. 2020 Jun 23;19:100601.
doi: 10.1016/j.conctc.2020.100601. eCollection 2020 Sep.
Safety and Therapeutic Effects of Anti-Fibrotic Traditional Chinese Medicine Fuzheng Huayu on Persistent Advanced Stage Fibrosis Following 2 Years Entecavir Treatment: Study Protocol for a Single Arm Clinical Objective Performance Criteria Trial
Yangyi Chen 1 , Zhimin Zhao 1 , Haina Fan 1 , Zhengxin Li 1 , Yingchun He 1 , Chenghai Liu 1 2
Affiliations
Background: Hepatitis B virus (HBV) infection is an important etiology for chronic hepatitis globally, and especially so in China. HBV infection can lead to the development of cirrhosis through the pathological process of liver fibrosis. The effective suppression of HBV replication with NAs or interferon-alpha can histologically regress the fibrotic pathological process, but there remain patients who have achieved anti-viral responses and normalization of serum liver tests, but not liver fibrosis regression. This subset of patients typically presents with advanced liver fibrosis at baseline. Therefore, it is reasonable to administer the anti-fibrotic agents, coupled with antivirals for patients with advanced liver fibrosis due to HBV, in order to improve the fibrotic regression of the patients. Fuzheng Huayu (FZHY) tablet is a botanical product with evidence demonstrating its efficacy against mild to moderate liver fibrosis. The current clinical trial evaluates the efficacy and safety of the combination therapy of traditional Chinese medicine (TCM) (FZHY and herbal granule) and entecavir for HBV compensated cirrhosis. We will enroll HBV patients who presented with a good viral response after 2 years of entecavir treatment but had advanced liver fibrosis (≥Ishak F5).
Methods: This is a single-arm clinical trial, conducted in 20 centers in mainland China over a period of 60 weeks, including 48 weeks of treatment observation and 12 weeks of follow-up. The main inclusion criteria include HBsAg positive more than 6 months, 2 years administration of entecavir, HBV DNA less than 20 IU/ml, liver fibrotic stage ≥ F5, and Child-Pugh scoring <7 (Stage A). The sample size is estimated to be about 190, considering a 20% drop-out and 60% of patient's compliance for the second liver biopsy so a total of 350 participants will be enrolled. All eligible participants are divided into 3 subgroups according to the TCM clinic pattern. And all patients will take 1 Entecavir tablet (0.5 mg) per day, 4 FZHY tablets (1.6 g) three times a day, and specific TCM granule three times a day, which is decided by TCM clinical patterns (CPs) differentiation. The patients were treated for 48 weeks, and follow-up visits at 12, 24, 36, 48 weeks and 60 weeks. The patients will receive the second liver biopsy at the end of 48 weeks, with a 12 weeks follow-up after that.The primary endpoint is the proportion of subjects with a 1-point improvement of liver fibrosis stage using the Ishak score from baseline to week 48 in the study, according to consensus readings evaluated by a panel of hepato-pathologists. The secondary endpoints are the brightness-mode ultrasonic, fibrotic biomarkers. The adverse events (AEs) will be recorded for 60 weeks, and the safety of the combination therapy will be evaluated. Meanwhile, the efficacy in the 3 sub-groups will be stratified and analyzed.
Discussion: The study has been designed to test the therapeutic effects and safety of the combination therapy of FZHY and herbal granule with entecavir on persistent advanced stage fibrosis/cirrhosis following 2 years entecavir treatment, and to explore an effective integrative therapy on HBV cirrhosis.
Trial registration: ClinicalTrials.gov. NCT02241616. Registered on September 16, 2014.
Keywords: AEs, adverse events; CPs, Clinical Patterns; CRC, Clinical Research Coodinator; CRO, Central Clinical Research Organization; Cirrhosis; EDC, Electronic Data Collection; Entecavir; FZHY, FuZheng HuaYu; Fuzheng huayu tablet; GMP, Good Manufacturing Practice; HBV, Hepatitis B virus; HSCs, Hepatic Stellate Cells; Hepatitis B virus; Liver fibrosis; NAs, Nucleos(t)ide analogues; NMPA, National Medical Products Administration; OPC, objective performance criteria; PDGF-BB, Platelet Derived Growth Factor-BB; PHBC-PRO, patient reported outcomes of post-hepatitic B cirrhosis; PI, principal investigator; Regression; TCM, Traditional Chinese medicine; TGF-β1, Transforming Growth Factor-beta 1; US FDA, United States Food and Drug Administration; WHO, World Health Organization.
方法:这是一项单臂临床试验,在中国大陆的20个中心进行,为期60周,包括48周的治疗观察和12周的随访。主要纳入标准包括6个月以上的HBsAg阳性,恩替卡韦治疗2年,HBV DNA低于20 IU / ml,肝纤维化阶段≥F5和Child-Pugh评分<7(A期)。考虑到第二次肝活检有20%的辍学率和60%的患者依从性,因此样本量估计约为190,因此将招募350名参与者。根据中医诊所模式,将所有符合条件的参与者分为3个亚组。所有患者每天将服用1片恩替卡韦片(0.5毫克),每天3次服用4片FZHY片剂(1.6克),并每天服用3次特定的中药颗粒,这取决于中医临床模式(CP)的差异。患者接受了48周的治疗,并在12、24、36、48周和60周进行了随访。患者将在48周结束时接受第二次肝活检,然后进行12周的随访。根据一组肝病理学家评估的共识性研究,主要终点是研究中从基线到第48周使用Ishak评分在肝纤维化阶段改善1分的受试者的比例。次要终点是亮度模式超声纤维化生物标记物。将记录不良事件(AEs)60周,并评估联合治疗的安全性。同时,将对这三个亚组的疗效进行分层和分析。