Effectiveness and Safety of Direct-Acting Antiviral Agents for the Treatment of Chronic Hepatitis C (C-DIAMOND)

Effectiveness and Safety of Direct-Acting Antiviral Agents for the Treatment of Chronic Hepatitis C: Multi-center, Prospective, Observational Real-world Study in EASTERN China

Clinical trials evaluating DAA have shown excellent rates of SVR and good safety profiles in patients with CHC infection. Real world data from TARGET, TRIO, IFI, DHCR, DALTON-C, as well as those cohorts from Japan, Taiwan and Korea further confirmed clinical trial findings of DAA in routine practice where populations are more complex. However, these populations are different from Chinese for different host and virus characteristics which limit the applicability of results to local practice.

As DAA launched in China since 2017, the availability of INF free DAA treatment will likely lead to better treatment outcome in routine practice, but there are currently no data available to test the hypothesis.

In clinical practice, the uptake of DAA regimen will depend on a combination of physician preference, patient's characteristics and drug access. This study will also identify how these three variables affect DAA regimen uptake.

This study to 1) characterize pts receiving IFN free DAA regimens, 2) represent common practice in China, 3) describe outcome of various INF free DAA therapy, and 4) confirm registration study results.

Study Overview

• Status: Recruiting
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Drug: Direct-acting antiviral agents

Detailed Description

Chronic Hepatitis C (hereinafter referred to as "CHC") is a viral hepatitis caused by the infection of Hepatitis C virus (HCV). In 2007, a cross-sectional study in six cities showed that the prevalence of HCV was 0.58% in China. It was estimated that there were about 10 million HCV patients in our country. If hepatitis C was not treated in time, about 75% of patients would progress into chronic hepatitis C six months after virus infection; the probability was 5%~15% for progression into cirrhosis and 2%~4% for progression into hepatocellular carcinoma 20 years after the infection of chronic hepatitis C. One analysis of cirrhosis etiology in northern China found that the proportion of CHC-induced cirrhosis was increased from 6.39% in 2002 to 13.91% in 2011.

As a result of the severely epidemiological burden of CHC, the World Health Organization (WHO) has established a target to eliminate the hepatitis harm in 2030 ("2030 global targets" for short) that 90% reduction in new cases of chronic hepatitis B and C in 2030, 80% of treatment-eligible people with chronic hepatitis B and C treated and 65% reduction in hepatitis B and C deaths. As a part of the strategy to achieve this target, WHO includes the treatment with direct-acting antiviral agents (DAAs) into the 2017 Essential Medicine List. In addition, the Viral Hepatitis Prevention and Control Programs in China (2017-2020) also emphasize the application of more effective treatment as a part of the strategy to reduce the transmission of HCV.

Direct-acting antiviral agents (DAAs) are a new drug for the treatment of CHC now. In 2017, China Food and Drug Administration (CFDA)/ National Medical Products Administration (NMPA) approved the marketing of Sofosbuvir of Gilead, Ombitasvir/Paritaprevir/Ritonavir Tablets + Dasabuvir of AbbVie, Daclatasvir Tablets + Asunaprevir Capsules of Bristol-Myers Squibb; Elbasvir/Grazoprevir of MSD, Sofosbuvir/Velpatasvir and Ledipasvir/Sofosbuvir of Gilead and Danoprevir of Ascletis in 2018. Before the DAAs are marketed, the pegylated interferon combined with ribavirin (PR) therapy is the major therapy of antiviral for HCV-infected patients. However, the real-world study showed that the sustained virological response (SVR) of PR therapy was 71.1%. The DAAs therapy was demonstrated with shorter treatment time, better efficacy, fewer adverse events, and higher compliance compared with the PR therapy.

