Supplementary materials: Matching-adjusted indirect comparison between garadacimab and lanadelumab for the long-term prophylactic treatment of patients with hereditary angioedema

<b>These are peer-reviewed supplementary materials for the article</b><b> </b><b>'</b><b>Matching-adjusted indirect comparison between garadacimab and lanadelumab for the long-term prophylactic treatment of patients with hereditary angioedema</b><b>'</b><b> </b><b>published in the</b><b> </b><b><i>Journal of Comparative Effectiveness Research</i></b><b>.</b><b>Appendix A </b><b>Systematic Literature Review Materials and Methods</b><b>A.1:</b> Search Strategy<b>A.2: </b>PICOS<b>A.3:</b> Sources Searched<b>A.4:</b> Included Studies<b>A.5:</b> Excluded Studies<b>A.6:</b> PRISMA<b>A.7: </b>Quality Assessment<b>Appendix B Feasibility Assessment </b><b>Supplementary Table 6:</b> Summary of Trial Characteristics<b>Supplementary Table 7: </b>Study Baseline Characteristics<b>Appendix C </b><b>Eligibility Criteria</b><b>Supplementary Table 8: </b>Comparison of Eligibility Criteria*<b>Appendix D Outcome Definitions</b><b>Supplementary Table 9:</b> Outcomes for MAIC Analysis and Definitions<b>Appendix E Ranking of Treatment Effect Modifiers</b><b>Supplementary Table 10:</b> Final Ranking of Treatment Effect Modifiers and Availability in the VANGUARD, Phase 2 Garadacimab Trial, and HELP<b>Appendix F Additional MAIC Methods</b>MAIC Method<b>Aim: </b>This study aimed to estimate the relative efficacy between garadacimab 200 mg once monthly (200 QM) and two dosing regimens of lanadelumab (300 mg once every 2 weeks [300 Q2W] and 300 mg once every 4 weeks [300 Q4W]) in adolescent/adult patients with hereditary angioedema (HAE) using matching-adjusted indirect comparisons (MAICs), in the absence of head-to-head randomized controlled trials. <b>Materials &amp; methods: </b>Individual patient data were available from the phase II (NCT03712228) and the phase III VANGUARD (NCT04656418) trials investigating garadacimab, and published summary level data from the phase III HELP trial investigating lanadelumab (NCT02586805). The primary outcome was time-normalized number of HAE attacks. Secondary efficacy outcomes included time-normalized number of HAE attacks requiring on-demand treatment, time-normalized number of moderate and/or severe HAE attacks, and proportion of attack-free patients. Quality of life (QoL) was also assessed via change from baseline in AE-QoL total score. <b>Results:</b> Compared with lanadelumab 300 Q2W, garadacimab 200 QM statistically significantly reduced number of moderate and/or severe HAE attacks (rate ratio [RR]; 95% confidence interval: 0.25; 0.07, 0.84) and improved AE-QoL score (mean difference: -17.38; - 33.67, -1.08). Compared with lanadelumab 300 Q4W, garadacimab 200 QM showed statistically significant improvements in all outcomes: HAE attacks (RR: 0.29; 0.13, 0.63), attacks requiring on-demand treatment (RR: 0.29; 0.13, 0.66), moderate and/or severe HAE attacks (RR: 0.15; 0.05, 0.49), proportion of attack free patients (hazard ratio: 3.25; 1.45, 7.29), and AE-QoL score (mean difference: -21.29; -37.39, - 5.18). <b>Conclusion:</b> These MAICs showed improved efficacy and QoL with garadacimab compared with lanadelumab across multiple endpoints. These findings demonstrate that garadacimab may provide improved therapeutic benefit compared with lanadelumab in the long-term prophylactic treatment of patients with HAE.

本文件为发表于《Journal of Comparative Effectiveness Research》（《比较效果研究杂志》）的论文《格拉达昔单抗（garadacimab）与拉那芦单抗（lanadelumab）用于遗传性血管性水肿（hereditary angioedema, HAE）患者长期预防性治疗的匹配调整间接比较》的同行评议补充材料。
附录A 系统综述材料与方法
A.1：检索策略
A.2：PICOS
A.3：检索来源
A.4：纳入研究
A.5：排除研究
A.6：PRISMA
A.7：质量评估
附录B 可行性评估
补充表6：试验特征汇总
补充表7：研究基线特征
附录C 入选标准
补充表8：入选标准对比*
附录D 结局指标定义
补充表9：匹配调整间接比较（Matching-adjusted indirect comparison, MAIC）分析所用结局指标及定义
附录E 治疗效应修饰因子排序
补充表10：治疗效应修饰因子最终排序及在Ⅱ期格拉达昔单抗试验VANGUARD与HELP试验中的可及性
附录F 补充匹配调整间接比较方法

匹配调整间接比较方法
研究目的：本研究旨在在缺乏头对头随机对照试验的情况下，采用匹配调整间接比较（MAIC），评估遗传性血管性水肿（HAE）青少年及成年患者中，每月一次200mg格拉达昔单抗（200 QM）与拉那芦单抗两种给药方案（每2周一次300mg[300 Q2W]、每4周一次300mg[300 Q4W]）的相对疗效。
材料与方法：本研究获取了格拉达昔单抗的Ⅱ期试验（NCT03712228）与Ⅲ期试验VANGUARD（NCT04656418）的个体患者数据，以及拉那芦单抗的Ⅲ期试验HELP（NCT02586805）的已发表汇总数据。本研究的主要结局指标为时间标准化HAE发作次数。次要疗效结局指标包括：需按需治疗的HAE发作次数时间标准化值、中重度及以上HAE发作次数时间标准化值，以及无发作患者比例。本研究还通过患者报告的AE-QoL总分较基线的变化评估了生活质量（Quality of Life, QoL）。
结果：与拉那芦单抗300 Q2W相比，格拉达昔单抗200 QM可显著降低中重度及以上HAE发作次数（速率比[RR]；95%置信区间：0.25；0.07, 0.84），并改善AE-QoL总分（均数差：-17.38；-33.67, -1.08）。与拉那芦单抗300 Q4W相比，格拉达昔单抗200 QM在所有结局指标上均展现出统计学显著改善：HAE发作次数（RR: 0.29; 0.13, 0.63）、需按需治疗的发作次数（RR: 0.29; 0.13, 0.66）、中重度及以上HAE发作次数（RR: 0.15; 0.05, 0.49）、无发作患者比例（风险比：3.25; 1.45, 7.29）以及AE-QoL总分（均数差：-21.29; -37.39, -5.18）。
结论：本项匹配调整间接比较结果显示，相较于拉那芦单抗，格拉达昔单抗在多项终点指标上均具备更优的疗效与生活质量改善效果。上述研究结果表明，在HAE患者的长期预防性治疗中，格拉达昔单抗或可提供优于拉那芦单抗的治疗获益。