijing	Beijing
China	the First Bethune Hospital Of Jilin University	Chang chun	Jilin
China	the Second Xiangya Hospital of Central South University	Changsha	Hunan
China	Xiangya Hospital Central South University	Changsha	Hunan
China	Sichuan Provincial People's Hospital	Chengdu	Sichuan
China	West China Hospital of Sichuan University	Chengdu	Sichuan
China	The Second Affiliated Hospital of Chongqing Medical University	Chongqing	Chongqing
China	the Southwest Hospital of AMU	Chongqing	Chongqing
China	First Affiliated Hospital of Fujian Medical University	Fuzhou	Fujian
China	The Affiliated Hospital Of Guizhou Medical University	Guiyang	Guizhou
China	The Second Affiliated Hospital of Harbin Medical University	Ha'erbin	Ha'erbin
China	Hainan General Hospital	Haikou	Hainan
China	Shulan (Hangzhou) Hospital	Hangzhou	Zhejiang
China	Anhui Provincial Hospital	Hefei	Anhui
China	The First Affiliated Hospital of Anhui Medical University	Hefei	Anhui
China	Shandong Provincial Hospital Affiliated to Shandong First Medical University	Jinan	Shandong
China	The Second Hospital of Shandong University	Jinan	Shandong
China	First People's Hospital of Yunnan Province	Kunming	Yunnan
China	the First Hospital of Lanzhou University	Lanzhou	Gansu
China	Third Affiliated Hospital, Sun Yat-Sen University	Meizhou	Xiamen
China	the First Affiliated Hospital of Nanchang University	Nanchang	Jiangxi
China	Jiangsu Province Hospital	Nanjing	Jiangsu
China	The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School	Nanjing	Jiangsu
China	the Second Hospital of Nangjing	Nanjing	Jiangsu
China	First Affiliated Hospital of Guangxi Medical University	Nanning	Guangxi
China	No. 6 People's Hospital of Qingdao	Qingdao	Shandong
China	Huashan Hospital	Shanghai
China	Ruijin Hospital	Shanghai	Shanghai
China	Shengjing Hospital of China Medical University	Shenyang	Liaoning
China	the Third Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	First Hospital of Shanxi Medical University	Taiyuan	Shanxi
China	Tianjin Second People's Hospital	Tianjin	Tianjin
China	Xinjiang Uygur Autonomous Region Hospital of Traditional Chinese Medicine	Ürümqi	Xinjiang Uygur Autonomous Region
China	Renmin Hospital of Wuhan University	Wuhan	Hubei
China	Tongji Hospital	Wuhan	Hubei
China	Union Hospital, Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei
China	Tangdu Hospital, The Fourth Military Medical University	Xi'an	Shaanxi
China	the First Affiliated Hospital of Xi'an Jiaotong University	Xi'an	Shaanxi
China	Xiamen Hospital of Traditional Chinese Medicine	Xiamen	Fujian
China	the Affiliated Hospital of Xuzhou Medical University	Xuzhou	Jiangsu
China	Henan Provincial People's Hospital	Zhengzhou	Henan
China	The First Affiliated Hospital of Henan University of Traditional Chinese Medicine	Zhengzhou	Henan

Sponsors (45)

Lead Sponsor

Collaborator

Huashan Hospital

Anhui Provincial Hospital, Beijing YouAn Hospital, Central South University, First Affiliated Hospital of Fujian Medical University, First Affiliated Hospital of Guangxi Medical University, First Affiliated Hospital of Xinjiang Medical University, First Affiliated Hospital Xi'an Jiaotong University, Hainan General Hospital, Hebei Medical University Third Hospital, Henan Provincial People's Hospital, LanZhou University, Peking University First Hospital, Peking University People's Hospital, Qingdao Sixth People's Hospital, Renmin Hospital of Wuhan University, Ruijin Hospital, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shengjing Hospital, Shulan (Hangzhou) Hospital, Sichuan Provincial People's Hospital, Southwest Hospital, China, Tang-Du Hospital, The Affiliated Hospital Of Guizhou Medical University, The Affiliated Hospital of Xuzhou Medical University, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, The First Affiliated Hospital of Anhui Medical University, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, The First Affiliated Hospital of Nanchang University, The First Affiliated Hospital of Shanxi Medical University, The First Affiliated Hospital with Nanjing Medical University, The First Hospital of Jilin University, The First People's Hospital of Yunnan, The Second Affiliated Hospital of Chongqing Medical University, The Second Affiliated Hospital of Harbin Medical University, the Second Hospital of Nangjing, The Second Hospital of Shandong University, Third Affiliated Hospital, Sun Yat-Sen University, Tianjin Second People's Hospital, Tongji Hospital, West China Hospital, Wuhan Union Hospital, China, Xiamen Hospital of Traditional Chinese Medicine, Xiangya Hospital of Central South University, Zhejiang University

Country where clinical trial is conducted

China, 

References & Publications (15)

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 disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018 Apr;68(4):672-681. doi: 10.1016/j.jhep.2017.11.039. Epub 2018 Jan 17. — View Citation

Chinese Society of Hepatology, Chinese Medical Association. [Expert opinion on expanding anti-HBV treatment for chronic hepatitis B]. Zhonghua Gan Zang Bing Za Zhi. 2022 Feb 20;30(2):131-136. doi: 10.3760/cma.j.cn501113-20220209-00060. Chinese. — View Citation

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. — View Citation

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. — View Citation

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; 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. — View Citation

Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, Lee HC, Chung YH, Lee YS, Suh DJ. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut. 2014 Aug;63(8):1325-32. doi: 10.1136/gutjnl-2013-305517. Epub 2013 Oct 25. — View Citation

Lim TH, Gane E, Moyes C, Borman B, Cunningham C. HBsAg loss in a New Zealand community study with 28-year follow-up: rates, predictors and long-term outcomes. Hepatol Int. 2016 Sep;10(5):829-37. doi: 10.1007/s12072-016-9709-6. Epub 2016 Mar 8. — View Citation

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. — View Citation

National Health and Family Planning Commission of the People's Republic of China. China Statistical Yearbook. Beijing: Peking Union Medical College Press, 2020.

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. — View Citation

Sinn DH, Kim SE, Kim BK, Kim JH, Choi MS. The risk of hepatocellular carcinoma among chronic hepatitis B virus-infected patients outside current treatment criteria. J Viral Hepat. 2019 Dec;26(12):1465-1472. doi: 10.1111/jvh.13185. Epub 2019 Aug 13. — View Citation

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. — View Citation

Wang G, Duan Z. Guidelines for Prevention and Treatment of Chronic Hepatitis B. J Clin Transl Hepatol. 2021 Oct 28;9(5):769-791. doi: 10.14218/JCTH.2021.00209. Epub 2021 Sep 28. — View Citation

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. — View Citation

ZHUANG H. Should chronic hepatitis B in the indeterminate phase be treated?[J]. J Clin Hepatol, 2021, 37(9): 2033-2036.

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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