Multiple clinical trials indicated a high SVR rate and safety of DAAs in CHC patients. The real-world studies with more complicated patient populations, including TARGET, TRIO, IFI, DHCR, and DALTON-C as well as the cohort studies from Japan, Taiwan, and the Republic of Korea also further demonstrated good clinical efficacy with DAAs. While GT 1-3 is prevalent worldwide, subtypes of 1b, 2a, 3a, 3b, and 6a are prevalent in China, and among them, GT 3 and 6 are expanding. Since the host and virus characteristics of these populations are different from the Chinese population, the BMI of the Chinese population is smaller than that of the European and American population, IL28 CC GT is predominant, and HCV patients of GT 3b is most common among HCV patients of GT 3. So, it is necessary to further demonstrate the applicability of the results of these studies to Chinese patients.

DAAs have been marketed in China since 2017. The treatment with DAAs unnecessary to combine with any interferon (IFN) may obtain better therapeutic effect in clinical practice. However, there is a lack of real-world data to verify this hypothesis now.

In clinical practice, the selection of therapy with DAAs will depend on the physician preference, patient baseline characteristics, and drug accessibility. This study will also determine the baseline status of patients receiving different DAA treatments and possible reasons for doctors' prescriptions in the real world.

In the eastern part of China, the GTs of HCV infected patients are GT 1b (69.2%), GT 2a (20.8%), GT 3a (2.2%), GT 3b (4.4%) and GT 6 (3.2%).To demonstrate whether DAAs provide good efficacy and safety to the patients, including the patients with cirrhosis, accompanying with infection, kidney/liver transplantation, or no response to PR therapy, the purpose of this study is to 1) describe the patient characteristics for DAA therapy unnecessary to combine with any IFN in routine clinical practice in China; 2) describe the therapeutic effect of multiple DAAs unnecessary to combine with any IFN to verify above hypothesis.

• Study Type: Observational
• Enrollment (Anticipated): 300

Contacts and Locations

• Study Contact: Name: Qing Xie, MD; Phone Number: 008613651804273; Email: xieqingrjh@163.com
• Study Contact Backup: Name: Lichang Chen, MD; Phone Number: 008618817555940; Email: clc@sjtu.edu.cn

