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Haptoglobin Genotype and Vitamin E Versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis in China: A Multicenter, Randomized, Placebo-Controlled Trial Design

Abstract

Introduction

Vitamin E is one of the most promising agents for nonalcoholic steatohepatitis (NASH) treatment, and its drug responsiveness may be closely associated with haptoglobin (Hp) genotype. However, its efficacy and safety remain unknown in China. This clinical trial of vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis (VENS) is conducted to evaluate (a) the efficacy and safety of treatment with vitamin E softgel (300 mg/day) determined from standardized histologic scoring of liver biopsies, (b) whether treatment with vitamin E improves biochemical parameters, cytokines, anthropometric parameters, controlled attenuation parameter (CAP), and transient elastography (TE) values determined by Fibroscan and health-related quality of life (SF-36), (c) whether the efficacy of vitamin E treatment is associated with the Hp genotype in nondiabetic adults with NASH.

Methods

VENS is a multicenter, randomized, double-masked, placebo parallel controlled trial to evaluate the efficacy and safety of treatment with vitamin E softgel in nondiabetic adults with NASH versus treatment with placebo in China. Liver biopsies are read by a pathological evaluation committee independently according to the NASH Clinical Research Network (CRN) scoring system. The NAFLD activity score (NAS) represents the sum of scores for steatosis, lobular inflammation, and hepatocyte ballooning. The definition of histologic improvement requires all three of the following criteria to be met: (a) either improvement in NAS by at least 2 points or post-treatment NAS score no higher than 3, (b) at least 1-point improvement in the score for ballooning, and (c) no worsening of fibrosis stages. We plan to recruit 120 biopsy-proven NASH patients from13 centers in China. Participants will be randomly assigned to groups treated with either with vitamin E (100 mg, tid) or placebo for 96 weeks then followed by 24 weeks of post-treatment observation. Biochemical parameters, cytokines, anthropometric parameters, CAP and TE values, Hp genotype, and several questionnaires will be collected as per the schedule. This protocol was approved by the Ethics Committee of Hangzhou Normal University Affiliated Hospital to ensure patients safety, and R&G Pharmastudies Co., Ltd. was established for monitoring the accumulated interim data to review efficacy and quality of data collection and overall study management.

Results

As a preliminary study, a mobile phone application (app) for lifestyle modification and database recording (http://laiyivens.365hy.com) was exploited for every participant. The percentage of NAFLD patients with Hp 2-2 allele is much higher than that of Western patients (65.71% vs 36%, respectively), which suggests that the Chinese benefit more from vitamin E treatment.

Conclusion

VENS is the first randomized controlled trial (RCT) to evaluate the efficacy of Vitamin E in treating nondiabetic NASH patients in China.

Trial Registration

This study registered at https://clinicaltrials.gov (registration number: NCT02962297).

Funding

Zhejiang Medicine Co., Ltd.

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Acknowledgements

Funding

Vitamin E used in this study and the article processing charges were sponsored by Zhejiang Medicine Co., Ltd. Statistical analysis is supported by the School of Public Health Nanjing Medical University, Department of Biostatistics. We thank Hao yu (PhD) from the Nanjing Medical University statistical team for his contributions to our study design. Clinical data management is provided by R&G Pharma Studies (China) Co., Ltd.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. The authors, individually and collectively, are responsible for all content and editorial decisions and received no payment from any of the above companies directly or indirectly (through a third party) related to this publication. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Disclosures

Shufei Zang, Jin Chen, Yu Song, Bingyuan Wang, and Junping Shi declare that they have nothing to disclose. Lang Bai is a leader of one of the clinical research subcenters. Jinjun Chen is a leader of one of the clinical research subcenters. Xiaoling Chi is a leader of one of the clinical research subcenters. Fangping He is a leader of one of the clinical research subcenters. Huiping Sheng is a leader of one of the clinical research subcenters. Jing Wang is a leader of one of the clinical research subcenters. Wen Xie is a leader of one of the clinical research subcenters. Yongfeng Yang is a leader of one of the clinical research subcenters. Jing Zhang is a leader of one of the clinical research subcenters. Minghua Zheng is a leader of one of the clinical research subcenters. Zhengsheng Zou is a leader of one of the clinical research subcenters. Shilong Xie is an employee of Zhejiang Medicine Co., Ltd Hangzhou Branch.

Compliance with Ethics Guidelines

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study. Prior to the start of the trial, the detailed protocol and information of experimental drugs, informed consent, and other necessary materials were submitted to the ethics committee for review and were approved. During the trial, if any changes are required to this protocol or informed consent, permission should be given again. In addition, any adverse events monitored in the trial should be reported regularly to the ethics committee during the progress of the trial.

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Correspondence to Bingyuan Wang or Junping Shi.

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Zang, S., Chen, J., Song, Y. et al. Haptoglobin Genotype and Vitamin E Versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis in China: A Multicenter, Randomized, Placebo-Controlled Trial Design. Adv Ther 35, 218–231 (2018). https://doi.org/10.1007/s12325-018-0670-8

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Keywords

  • Haptoglobin genotype
  • Hepatology
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Randomized controlled trial
  • Vitamin E