Abstract：
OBJECTIVE: This study aims to investigate the underexplored prevalence of placebo-reported immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) trials.
METHODS: We searched public databases for randomized clinical trials (RCTs) involving ICI versus placebo treatments in patients with malignancies. Study characteristics and irAEs occurrences were extracted for meta-analyses using a random-effects model.
RESULTS: Proportions of patients reported to experience any grade and grade 3 to 5 placebo irAEs; the risk ratio (RR) of reporting \'false\' irAEs in the experiment arm (defined as \'false-irAE ratio\', calculated by dividing the proportion of patients documented with irAEs in the placebo arm by that in the experimental arm).
RESULTS: 47 RCTs with 30,119 patients were analyzed. The pooled proportion of patients reported to experience any grade and grade 3 to 5 irAEs among placebo participants was 22.85 % (17.33 %-29.50 %) and 3.40 % (2.35 %-4.63 %), respectively. The pooled proportion of placebo-treated patients who experienced serious irAEs was 0.67 % (0.03 %-1.91 %). Treatment discontinuation and death due to placebo irAEs occurred in 0.69 % (<0.01 %-1.30 %) and 0.12 % (<0.01 %-0.40 %) of patients, respectively. The false-irAE ratio for any grade and grade 3 to 5 irAEs were 0.49 and 0.28. The false-irAE ratio was significantly higher in RCTs with control arms of placebo plus non-immunotherapy than in those with placebo alone (any grade: 0.57 vs. 0.32, P < 0.001; grade 3 to 5: 0.36 vs. 0.12, P = 0.009).
CONCLUSIONS: Our analyses of placebo-treated participants in ICI RCTs document the common occurrence of placebo irAEs. These findings are important for interpreting irAE profiles, avoiding inappropriate therapeutic interventions.
METHODS: We searched public databases for randomized clinical trials (RCTs) involving ICI versus placebo treatments in patients with malignancies. Study characteristics and irAEs occurrences were extracted for meta-analyses using a random-effects model.
RESULTS: Proportions of patients reported to experience any grade and grade 3 to 5 placebo irAEs; the risk ratio (RR) of reporting \'false\' irAEs in the experiment arm (defined as \'false-irAE ratio\', calculated by dividing the proportion of patients documented with irAEs in the placebo arm by that in the experimental arm).
RESULTS: 47 RCTs with 30,119 patients were analyzed. The pooled proportion of patients reported to experience any grade and grade 3 to 5 irAEs among placebo participants was 22.85 % (17.33 %-29.50 %) and 3.40 % (2.35 %-4.63 %), respectively. The pooled proportion of placebo-treated patients who experienced serious irAEs was 0.67 % (0.03 %-1.91 %). Treatment discontinuation and death due to placebo irAEs occurred in 0.69 % (<0.01 %-1.30 %) and 0.12 % (<0.01 %-0.40 %) of patients, respectively. The false-irAE ratio for any grade and grade 3 to 5 irAEs were 0.49 and 0.28. The false-irAE ratio was significantly higher in RCTs with control arms of placebo plus non-immunotherapy than in those with placebo alone (any grade: 0.57 vs. 0.32, P < 0.001; grade 3 to 5: 0.36 vs. 0.12, P = 0.009).
CONCLUSIONS: Our analyses of placebo-treated participants in ICI RCTs document the common occurrence of placebo irAEs. These findings are important for interpreting irAE profiles, avoiding inappropriate therapeutic interventions.
摘要：
目的：本研究旨在调查免疫检查点抑制剂（ICI）试验中安慰剂报告的免疫相关不良事件（irAE）的开发不足的发生率。
方法：我们在公共数据库中搜索了ICI与安慰剂治疗恶性肿瘤患者的随机临床试验（RCT）。使用随机效应模型提取研究特征和irAE发生情况进行荟萃分析。
结果：报告经历任何级别和3至5级安慰剂irAE的患者比例；在实验组中报告“假”irAE的风险比（RR）（定义为“假irAE比”，通过将安慰剂组中记录有irAE的患者比例除以实验组中的比例来计算）。
结果：分析了47例RCTs和30,119例患者。安慰剂参与者中报告经历任何级别和3至5级irAE的患者的合并比例为22.85％（17.33％-29.50％）和3.40％（2.35％-4.63％），分别。经历严重irAE的安慰剂治疗患者的合并比例为0.67％（0.03％-1.91％）。0.69％（<0.01％-1.30％）和0.12％（<0.01％-0.40％）的患者因安慰剂irAE而停止治疗和死亡，分别。任何级别和3至5级irAE的假irAE比率分别为0.49和0.28。安慰剂加非免疫疗法对照组的RCT中的假irAE比率明显高于单独使用安慰剂的RCT（任何等级：0.57vs.0.32，P<0.001；3至5级：0.36vs.0.12,P=0.009)。
结论：我们对ICI随机对照试验中安慰剂治疗参与者的分析记录了安慰剂不良反应的常见发生率。这些发现对于解释irAE概况很重要，避免不适当的治疗干预。
方法：我们在公共数据库中搜索了ICI与安慰剂治疗恶性肿瘤患者的随机临床试验（RCT）。使用随机效应模型提取研究特征和irAE发生情况进行荟萃分析。
结果：报告经历任何级别和3至5级安慰剂irAE的患者比例；在实验组中报告“假”irAE的风险比（RR）（定义为“假irAE比”，通过将安慰剂组中记录有irAE的患者比例除以实验组中的比例来计算）。
结果：分析了47例RCTs和30,119例患者。安慰剂参与者中报告经历任何级别和3至5级irAE的患者的合并比例为22.85％（17.33％-29.50％）和3.40％（2.35％-4.63％），分别。经历严重irAE的安慰剂治疗患者的合并比例为0.67％（0.03％-1.91％）。0.69％（<0.01％-1.30％）和0.12％（<0.01％-0.40％）的患者因安慰剂irAE而停止治疗和死亡，分别。任何级别和3至5级irAE的假irAE比率分别为0.49和0.28。安慰剂加非免疫疗法对照组的RCT中的假irAE比率明显高于单独使用安慰剂的RCT（任何等级：0.57vs.0.32，P<0.001；3至5级：0.36vs.0.12,P=0.009)。
结论：我们对ICI随机对照试验中安慰剂治疗参与者的分析记录了安慰剂不良反应的常见发生率。这些发现对于解释irAE概况很重要，避免不适当的治疗干预。
