Efficacy and Safety of Bicyclol for Treating Patients With Idiosyncratic Acute Drug-induced Liver Injury

A Multicenter, Randomized, Phase II Trial

Jieting Tang; Jin Gu; Naihui Chu; Yu Chen; Yongliang Wang; Dongying Xue; Qing Xie; Lei Li; Zaoxian Mei; Xiaojin Wang; Jun Li; Jun Chen; Yi Li; Changqing Yang; Yingxin Wang; Jia Shang; Wen Xie; Peng Hu; Dongliang Li; Limin Zhao; Pei Lan; Chen Wang; Chengwei Chen; Yimin Mao


Liver International. 2022;42(8):1803-1813. 

In This Article

Abstract and Introduction


Background and Aims: Evidence for using bicyclol in drug-induced liver injury (DILI) is limited. This study aimed to explore the efficacy and safety of bicyclol in acute DILI.

Methods: This was a multicenter, randomized, double-blinded, double-dummy, active-controlled, superiority and phase II trial. Patients with idiosyncratic acute DILI were randomized 1: 1:1 to low-dose bicyclol (25 mg times a day [TID]), high-dose bicyclol (50 mg TID) and polyene phosphatidylcholine (control) groups. The primary endpoint was the decrease from baseline in serum alanine aminotransferase (ALT) levels at post-treatment for 4 weeks.

Results: Overall, 241 patients were included in the full analysis set, with 81, 82 and 78 patients in the low-dose bicyclol, high-dose bicyclol, and control groups respectively. ALT levels decreased across groups (−249.2 ± 151.1, −273.6 ± 203.1, and −180.8 ± 218.2 U/L in the low-dose bicyclol, high-dose bicyclol and control groups, respectively; both p < .001, the bicyclol-dependent groups vs. control group). The ALT normalization rates at weeks 1, 2, 4, 6 and 8 were higher in the bicyclol-dependent groups than in the control group (p = .002 at week 1 and all p < .001 at weeks 2, 4, 6 and 8 respectively). The median times to ALT normalization in the low-dose bicyclol, high-dose bicyclol and control groups were 29, 16 and 43 days respectively. Adverse events, serious adverse events and adverse drug reactions were similar across groups.

Conclusions: Bicyclol (25 and 50 mg TID) appeared efficacious and safe for treating idiosyncratic acute DILI, while bicyclol 50 mg TID showed higher efficacy.

Trial Registration Number: www.Clinicaltrials.gov (registration no. NCT02944552).


Drug-induced liver injury (DILI) may lead to acute hepatitis[1] or acute liver failure (ALF).[2] In China, the annual incidence of DILI was estimated to be 23.80 per 100 000 individuals.[3] Typically, DILI events result from the combined effects of the first hit from potential hepatotoxic drugs, genetic and nongenetic risk factors and adaptive injury repair mechanisms.[4,5] DILI is classified as either idiosyncratic or intrinsic. Idiosyncratic DILI occurs rarely in the general population,[6,7] whilst intrinsic DILI accounts for nearly half of acute liver failure cases in European countries and the United States.[8]

At present, except for avoidance of exposure to causative agents,[2,9–11] effective and safe approaches for treating idiosyncratic DILI are unavailable. Regarding the use of corticosteroids for the treatment of DILI, patients with drug-induced autoimmune hepatitis[12,13] and immune checkpoint inhibitor-induced hepatotoxicity[14] usually can benefit from corticosteroid use. Nevertheless, evidence on the efficacy of corticosteroids for the management of ALF caused by DILI is scarce and inconsistent.[5,15–19] Intravenous injection of N-acetylcysteine (NAC) during early treatment could be beneficial to patients with non-APAP-induced ALF.[20] However, a meta-analysis of two randomized controlled trials (RCTs) demonstrated that the use of NAC in adult patients with idiosyncratic DILI-related ALF did not improve overall survival (OS) rates.[21] Cholestyramine has been recommended to speed up leflunomide clearance. Nevertheless, there is no evidence confirming that cholestyramine can accelerate DILI recovery.[2,5] Thus, currently, only a few drugs are being studied in RCTs with a focus on the management of DILI, and research progress in the treatment of acute DILI is slow. There has been substantial interest in the identification of efficient drugs for the treatment of DILI.

Bicyclol, a hepatoprotective and anti-inflammatory drug that has been approved in China since 2001, can inhibit the expression and activity of several inflammatory factors induced by liver injury, relieve oxidative stress, inhibit hepatocyte apoptosis, stabilize hepatocyte plasma membrane, improve mitochondrial function and protect the structure and function of liver nuclear DNA.[22] It has been used in treating the elevation of aminotransferase levels in patients with chronic viral hepatitis.[23] Previous studies indicated that bicyclol might prevent or reduce the occurrence of DILI in patients with tuberculosis (TB).[24] Prophylactic administration of bicyclol also effectively reduces the incidence or alleviates the degree of DILI in elderly cancer patients receiving chemotherapy.[25] In patients with statin-induced liver injury, bicyclol treatment for 4 weeks could significantly reduce alanine aminotransferase (ALT) levels.[26] Nevertheless, these trials employed different diagnostic criteria for DILI and showed methodological flaws.[21] The limitations in study designs weakened the strength of their conclusions. Thus, the efficacy of bicyclol in the treatment of DILI needs to be comprehensively elucidated.

Therefore, we conducted this RCT to explore whether different doses (25 and 50 mg, three times a day [TID]) of bicyclol were superior to polyene phosphatidylcholine (PPC), the most commonly used hepatoprotective agent in China, in reducing the serum ALT level in patients with idiosyncratic acute DILI.