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voxelotor治疗镰状细胞病的3期随机试验
A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease


Elliott Vichinsky ... 其他 • 2019.08.08
NEJM 动画解读

voxelotor治疗镰状细胞病

摘要


背景

脱氧镰刀状血红蛋白(HbS)的聚合驱动了镰状细胞病的病理生理学。因此,直接抑制HbS聚合具有改善疾病结局的潜力。voxelotor是一种HbS聚合抑制剂。

 

方法

在一项多中心、3期、双盲、随机、安慰剂对照试验中,我们在镰状细胞病患者中将两种剂量水平的voxelotor(1,500 mg和900 mg,每日1次口服给药)与安慰剂进行了疗效和安全性比较。主要终点是在意向治疗分析中,有血红蛋白应答的参与者百分比,血红蛋白应答的定义是第24周的血红蛋白相对于基线增加超过1.0 g/dL。

 

结果

我们以1∶1∶1的比例将274例参与者随机分组,分别接受1,500 mg voxelotor、900 mg voxelotor或安慰剂每日1次口服治疗。大多数参与者患镰状细胞贫血(纯合子血红蛋白S或血红蛋白Sβ0地中海贫血),基线时约2/3在接受羟基脲治疗。在意向治疗分析中,1,500 mg voxelotor组(51%;95%置信区间[CI],41~61)产生血红蛋白应答的参与者比例显著高于安慰剂组(7%;95% CI,1~12)。从基线至第24周,各voxelotor剂量组发生贫血恶化的参与者数量均少于安慰剂组。第24周时,1,500 mg voxelotor组的间接胆红素水平和网织红细胞百分比相对于基线的降幅显著超过安慰剂组。在各试验组之间,治疗期间发生不良事件或不良事件恶化的参与者百分比相似。1,500 mg voxelotor组26%的参与者、900 mg voxelotor组23%的参与者和安慰剂组26%的参与者发生了≥3级不良事件。研究者认为大多数不良事件与试验药物或安慰剂无关。

 

结论

在对镰状细胞病患者进行的这项3期随机、安慰剂对照试验中,voxelotor显著增加了血红蛋白水平,减少了溶血标志物。这些结果与抑制HbS聚合相符,voxelotor表现出改善疾病的潜力(由Global Blood Therapeutics资助;HOPE在ClinicalTrials.gov注册号为NCT03036813)。





作者信息

Elliott Vichinsky, M.D., Carolyn C. Hoppe, M.D., Kenneth I. Ataga, M.D., Russell E. Ware, M.D., Ph.D., Videlis Nduba, M.B., Ch.B., M.P.H., Amal El-Beshlawy, M.D., Hoda Hassab, M.D., Maureen M. Achebe, M.D., M.P.H., Salam Alkindi, M.B., B.Ch., R. Clark Brown, M.D., Ph.D., David L. Diuguid, M.D., Paul Telfer, M.D., Dimitris A. Tsitsikas, M.D., Ashraf Elghandour, M.D., Victor R. Gordeuk, M.D., Julie Kanter, M.D., Miguel R. Abboud, M.D., Joshua Lehrer-Graiwer, M.D., Margaret Tonda, Pharm.D., Allison Intondi, Ph.D., Barbara Tong, Ph.D., and Jo Howard, M.D. for the HOPE Trial Investigators*
From the University of California, San Francisco (UCSF) Benioff Children’s Hospital Oakland, Oakland (E.V.), and Global Blood Therapeutics, South San Francisco (C.C.H., J.L.-G., M.T., A.I., B.T.) — both in California; the University of Tennessee Health Science Center at Memphis, Memphis (K.I.A.); Cincinnati Children’s Hospital and University of Cincinnati, Cincinnati (R.E.W.); Kenya Medical Research Institute, Kisumu, Kenya (V.N.); Cairo University, Cairo (A.E.-B.), and the Pediatric Department and Clinical Research Center, Faculty of Medicine (H.H.), and the Faculty of Medicine (A.E.), Alexandria University, Alexandria — all in Egypt; Brigham and Women’s Hospital and Harvard Medical School, Boston (M.M.A.); Sultan Qaboos University, Muscat, Oman (S.A.); Emory University and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta (R.C.B.); New York–Presbyterian/Columbia University Medical Center, New York (D.L.D.); Barts Health NHS Trust (P.T.), Homerton University Hospital NHS Foundation Trust (D.A.T.), and Guy’s and St. Thomas’ NHS Foundation Trust and King’s College (J.H.) — all in London; the University of Illinois at Chicago, Chicago (V.R.G.); the University of Alabama at Birmingham, Birmingham (J.K.); and the American University of Beirut Medical Center, Beirut, Lebanon (M.R.A.). Address reprint requests to Dr. Vichinsky at the UCSF Benioff Children’s Hospital Oakland, 747 52nd St., Oakland, CA 94609, or at evichinsky@mail.cho.org. *A complete list of the investigators in the HOPE trial is provided in the Supplementary Appendix, available at NEJM.org.

 

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