1 Duke Clinical Research Institute, Durham, NC, USA.
2 Division of Cardiology, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Clin Trials. 2019 Jun;16(3):253-262. doi: 10.1177/1740774519836766. Epub 2019 Mar 18.
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.
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.
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.
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.
不同的安全事件收集方法会影响药物开发项目中肝毒性的确定。本文介绍了法西他滨诱导肝损伤的检测方法。
该八项临床试验药物开发计划旨在评估法西他滨（25mg、50mg）与安慰剂或阳性对照物（格列美脲、西他列汀）在大约 11000 名 2 型糖尿病患者（因肝毒性于 2013 年 12 月终止）中的疗效。肝安全性已预先确定为关注重点，在 3 期试验中，通过（1）不良事件报告、（2）中央预设的肝脏监测计划以及潜在药物性肝损伤的各种阈值、（3）药物性肝损伤专家小组对严重肝毒性的盲法裁决来测量。一个单一的数据监测委员会为计划内的所有试验提供安全性监督。
在计划终止前，八项试验中的 7602 名随机参与者（7595 名）中的 7595 名（99.9%）接受了至少一剂研究药物（法西他滨、安慰剂或阳性对照物）。地方站点调查员报告的不良或严重不良事件频率、可疑意外严重不良事件、丙氨酸或天冬氨酸转氨酶升高或肝胆或胃肠道不良事件无令人担忧的趋势。然而，中央肝脏安全性测量显示，法西他滨组可能发生 Hy's 法则的病例（5 例与 2 例）更多，与安慰剂/阳性对照物相比，丙氨酸或天冬氨酸转氨酶升高（相对于正常上限）的相对风险增加 3-7 倍：丙氨酸或天冬氨酸转氨酶>3×：相对风险 3.34（95%置信区间 2.29-4.90），丙氨酸或天冬氨酸转氨酶>5×：相对风险 6.60（95%置信区间 3.03-14.38），丙氨酸或天冬氨酸转氨酶>8×：相对风险 6.14（95%置信区间 2.18-17.27），丙氨酸或天冬氨酸转氨酶>10×：相对风险 6.74（95%置信区间 2.05-22.14）。所有升高均在停药后恢复正常。药物性肝损伤的裁决在 0.64%的法西他滨治疗患者中为高度可能或可能相关，在 0.06%的安慰剂或阳性对照物治疗患者中为低度可能或可能不相关。
尽管通过系统监测计划明确检测到肝毒性，但仅通过调查员不良事件报告无法识别肝安全性信号。通过将关键安全性监测流程整合到充分大小的临床试验的随机设计中，罕见但严重的肝毒性信号变得清晰，从而及时终止了该计划。
