我们调查了mavorixafor的疗效和安全性,用于疣患者的口服CXCR4拮抗剂,低丙种球蛋白血症,感染,和髓核(WHIM)综合征,由CXCR4功能获得变体引起的罕见免疫缺陷。这个随机(1:1),双盲,安慰剂对照,3期试验纳入年龄≥12岁且中性粒细胞绝对计数(ANC)≤400/μL的WHIM综合征参与者.参与者每天接受一次mavorixafor或安慰剂,持续52周。主要终点是超过ANC阈值≥500/μL的时间(小时)(TATANC;超过24小时)。次要终点包括TAT绝对淋巴细胞计数≥1000/μL(TATALC;定义类似于TATANC);白细胞(WBC)的绝对变化,ANC,和ALC从基线;年度感染率;感染持续时间和总感染评分(合并感染数量/严重程度)。在31名参与者中(mavorixafor,n=14;安慰剂,n=17),最小二乘(LS)平均TATANC为15.0小时,安慰剂2.8小时(P<0.001)。MavorixaforLS平均TATALC为15.8小时,安慰剂4.6小时(P<0.001)。绝对白细胞较高,ANC,在评估的每个时间点,使用mavorixafor比安慰剂观察到ALC水平。与安慰剂相比,mavorixafor的年化感染率降低了60%(LS均值为1.7比4.2;名义P=0.007),总感染评分降低了40%(7.4[95%CI,1.6-13.2]比12.3[95%CI,7.2-17.3])。用mavorixa治疗减少感染频率,严重程度,持续时间,抗生素的使用。没有因治疗引起的不良事件(TEAE)而停药;没有观察到相关的严重TEAE。总的来说,mavorixafor治疗的参与者显示LS平均TATANC和TATALC显着增加,减少感染频率,严重性/持续时间。Mavorixafor在WHIM综合征患者中耐受性良好。试验在ClinicalTrials.govNCT03995108注册。
UNASSIGNED: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with
warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3
trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/μL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/μL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/μL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The
trial was registered at www.clinicaltrials.gov as #NCT03995108.