Oral deucrictibant for on-demand treatment of hereditary angioedema attacks (RAPIDe-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

Treatment relies on medications to prevent attacks and on-demand therapies for attack manifestations.

治疗依赖于预防发作的药物和针对发作表现的按需治疗。

Parenteral administration associated with most available on-demand therapies often leads to treatment being delayed or forgone.

与大多数现有即时治疗相关的静脉给药常常导致治疗延迟或被忽略。

Deucrictibant is an orally bioavailable bradykinin B2 receptor antagonist under development for prophylaxis and on-demand treatment of hereditary angioedema attacks.

Deucrictibant是一种口服生物利用度高的缓激肽B2受体拮抗剂，目前正在开发中，用于预防和即时治疗遗传性血管性水肿发作。

We aimed to investigate the efficacy and safety of deucrictibant for the on-demand treatment of hereditary angioedema attacks.

我们的目标是研究deucrictibant对于遗传性血管性水肿发作的即需治疗的有效性和安全性。

Methods

RAPIDe-1 was a double-blind, randomised, placebo-controlled, crossover, dose-ranging, phase 2 trial that recruited adults aged 18-75 years with hereditary angioedema type 1 or 2 from 38 sites (eg, university hospitals and accredited angioedema centres) across North America, Europe, and Israel.

RAPIDe-1是一项双盲、随机、安慰剂对照、交叉、剂量范围、2期试验，招募了18-75岁的成年患者，这些患者患有遗传性血管性水肿1型或2型，来自北美、欧洲和以色列的38个地点（例如大学医院和认证的血管性水肿中心）。

Participants were required to have experienced two or more attacks within the past 2 months or three or more attacks within the past 4 months before screening.

参与者在筛选前的过去2个月内经历了两次或更多次发作，或在过去4个月内经历了三次或更多次发作。

An interactive response technology system randomly assigned eligible patients (1:1:1) to receive a blinded dose of oral deucrictibant (immediate-release capsule) 10 mg, 20 mg, or 30 mg during an attack-free period to assess pharmacokinetics and safety in the part 1 of the study; and, subsequently, to receive a crossover treatment sequence of two administrations of the same deucrictibant dose (10 mg, 20 mg, or 30 mg) and one of placebo to treat three investigator-confirmed angioedema attacks in the part 2.

互动式响应技术系统随机将符合条件的患者（1:1:1）分配到在无发作期间接受口服deucrictibant（即刻释放胶囊）10 mg、20 mg或30 mg的盲测剂量，以评估研究第一部分的药代动力学和安全性；随后，接受两次相同剂量的deucrictibant（10 mg、20 mg或30 mg）和一次安慰剂的交叉治疗序列，以治疗三例研究者确认的血管性水肿发作，这是研究的第二部分。

Randomisation was stratified by whether the participant was willing to participate in full pharmacokinetic sampling.

随机分组根据参与者是否愿意参与完整的药物动力学采样进行了分层。

Participants, investigators, site personnel, and the sponsor were masked to treatment assignment and capsules of deucrictibant and placebo were identical. For each attack, patients self-administered the oral study drug within 3 h after at least one symptom (skin pain, skin swelling, or abdominal pain) reached a visual analog scale (VAS) individual score of 30 or more out of 100 and within 6 h from symptom onset.

参与者、研究者、现场人员和赞助商对治疗分配进行了掩蔽，且德库瑞西坦和安慰剂的胶囊是相同的。对于每次发作，患者在至少一种症状（皮肤疼痛、皮肤肿胀或腹痛）达到视觉模拟量表（VAS）个体评分30或更多（满分100）后3小时内，并在症状发作后6小时内自行服用口服研究药物。

The primary endpoint was change in the patient-reported composite VAS-3 score measuring severity of attack manifestations from before treatment to 4 h post-treatment and assessed in the modified intention-to-treatand per-protocol populations.

主要终点是患者报告的复合VAS-3评分的变化，该评分测量从治疗前到治疗后4小时攻击表现的严重程度，并在修改后的意向治疗和按方案的人群中进行评估。

Safety was assessed in all patients who received any dose of study drug.

所有接受研究药物任何剂量的患者都进行了安全性评估。

RAPIDe-1 is registered with ClinicalTrials.gov (NCT04618211) and is completed.

RAPIDe-1 已在 ClinicalTrials.gov 注册（NCT04618211），且研究已完成。

Results

Between Feb 3, 2021, and June 23, 2022, 89 patients were screened, of whom 74 were randomly assigned between Feb 23, 2021, and July 26, 2022.

2021年2月3日至2022年6月23日期间，共有89名患者接受了筛查，其中74名患者在2021年2月23日至2022年7月26日期间被随机分配。

For the primary analysis set, the median follow-up was 130·0 (IQR 92·5 to 212·5) days for the deucrictibant 10 mg group, 166·5 (80·0 to 275·0) days for the deucrictibant 20 mg group, and 172·0 (65·0 to 242·0) days for the deucrictibant 30 mg group.

主要分析集的中位随访时间对于10毫克组为130.0天（四分位数间距92.5至212.5天），对于20毫克组为166.5天（四分位数间距80.0至275.0天），对于30毫克组为172.0天（四分位数间距65.0至242.0天）。

The primary efficacy analysis included 147 attacks in 62 patients, of whom 42 (68%) were female and 60 (97%) were White.

主要疗效分析包括62名患者的147次发作，其中42名（68%）为女性，60名（97%）为白人。

Least squares mean differences of change in VAS-3 score between deucrictibant and placebo was -16·75 (95% CI -21·52 to -11·97) for 10 mg, -15·02 (-20·22 to -9·81; p<0·0001) for 20 mg, and -16·28 (-21·27 to -11·29; p<0·0001) for 30 mg.

deucrictibant 和安慰剂之间 VAS-3 评分变化的最小二乘平均差异为 10 mg 组的 -16.75 (95% 置信区间 -21.52 至 -11.97)，20 mg 组的 -15.02 (-20.22 至 -9.81; p<0.0001)，以及 30 mg 组的 -16.28 (-21.27 至 -11.29; p<0.0001)。

In part 1, all treatment-emergent adverse events were grades 1-2, with the most common in two or more patients being headache (two [8%] of 25) and nasopharyngitis (two [8%] of 25) in the deucrictibant 30 mg group.

在第1部分中，所有治疗后出现的不良事件为1-2级，其中两个或更多患者中最常见的为头痛（25名患者中的2名[8%]）和鼻咽炎（25名患者中的2名[8%]）出现在 deucrictibant 30 mg 组。

In part 2, no single treatment-emergent adverse eventwas reported by two or more patients in any treatment group.

在第二部分中，任何治疗组中没有两个或更多患者报告单一治疗后不良事件。

Most adverse events were considered unrelated to the study drug and there were no grade 3 or worse adverse events.

大多数不良事件被认为与研究药物无关，且没有3级或更严重的不良事件。

interpretation

Deucrictibant significantly reduced the severity of hereditary angioedema attacks compared with placebo; these results support continued investigation of antagonism of the bradykinin B2 receptor with an orally available agent as a potentially effective approach, with a safety profile similar to placebo, for on-demand treatment.

Deucrictibant与安慰剂相比显著减轻了遗传性血管性水肿发作的严重程度；这些结果支持继续研究口服药物拮抗缓激肽B2受体作为潜在有效的方法，其安全性与安慰剂相似，用于按需治疗。

funding

Pharvaris.

Pharvaris公司。