Cohn Danny M, Aygören-Pürsün Emel, Bernstein Jonathan A, Farkas Henriette, Lumry William R, Maurer Marcus, Zanichelli Andrea, Iverson Matthew, Hao James, Smith Michael D, Yea Christopher M, Audhya Paul K, Riedl Marc A
Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany.
Clin Transl Allergy. 2023 Sep;13(9):e12288. doi: 10.1002/clt2.12288.
Hereditary angioedema (HAE) with C1-inhibitor deficiency (HAE-C1-INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on-demand treatment of HAE-C1-INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo-controlled, three-way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE-C1-INH.
To determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation-based approach using phase 2 data.
Patient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI-C) over other measures and indicated a rating of "A Little Better" as a clinically meaningful milestone. In phase 2, a rating of "A Little Better" demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than "Better." Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI-C rating of at least "A Little Better" for two time points in a row.
Patient feedback and phase 2 data support PGI-C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on-demand treatment for HAE-C1-INH attacks.
伴有C1抑制剂缺乏的遗传性血管性水肿（HAE-C1-INH）的特征是反复出现使人衰弱的肿胀发作。塞贝司他是一种口服血浆激肽释放酶抑制剂，在一项2期试验中显示出对HAE-C1-INH进行按需治疗的有前景的疗效。我们描述了为KONFIDENT试验设计提供信息的多方面方法，这是一项3期随机、安慰剂对照、三向交叉试验，评估塞贝司他在≥12岁的HAE-C1-INH患者中的疗效和安全性。
为了确定在KONFIDENT试验中测量症状缓解开始的最佳终点，我们让HAE患者参与临床结局测量，随后对2期结果进行分析。样本量通过使用2期数据的基于模拟的方法确定。
患者访谈显示，与其他测量方法相比，患者对患者整体变化印象（PGI-C）有强烈偏好（71%），并表明“稍有好转”的评分是一个具有临床意义的里程碑。在2期试验中，“稍有好转”的评分与发作严重程度的改善以及患者整体严重程度印象上的症状缓解相一致，并且比“好转”具有更高的敏感性。模拟表明，84名完成治疗的患者将确保至少90%的检验效能，以评估症状缓解开始时间的主要终点，该终点定义为连续两个时间点PGI-C评分至少为“稍有好转”。
患者反馈和2期数据支持将PGI-C作为3期KONFIDENT试验中评估塞贝司他的主要结局指标，塞贝司他有可能成为首个用于HAE-C1-INH发作的口服按需治疗药物。
