Supplementary materials: Indirect treatment comparison of lanadelumab and a C1-esterase inhibitor in pediatric patients with hereditary angioedema

<b>These are peer-reviewed supplementary materials for the article</b><b> </b><b>'</b><b>Indirect treatment comparison of </b><b>lanadelumab and a C1-esterase inhibitor in </b><b>pediatric patients with hereditary </b><b>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>Inverse probability weighting</b><b>Supplementary Table 1: </b>Eligibility criteria for the systematic literature review<b>Supplementary Table 2: </b>Baseline and prognostic factors of the SPRING and C1-INH studies as estimated per individual patient data<b>Supplementary Table 3: </b>Baseline and prognostic factors considered for ITC analyses SPRING vs. Aygören Pürsün before and after IPTW <b>Supplementary Table 4: </b>Trial design of the SPRING and C1-INH 2019 studies used for indirect treatment comparison analysis<b>Supplementary Figure 1: </b>Flow chart for the identification and selection of published sources for this indirect treatment comparison<b>References</b><b>Aim: </b>To compare the efficacy and safety of lanadelumab versus other approved long-term prophylaxis (LTP) treatments in patients with pediatric hereditary angioedema (HAE) aged &lt;12 years. <b>Materials &amp; </b><b>methods</b>: A systematic literature review was conducted to identify studies of LTP in patients with HAE aged &lt;12 years. Two studies met the inclusion criteria in an indirect treatment comparison of efficacy and safety data in pediatric HAE patients. These were for lanadelumab (SPRING, NCT04070326) and intravenous-C1-esterase inhibitor (C1-INH[IV], NCT02052141). A propensity score analysis used individual patient-level data from both studies in a logistic regression model to estimate inverse probability weights. To avoid convergence issues and an underpowered analysis due to the small sample size (n = 29), the base case was defined as Poisson regression analyses on monthly attack rate adjusting for one covariate (baseline attack rate). Model selection among unadjusted, adjusted and weighted regression models was conducted through the Akaike and Bayesian Information Criteria. <b>Results:</b> Lanadelumab 150 mg every 2 weeks (Q2W) reduced the monthly HAE attack rate by 82.1% versus C1-INH(IV) 1000 IU twice weekly (every 3–4 days [BIW]; rate ratio [RR], 0.1792 [95% CI: 0.0296–1.0853]) and by 88.9% versus C1-INH(IV) 500 IU BIW (RR: 0.1107 [95% CI: 0.0234–0.5239]). Treatment with lanadelumab Q2W reduced the risk of total adverse events by 56.2% versus C1-INH(IV) 1000 IU BIW (RR:0.4377 [95% CI: 0.1536–1.2469]) and by 66.0% versus C1-INH(IV) 500 IU BIW (RR: 0.3401 [95% CI: 0.1234–0.9371]). <b>Conclusion:</b> This exploratory analysis suggested a trend toward greater efficacy and fewer adverse events with lanadelumab 150 mg Q2W compared with C1-INH(IV) BIW 1000 IU and 500 IU in pediatric patients with HAE. Future studies could potentially assess larger samples over longer perio

**本材料为发表于《比较效果研究杂志》（*Journal of Comparative Effectiveness Research*）的论文《儿童遗传性血管性水肿（HAE）患者中拉那芦单抗（lanadelumab）与C1酯酶抑制剂（C1-esterase inhibitor）的间接治疗比较》的同行评议补充材料**。
逆概率加权（Inverse probability weighting）
**补充表1**：系统文献综述的合格标准
**补充表2**：基于个体患者数据估算的SPRING研究与C1-INH研究的基线及预后因素
**补充表3**：逆概率加权（IPTW）前后，用于间接治疗比较（ITC）分析的SPRING与Aygören Pürsün研究的基线及预后因素
**补充表4**：用于间接治疗比较分析的SPRING与2019年C1-INH研究的试验设计
**补充图1**：本间接治疗比较研究的公开文献识别与筛选流程图
**参考文献**
**研究目的**：对比拉那芦单抗与其他获批的长期预防性治疗（LTP）方案在年龄<12岁的儿童遗传性血管性水肿患者中的疗效与安全性。
**材料与方法**：本研究开展系统文献综述，以筛选年龄<12岁的HAE患者接受LTP治疗的相关研究。最终有两项研究符合儿科HAE患者疗效与安全性数据间接治疗比较的纳入标准，分别为拉那芦单抗相关的SPRING研究（临床试验注册号：NCT04070326）与静脉用C1酯酶抑制剂（C1-INH[IV]）相关研究（临床试验注册号：NCT02052141）。本研究采用倾向得分分析，基于两项研究的个体患者数据构建logistic回归模型以估算逆概率权重。考虑到样本量较小（n=29）可能导致收敛问题与检验效能不足，本研究的基础分析方案定义为：以基线发作率为协变量，对月度发作率进行泊松回归分析。通过赤池信息准则（AIC）与贝叶斯信息准则（BIC）在未校正、校正与加权回归模型中进行模型选择。
**结果**：与每周2次（每3~4天给药1次，BIW）的1000 IU静脉C1-INH治疗相比，每2周1次（Q2W）的150mg拉那芦单抗治疗可使HAE月度发作率降低82.1%（率比RR=0.1792，95%置信区间CI：0.0296~1.0853）；与每周2次的500 IU静脉C1-INH治疗相比，该方案可使HAE月度发作率降低88.9%（RR=0.1107，95%CI：0.0234~0.5239）。与1000 IU BIW静脉C1-INH治疗相比，Q2W的拉那芦单抗治疗可使总不良事件发生风险降低56.2%（RR=0.4377，95%CI：0.1536~1.2469）；与500 IU BIW静脉C1-INH治疗相比，该方案可使总不良事件发生风险降低66.0%（RR=0.3401，95%CI：0.1234~0.9371）。
**结论**：本探索性分析显示，在儿童HAE患者中，与1000 IU、500 IU BIW静脉C1-INH治疗相比，每2周1次150mg拉那芦单抗治疗呈现出更优的疗效与更少的不良事件趋势。未来可开展更大样本量、更长随访周期的研究以进一步验证上述结果。