Claude Bernard Lyon 1 University, Lyon, France.
University of the Witwatersrand and NHLS, Johannesburg, South Africa.
Lancet Haematol. 2023 Mar;10(3):e168-e177. doi: 10.1016/S2352-3026(22)00377-5. Epub 2023 Jan 27.
Clinical trial data are scarce for the use of prophylaxis in people with non-severe haemophilia A. The HAVEN 6 study aims to assess safety and efficacy of emicizumab prophylaxis in people with non-severe haemophilia A without factor VIII (FVIII) inhibitors.
HAVEN 6 is a multicentre, open-label, single-arm, phase 3 study taking place in 22 specialty clinics and hospitals in Europe, North America, and South Africa. Eligible participants were people of all ages weighing at least 3 kg with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) haemophilia A without FVIII inhibitors requiring prophylaxis as assessed by the treating physician. Participants received subcutaneous emicizumab 3 mg/kg of bodyweight once weekly for 4 weeks, followed by the participant's choice of maintenance dose: 1·5 mg/kg once weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. Safety was the primary objective of the study. Safety endpoints included adverse events, serious adverse events, and adverse events of special interest including thromboembolic events and thrombotic microangiopathies. The primary efficacy endpoint was the annualised bleed rate for treated bleeds. Analyses were done for participants who received at least one dose of emicizumab. This study is registered with ClinicalTrials.gov, number NCT04158648, and is active but not recruiting.
Between Feb 10, 2020, and Aug 31, 2021, we assigned 73 people to treatment. 72 participants received at least one dose of emicizumab (51 moderate [71%]; 21 mild [29%]; 69 male [96%]; three female [4%]; and 61 White [85%]). Median age was 23·5 years (IQR 12·0-36·0); median follow-up was 55·6 weeks (IQR 52·3-61·6) weeks. At baseline, 24 participants (33%) had target joints and 37 (51%) were receiving FVIII prophylaxis. 60 participants (83%) had at least one adverse event; the most common adverse events were headache (in 12 participants [17%]), injection-site reaction (12 [17%]), and arthralgia (11 [15%]). 15 (21%) had at least one emicizumab-related adverse event; no adverse events led to treatment withdrawal, modification, or interruption. Eight participants (11%) reported ten serious adverse events in total, none emicizumab-related. There were no deaths or thrombotic microangiopathies. One participant had grade 1 thrombosed haemorrhoids (classified as a thromboembolic event), unrelated to emicizumab. The annualised bleed rate was 0·9 (95% CI 0·55-1·52) for treated bleeds. 48 participants (67%) had no treated bleeds. All-bleed annualised bleed rates were 10·1 (95% CI 6·93-14·76) from 24 weeks pre-study and 2·3 (1·67-3·12) on-study after a median follow-up of 55·6 weeks.
These data show efficacy and a favourable safety profile of emicizumab in people with non-severe haemophilia A without FVIII inhibitors who warrant prophylaxis, confirming emicizumab as a valuable treatment option in this population.
F Hoffmann-La Roche.
在非重度血友病 A 患者中，预防使用的临床研究数据稀缺。HAVEN 6 研究旨在评估emicizumab 在无因子 VIII（FVIII）抑制剂的非重度血友病 A 人群中的预防安全性和疗效。
HAVEN 6 是一项多中心、开放标签、单臂、3 期研究，在欧洲、北美和南非的 22 个专业诊所和医院进行。符合条件的参与者为所有年龄的人群，体重至少 3kg，诊断为中度（FVIII 活性≥1%-≤5%）或轻度（FVIII >5%-<40%）血友病 A，且根据治疗医生的评估需要预防治疗。参与者接受皮下emicizumab 3mg/kg 体重，每周 1 次，连续 4 周，随后根据参与者的选择维持剂量：每周 1.5mg/kg、每 2 周 3mg/kg 或每 4 周 6mg/kg。安全性是该研究的主要目标。安全性终点包括不良事件、严重不良事件和特别关注的不良事件，包括血栓栓塞事件和血栓性微血管病。主要疗效终点是治疗性出血的年出血率。对至少接受 1 剂 emicizumab 的参与者进行分析。该研究在 ClinicalTrials.gov 上注册，编号为 NCT04158648，目前处于活跃状态但不招募。
2020 年 2 月 10 日至 2021 年 8 月 31 日，我们将 73 人分配至治疗组。72 名参与者至少接受 1 剂 emicizumab（51 例中度[71%]；21 例轻度[29%]；69 名男性[96%]；3 名女性[4%]；61 名白人[85%]）。中位年龄为 23.5 岁（IQR 12.0-36.0）；中位随访时间为 55.6 周（IQR 52.3-61.6）周。基线时，24 名参与者（33%）有目标关节，37 名参与者（51%）正在接受 FVIII 预防治疗。60 名参与者（83%）至少有 1 次不良事件；最常见的不良事件是头痛（12 名参与者[17%]）、注射部位反应（12 名参与者[17%]）和关节痛（11 名参与者[15%]）。15 名参与者（21%）有至少 1 次与 emicizumab 相关的不良事件；没有不良事件导致治疗停止、改变或中断。8 名参与者（11%）总共报告了 10 例严重不良事件，均与 emicizumab 无关。没有死亡或血栓性微血管病。1 名参与者有 1 级血栓性痔（归类为血栓栓塞事件），与 emicizumab 无关。治疗性出血的年化出血率为 0.9（95%CI 0.55-1.52）。48 名参与者（67%）无治疗性出血。所有出血的年化出血率在研究前 24 周为 10.1（95%CI 6.93-14.76），在中位随访 55.6 周后的研究期间为 2.3（1.67-3.12）。
这些数据表明，emicizumab 在无 FVIII 抑制剂的非重度血友病 A 患者中预防使用具有疗效和良好的安全性，证实 emicizumab 是该人群中一种有价值的治疗选择。
F Hoffmann-La Roche。
