Evaluation of patient-reported outcome measures for on-demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat

IF 4.6 2区 医学 Q2 ALLERGY Clinical and Translational Allergy Pub Date : 2023-09-04 DOI:10.1002/clt2.12288
Danny M. Cohn, Emel Aygören-Pürsün, Jonathan A. Bernstein, Henriette Farkas, William R. Lumry, Marcus Maurer, Andrea Zanichelli, Matthew Iverson, James Hao, Michael D. Smith, Christopher M. Yea, Paul K. Audhya, Marc A. Riedl
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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评估患者报告的按需治疗遗传性血管性水肿发作的结果指标,并设计KONFIDENT,一项皮脂四脂蛋白的3期试验。
背景:遗传性血管性水肿(HAE)伴C1抑制剂缺乏症(HAE-C1-INH)的特点是反复出现使人衰弱的肿胀。Sebetralstat是一种正在研究的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按需治疗的良好疗效。我们描述了为KONFIDENT的设计提供信息的多管齐下方法,这是一项3期随机、安慰剂对照、三方交叉试验,评估了Sebettralstat对年龄≥12岁的HAE-C1-INH患者的疗效和安全性。方法:为了确定衡量KONFIDENT症状缓解开始的最佳终点,我们对HAE患者进行了临床结果测量,随后对2期结果进行了分析。通过使用第2阶段数据的基于模拟的方法来确定样本量。结果:与其他指标相比,患者访谈显示(71%)强烈倾向于患者整体变化印象(PGI-C),并表示“稍微好一点”是一个具有临床意义的里程碑。在第2阶段,“稍微好一点”的评级与发作严重程度的改善和患者严重程度的整体印象的解决方案一致,并且具有比“更好”更好的敏感性。“模拟表明,84名完成治疗的患者将确保至少90%的能力来评估症状缓解开始时间的主要终点,定义为PGI-C评级至少为“稍微好一点”结论:患者反馈和2期数据支持PGI-C作为评估Sebettralstat的3期KONFIDENT试验的主要结果指标,该试验有可能成为HAE-C1-INH发作的第一种口服按需治疗。
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来源期刊
Clinical and Translational Allergy
Clinical and Translational Allergy Immunology and Microbiology-Immunology
CiteScore
7.50
自引率
4.50%
发文量
117
审稿时长
12 weeks
期刊介绍: Clinical and Translational Allergy, one of several journals in the portfolio of the European Academy of Allergy and Clinical Immunology, provides a platform for the dissemination of allergy research and reviews, as well as EAACI position papers, task force reports and guidelines, amongst an international scientific audience. Clinical and Translational Allergy accepts clinical and translational research in the following areas and other related topics: asthma, rhinitis, rhinosinusitis, drug hypersensitivity, allergic conjunctivitis, allergic skin diseases, atopic eczema, urticaria, angioedema, venom hypersensitivity, anaphylaxis, food allergy, immunotherapy, immune modulators and biologics, animal models of allergic disease, immune mechanisms, or any other topic related to allergic disease.
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