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Determination of fasiglifam-induced liver toxicity: Insights from the data monitoring committee of the fasiglifam clinical trials program

Lookup NU author(s): Emeritus Professor Philip Home


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© The Author(s) 2019. Background: Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided. Methods: This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity). Liver safety had been pre-identified as a concern, and within the phase 3 trials, was measured through (1) adverse event reporting, (2) central predefined liver monitoring schedule with various thresholds for potential drug-induced liver injury, and (3) blinded adjudication of serious liver toxicity by a panel of experts in drug-induced liver injury. A single data monitoring committee provided safety oversight across all trials within the program. Findings: Prior to program termination, 7595 of 7602 (99.9%) randomized participants across the eight trials received at least one dose of the study drug (fasiglifam, placebo, or active control). No concerning trends were noted in adverse or serious adverse event frequency, suspected unexpected serious adverse reaction, alanine or aspartate transaminase elevations, or hepatobiliary or gastrointestinal adverse events as reported by local site investigators. However, the predefined central liver safety measurements revealed a greater frequency of possible Hy’s Law cases (5 vs 2) and a 3- to 7-fold greater relative risk in alanine or aspartate transaminase elevation (with respect to upper limit of normal) within fasiglifam recipients compared with placebo/active control: alanine or aspartate transaminase > 3×: relative risk 3.34 (95% confidence interval 2.29–4.90), alanine or aspartate transaminase > 5×: relative risk 6.60 (95% confidence interval 3.03–14.38), alanine or aspartate transaminase > 8×: relative risk 6.14 (95% confidence interval 2.18–17.27), and alanine or aspartate transaminase > 10×: relative risk 6.74 (95% confidence interval 2.05, 22.14). All elevations resolved on study drug discontinuation. Drug-induced liver injury was adjudicated as highly likely or probably related in 0.64% of fasiglifam-treated versus 0.06% placebo or active control-treated patients. Conclusion: In spite of clear liver toxicity detected with a systematic surveillance program, liver safety signals were not identified from investigator adverse event reporting alone. By integrating key safety monitoring processes within the randomized design of adequately sized clinical trials, the rare but serious liver toxicity signal became clear, leading to timely program termination.

Publication metadata

Author(s): Shavadia JS, Sharma A, Gu X, Neaton J, DeLeve L, Holmes D, Home P, Eckel RH, Watkins PB, Granger CB

Publication type: Article

Publication status: Published

Journal: Clinical Trials

Year: 2019

Volume: 16

Issue: 3

Pages: 253-262

Print publication date: 01/06/2019

Online publication date: 18/03/2019

Acceptance date: 02/04/2016

ISSN (print): 1740-7745

ISSN (electronic): 1740-7753

Publisher: Sage Publications Ltd


DOI: 10.1177/1740774519836766

PubMed id: 30880443


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