Université Paris Descartes and Assistance Publique–Hôpitaux de Paris, Hôpital Necker, INSERM Unité 845, Paris, France.
N Engl J Med. 2013 Jun 6;368(23):2169-81. doi: 10.1056/NEJMoa1208981.
Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease.
We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2).
A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period.
Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).
非典型溶血性尿毒综合征是一种由补体介导的血栓性微血管病引起的遗传、危及生命的慢性疾病。血浆置换或输注可能会暂时维持血液学指标的正常水平，但不能治疗潜在的系统性疾病。
我们进行了两项前瞻性 2 期临床试验，纳入年龄在 12 岁及以上的非典型溶血性尿毒综合征患者，接受依库珠单抗治疗 26 周，并在长期扩展阶段接受治疗。试验 1 纳入血小板计数较低且有肾脏损伤的患者，试验 2 纳入在血浆置换或输注过程中血小板计数未下降超过 25%且至少持续 8 周的患者。主要终点包括血小板计数的变化（试验 1）和血栓性微血管病无事件状态（血小板计数无>25%的下降，无血浆置换或输注，且无开始透析）（试验 2）。
共有 37 例患者（试验 1 17 例，试验 2 20 例）分别接受依库珠单抗治疗 64 周和 62 周。依库珠单抗使血小板计数增加；在试验 1 中，从基线到第 26 周的平均计数增加了 73×10^9/L（P<0.001）。在试验 2 中，80%的患者血栓性微血管病无事件状态。依库珠单抗与所有次要终点的显著改善相关，肾小球滤过率（GFR）估计值呈持续、时间依赖性增加。在试验 1 中，5 例患者中有 4 例停止了透析。更早地使用依库珠单抗干预与 GFR 估计值的显著改善相关。依库珠单抗还改善了与健康相关的生活质量。在扩展期内，未观察到治疗累积毒性或严重感染相关不良事件，包括脑膜炎球菌感染。
依库珠单抗抑制补体介导的血栓性微血管病，与非典型溶血性尿毒综合征患者肾功能的显著、时间依赖性改善相关。（由 Alexion 制药公司资助；C08-002 临床试验.gov 编号，NCT00844545[成人]和 NCT00844844[青少年]；C08-003 临床试验.gov 编号，NCT00838513[成人]和 NCT00844428[青少年]）。