Study Locations

• China
  • Jiangsu
    • Changzhou, Jiangsu, China, 213001
      • Recruiting
      • Changzhou Third People's Hospital
      • Contact: Longgen Liu, MD; Phone Number: 008613606140932
      • Principal Investigator: Longgen Liu, MD
      • Sub-Investigator: Jing Xie, MD
    • Nanjing, Jiangsu, China, 210008
      • Recruiting
      • Nanjing Drum Tower Hospital
      • Contact: Chao Wu, MD; Phone Number: 008613809022921
      • Principal Investigator: Chao Wu, MD
      • Sub-Investigator: Yongyang Zhang, MD
    • Nanjing, Jiangsu, China, 210029
      • Recruiting
      • Jiangsu Province Hospital
      • Principal Investigator: Jun Li, MD
      • Contact: Jun Li, MD; Phone Number: 008613905175333
      • Sub-Investigator: Jie Cai, MD
    • Nanjing, Jiangsu, China, 210003
      • Recruiting
      • The Second Hospital of Nanjing
      • Contact: Yongfeng Yang, MD; Phone Number: 008613951990210
      • Principal Investigator: Yongfeng Yang, MD
      • Sub-Investigator: Zengxiu Wang, MD
    • Suzhou, Jiangsu, China, 215007
      • Recruiting
      • The Fifth People's Hospital of Suzhou
      • Contact: Chuanwu Zhu, MD; Phone Number: 008613606202525
      • Principal Investigator: Chuanwu Zhu, MD
      • Sub-Investigator: Li Zhu, MD
    • Wuxi, Jiangsu, China, 214016
      • Recruiting
      • Wuxi No. 5 People's Hospital
      • Contact: Lihua Huang, MD; Phone Number: 008613601513551
      • Principal Investigator: Lihua Huang, MD
      • Sub-Investigator: Yanguang Li, MD
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Recruiting
      • Huashan Hospital
      • Contact: Jiming Zhang, MD; Phone Number: 008613816317838
      • Principal Investigator: Jiming Zhang, MD
      • Sub-Investigator: Jialin Jin, MD
    • Shanghai, Shanghai, China, 200025
      • Recruiting
      • Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
      • Contact: Qing Xie, MD; Phone Number: 008613651804273; Email: xieqingrjh@163.com
      • Contact: Lichang Chen, MD; Phone Number: 008618817555940; Email: clc@sjtu.edu.cn
      • Principal Investigator: Qing Xie, MD
      • Sub-Investigator: Lichang Chen, MD
      • Sub-Investigator: Huijuan Zhou, MD
    • Shanghai, Shanghai, China, 201058
      • Recruiting
      • Shanghai Public Health Clinical Center
      • Contact: Liang Chen, MD; Phone Number: 008618930810000
      • Principal Investigator: Liang Chen, MD
      • Sub-Investigator: Xun Qi, MD
  • Zhejiang
    • Jiaxing, Zhejiang, China, 314000
      • Recruiting
      • The First Hospital of Jiaxing
      • Contact: Xinsheng Xie, MD; Phone Number: 008613615833233
      • Principal Investigator: Xinsheng Xie, MD
      • Sub-Investigator: Min Deng, MD
    • Ningbo, Zhejiang, China, 315010
      • Recruiting
      • Hwa Mei Hospital
      • Contact: Hao Ying, MD; Phone Number: 008613806663345
      • Principal Investigator: Hao Ying, MD
      • Sub-Investigator: Si Chen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The primary objective of this study is to obtain the SVR12 rate of CHC patients in Eastern China. The previous study of Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine showed that the SVR12 rate was 0.988 (CI 95%: 0.952-1.0, Shanghai, China, Rui Jin Hospital, 26th APASL annual meeting, PO241). In this study, the estimated value of SVR is set to 95%, the bilateral significance level is 0.05 and the sampling error is 0.03. The estimated sample size is 225 as per the sample size calculation formula. Considering the patient withdrawal, this study is planned to collect 300 patients.

Description

Inclusion Criteria:

• All Chronic hepatitis C patients to be treated with the DAAs approved by CFDA/NMPA
• Age≥18 years

Exclusion Criteria:

• Patients experienced with DAAs
• Documented HCC, AFP>500ng/ml
• Unlikely to survive 1 year or inability to participate and follow up for the study period

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

DAA Group; Chronic hepatitis C patients treated with DAA

Drug: Direct-acting antiviral agents; The initial DAA treatment and its dose for all patients is determined by the infectionist or hepatologist based on the clinical diagnosis and treatment routine. The administration dose in the instructions for use for current DAAs marketed in China Mainland unnecessary to combine with any IFN is shown but not limited as follows: Sofosbuvir, Ombitasvir/Paritaprevir/Ritonavir, Dasabuvir, Daclatasvir, Asunaprevir, Elbasvir/Grazoprevir, Sofosbuvir/Velpatasvir and Ledipasvir/Sofosbuvir.; Other Names: pibrentasvir; glecaprevir; sofosbuvir; ledipasvir; dasabuvir; ombitasvir; daclatasvir; asunaprevir; paritaprevir; velpatasvir; elbasvir; grazoprevir; danoprevir; voxilaprevir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SVR12 rate of DAA	Sustained virological response at 12 week; ie, HCV RNA <15 IU/ ml at 12 weeks after the treatment with DAA regimen.	12 weeks after the treatment with DAA regimen

Collaborators and Investigators

• Sponsor: Qing XIe
• Collaborators: Gilead Sciences; Tigermed Consulting Co., Ltd
• Investigators: Principal Investigator: Qing Xie, MD, Director of Department of Infectious Disease, Rui Jin Hospital

