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Chinese Herbal Medicine Combined with Entecavir for HBeAg Positive Chronic Hepatitis B: Study Protocol for a Multi-Center, Double-Blind Randomized-Controlled Trial

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Abstract

Background

The domestic prevalence of chronic hepatitis B (CHB) in China is 7.18% in 2006, imposing great societal healthcare burdens. Nucleot(s)ide analogues (NUCs) anti-hepatitis B virus (HBV) therapies are widely applied despite the relatively low rate of seroconversion and high risk of drug-resistant mutation. More effective treatments for CHB deserve further explorations. Combined therapy of NUCs plus Chinese herbal medicine (CHM) is widely accepted in China, which is recognized as a prospective alternative approach. The study was primarily designed to confirm the hypothesis that Tiaogan-Yipi Granule (调肝益脾颗粒, TGYP) or Tiaogan-Jianpi-Jiedu Granule (调肝健脾解毒颗粒, TGJPJD) plus entecavir tablet (ETV) was superior over ETV monotherapy in enhancing HBeAg loss rate.

Methods

The study was a nationwide, large-scale, multi-center, double-blind, randomized, placebo-controlled trial with a designed duration of 108 weeks. A total of 16 hospitals and 596 eligible Chinese HBeAg positive CHB patients were enrolled from November 2012 to September 2013 and randomly allocated into 2 groups in 1:1 ratio via central randomization system: experimental group (EG) and control group (CG). Subjects in EG received CM formulae (TGYP or TGJPJD, 50 g per dose, twice daily) plus ETV tablet (or ETV placebo) 0.5 mg per day in the first 24 weeks (stage 1), and CHM granule plus ETV tablet (0.5 mg per day) from week 25 to 108 (stage 2). Subjects in CG received CHM Granule placebo plus ETV tablet (0.5 mg per day) for 108 weeks throughout the trial. The assessments of primary outcomes (HBV serum markers and HBV-DNA) were conducted by a third-party College of American Pathologists (CAP) qualified laboratory. Adverse effects were observed in the hospitals of recruitment.

Discussion

The study was designed to compare the curative effect of CM plus ETV and ETV monotherapy in respect of HBeAg loss, which is recognized by the European Association for the Study of the Liver as “a valuable endpoint”. We believe this trial could provide a reliable status for patients’ “journey” towards durable responses after treatment discontinuation. The trial was registered before recruitment on Chinese Clinical trial registry (No. ChiCTR-TRC-12002784, Version 1.0, 2015/12/23).

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Authors and Affiliations

  1. Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China

    Yong-an Ye, Xiao-ke Li, Feng Jiang, Hong-bo Du, Xian-zhao Yang, Da-nan Gan & Zhi-guo Li

  2. Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, 518033, China

    Da-qiao Zhou

  3. Department of Hepatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510006, China

    Xiao-ling Chi

  4. Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China

    Qin Li

  5. Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, 610066, China

    Li Wang

  6. Department of Hepatology, Liaoning Hospital of Traditional Chinese Medicine, Shenyang, 110032, China

    Bing-jiu Lu

  7. Department of Hepatology, the First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530023, China

    De-wen Mao

  8. Department of Hepatology, the Third People’s Hospital of Shenzhen, Shenzhen, Guangdong Province, 518112, China

    Qi-kai Wu

  9. Department of Hepatology, Beijing Ditan Hospital, Beijing, 100015, China

    Xian-bo Wang

  10. Department of Hepatology, the Sixth People’s Hospital of Shenyang, Shenyang, 110006, China

    Ming-xiang Zhang

  11. Department of Hepatology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an, 710003, China

    Jing-dong Xue

  12. Department of Hepatology, Shandong Hospital of Traditional Chinese Medicine, Jinan, 250011, China

    Yong Li

  13. Department of Hepatology, the Second People’s Hospital of Tianjin, Tianjin, 300000, China

    Wei Lu

  14. Department of Hepatology, Xixi Hospital of Hangzhou, Hangzhou, 310023, China

    Jian-chun Guo

  15. Department of Hepatology, 302 Military Hospital of China, Beijing, 100039, China

    Xin-wei Zhang

  16. Department of Hepatology, the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300000, China

    Hui Guo

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  1. Yong-an Ye
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  2. Xiao-ke Li
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  3. Da-qiao Zhou
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  5. Qin Li
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  6. Li Wang
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  8. De-wen Mao
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  10. Xian-bo Wang
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  13. Yong Li
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  14. Wei Lu
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  15. Jian-chun Guo
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  18. Hong-bo Du
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  19. Xian-zhao Yang
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  20. Hui Guo
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  21. Da-nan Gan
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  22. Zhi-guo Li
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Correspondence to Yong-an Ye.

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Supported by China National Science and Technology Major Projects 12th 5-year Plan (No.2012ZX10005004)

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Ye, Ya., Li, Xk., Zhou, Dq. et al. Chinese Herbal Medicine Combined with Entecavir for HBeAg Positive Chronic Hepatitis B: Study Protocol for a Multi-Center, Double-Blind Randomized-Controlled Trial. Chin. J. Integr. Med. 24, 653–660 (2018). https://doi.org/10.1007/s11655-018-3011-5

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