Chinese herbal medicine combined with entecavir to reduce the off-therapy recurrence risk in HBeAg-positive chronic hepatitis B patients: a multicener, double-blind, randomized controlled trial in China

Study protocol Open Access Published: 12 August 2020 Chinese herbal medicine combined with entecavir to reduce the off-therapy recurrence risk in HBeAg-positive chronic hepatitis B patients: a multicener, double-blind, randomized controlled trial in China Xiaoke Li1 na1, Ludan Zhang1 na1, Mei Qiu2, Yi Huang3, Huanming Xiao4, Bingjiu Lu5, Yuyong Jiang6, Fuli Long7, Hui Lin8, Jinyu He9, Qikai Wu10, Mingxiang Zhang11, Li Wang12, Xiaoning Zhu13, Man Gong14, Xuehua Sun15, Jianguang Sun16, Fengxia Sun17, Wei Lu18, Weihua Xu19, Guang Chen1, Zhiguo Li1, Danan Gan1, Xianzhao Yang1, Hongbo Du1 & Yong’an Ye  ORCID: orcid.org/0000-0001-9765-46651  Trials volume 21, Article number: 708 (2020) Cite this article 161 Accesses Metrics details Abstract Background Nucleos(t)ide analogues (NAs) are the first-line option against chronic hepatitis B (CHB). NAs produce potent suppression of viral replication with a small chance of HBsAg seroclearance and a high risk of virological relapse after discontinuation. The combined therapy of NAs plus traditional Chinese medicine (TCM) is widely accepted and has been recognized as a prospective alternative approach in China. Based on preliminary works, this study was designed to observe the therapeutic effect of TCM plus entecavir (ETV) against HBeAg-positive chronic hepatitis B with respect to reducing the recurrence risk after NA withdrawal. Methods/design The study is a nationwide, multicenter, double-blind, randomized, placebo-controlled trial with a duration of 120 weeks. A total of 18 hospitals and 490 eligible Chinese HBeAg-positive CHB patients will be enrolled and randomly allocated into the experimental group and control group in a 1:1 ratio. Patients in the experimental group will be prescribed TCM formulae (Tiaogan-BuXu-Jiedu granules) plus ETV 0.5 mg per day for consolidation therapy for 96 weeks. Patients in the control group will be prescribed TCM granule placebo plus ETV 0.5 mg per day for the same course. After consolidation therapy, all patients will discontinue their trial drugs and be closely monitored over the next 24 weeks. Once clinical recurrence (CR) occurs, ETV treatment will be restarted. The primary outcome is the cumulative rate of CR at the end of this trial. Conclusion This study is the first of its kind to observe therapeutic effects with respect to reducing recurrence after NA withdrawals after unified integrative consolidation therapy in the CHB population. Trial registration Chinese Clinical Trial Registry No. ChiCTR1900021232. Registered on February 2, 2019 Peer Review reports Chronic hepatitis B (CHB) has been one of the most concerning diseases worldwide. Every year, approximately 1 million people die of CHB-related cirrhosis and hepatocellular carcinoma [1]. Nucleos(t)ide analogues (NAs) therapy is widely applied in patients with chronic hepatitis B virus (HBV) infection. Currently, six NAs are available against CHB: lamivudine, telbivudine, entecavir (ETV), adefovir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), of which ETV and TDF are recommended as first-line therapies [2,3,4]. NAs inhibit the reverse transcriptase activity of the HBV polymerase and thus suppress viral replication. However, NAs exert little effect on viral covalently closed circular DNA (cccDNA) in the nucleus [5]. Hence, they cannot permanently eradicate the virus. Currently, hepatitis B surface antigen (HBsAg) loss is the most widely accepted endpoint to guide cessation of NA treatment. However, as HBsAg loss is an infrequent event, this strategy entails an indefinite therapeutic duration that could be lifelong for the vast majority of NA-treated patients [6]. Therefore, the benefit of long-term treatment should be weighed against the burden of life-long medication, monitoring, and adherence. In addition, the long-term risk for the development of resistance and adverse events (AEs) remains unclear. In recent years, some scholars have attempted to find approaches for preventing relapses after NAs withdrawal [7,8,9]. A previous study observed the outcomes after the cessation of ETV therapy among patients who fulfilled the stopping rules of the Asia-Pacific Association for the Study of the Liver (APASL) [10]. The 2-year cumulative rates of virological and clinical relapse were 41.3% and 33% in hepatitis B e antigen (HBeAg)-positive patients, and the 3-year cumulative rates of virological and clinical relapse were 62.7% and 48.3% in HBeAg-negative patients, respectively. The risk after discontinuation of the therapy is concerning. Traditional Chinese medicine (TCM) therapy has a long history and definite curative effect for treating various chronic liver diseases including chronic hepatitis and fibrosis/cirrhosis [11,12,13], and abundant data and experience have accumulated in long-term clinical practice and scientific research. Although TCM therapy alone has no explicit antiviral effect, it has some advantages in improving clinical symptoms [14], alleviating liver inflammation, anti-fibrosis [15], and regulating immune function [16]. In China, supported by major national special research projects funded by the Ministry of Health, some research results have been obtained regarding the treatment of chronic hepatitis B by the combination of TCM and NAs, the advantages of TCM therapy in the treatment of chronic hepatitis B have been preliminarily clarified [17], an integrated TCM and NAs therapeutic schedule has been developed [18], and it has been proven that the combination of TCM and NAs can significantly enhance the negative conversion ratio of HBeAg, including that seen in refractory diseases [19, 20]. Based on the preliminary work, this study carries out research on combination TCM and NAs strategies for HBeAg-positive chronic hepatitis B. Through a national multicenter double-blind, randomized controlled study, we will verify the effect of combination TCM and NA therapy in reducing the recurrence rate after drug withdrawal. Registration We had registered this trial before recruitment on the Chinese Clinical Trial Registry (No. ChiCTR1900021232). This trial will be conducted following the principles of the Declaration of Helsinki (2004 version). The study protocol has been approved by the Ethics Committee of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine before recruitment (Approval number: DZMEC-KY-2018-61). Recruitment A total of 490 patients will be recruited by nineteen clinical centers in China nationwide listed as follows: Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Guangdong Hospital of Traditional Chinese Medicine, Liaoning Hospital of Traditional Chinese Medicine, the First Affiliated Hospital of Guangxi University of Chinese Medicine, Shaanxi Hospital of Traditional Chinese Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Beijing C (...truncated)