Publications and helpful links

General Publications

• Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, Abergel A, Mangia A, Lai CL, Chan HL, Mazzotta F, Moreno C, Yoshida E, Shafran SD, Towner WJ, Tran TT, McNally J, Osinusi A, Svarovskaia E, Zhu Y, Brainard DM, McHutchison JG, Agarwal K, Zeuzem S; ASTRAL-1 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015 Dec 31;373(27):2599-607. doi: 10.1056/NEJMoa1512610. Epub 2015 Nov 16.
• Lu J, Zhou Y, Lin X, Jiang Y, Tian R, Zhang Y, Wu J, Zhang F, Zhang Y, Wang Y, Bi S. General epidemiological parameters of viral hepatitis A, B, C, and E in six regions of China: a cross-sectional study in 2007. PLoS One. 2009 Dec 24;4(12):e8467. doi: 10.1371/journal.pone.0008467.
• Chen YS, Li L, Cui FQ, Xing WG, Wang L, Jia ZY, Zhou MG, Gong XH, Wang FZ, Zheng H, Luo HM, Bi SL, Wang N, Yang WZ, Liang XF. [A sero-epidemiological study on hepatitis C in China]. Zhonghua Liu Xing Bing Xue Za Zhi. 2011 Sep;32(9):888-91. Chinese.
• Rao HY, Li H, Chen H, Shang J, Xie Q, Gao ZL, Li J, Sun Y, Jiang J, Wang L, Zhao L, Zhang L, Yang W, Niu J, Gong Z, Gong G, Yang R, Lee MH, Wei L. Real-world treatment patterns and clinical outcomes of HCV treatment-naive patients in China: an interim analysis from the CCgenos study. J Gastroenterol Hepatol. 2017 Jan;32(1):244-252. doi: 10.1111/jgh.13467.
• Lu L, Nakano T, He Y, Fu Y, Hagedorn CH, Robertson BH. Hepatitis C virus genotype distribution in China: predominance of closely related subtype 1b isolates and existence of new genotype 6 variants. J Med Virol. 2005 Apr;75(4):538-49. doi: 10.1002/jmv.20307.
• Chen Y, Yu C, Yin X, Guo X, Wu S, Hou J. Hepatitis C virus genotypes and subtypes circulating in Mainland China. Emerg Microbes Infect. 2017 Nov 1;6(11):e95. doi: 10.1038/emi.2017.77.
• Ogawa E, Furusyo N, Murata M, Hayashi T, Shimizu M, Mukae H, Toyoda K, Hotta T, Uchiumi T, Hayashi J. Impact of HCV kinetics on treatment outcome differs by the type of real-time HCV assay in NS3/4A protease inhibitor-based triple therapy. Antiviral Res. 2016 Feb;126:35-42. doi: 10.1016/j.antiviral.2015.12.001. Epub 2015 Dec 12.
• Matthews SJ, Lancaster JW. Telaprevir: a hepatitis C NS3/4A protease inhibitor. Clin Ther. 2012 Sep;34(9):1857-82. doi: 10.1016/j.clinthera.2012.07.011. Epub 2012 Aug 28.
• Heo YA, Deeks ED. Sofosbuvir/Velpatasvir/Voxilaprevir: A Review in Chronic Hepatitis C. Drugs. 2018 Apr;78(5):577-587. doi: 10.1007/s40265-018-0895-5.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2019
• Primary Completion (Anticipated): July 31, 2021
• Study Completion (Anticipated): August 31, 2021

Study Registration Dates

• First Submitted: June 24, 2021
• First Submitted That Met QC Criteria: July 4, 2021
• First Posted (Actual): July 7, 2021

Study Record Updates

• Last Update Posted (Actual): July 7, 2021
• Last Update Submitted That Met QC Criteria: July 4, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Chronic hepatitis C; Direct-acting antiviral agents; Sustained virological response
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protease Inhibitors; Sofosbuvir; Velpatasvir; Antiviral Agents; Ledipasvir; Asunaprevir; Grazoprevir
• Other Study ID Numbers: IN-CN-342-5424

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No