Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial
Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial
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DOI：
10.1016/s1473-3099(11)70024-x
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发表时间：
2011-04-01
影响因子：
56.3
通讯作者：
Boeckh, Michael
中科院分区：
文献类型：
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作者：
Marty, Francisco M.;Ljungman, Per;Boeckh, Michael
背景现有的抗巨细胞病毒药物有不良反应，影响其在异基因干细胞移植受者中的预防性使用。我们评估了口服Maribavir在此类患者中的安全性、耐受性和抗病毒活性。方法在这项安慰剂对照、随机、双盲、多中心III期研究中，我们招募了接受者血清阳性或供体血清阳性的成年患者巨细胞病毒接受过异基因干细胞移植。从加拿大、欧洲和美国的90个中心招募患者。植入后，按接受者巨细胞病毒血清状态和预处理方案（清髓性或降低强度）对患者进行分层，并通过设盲的计算机生成的随机化序列分配（2：1）接受Maribavir 100 mg每日两次或安慰剂治疗长达12周，每周进行一次血巨细胞病毒监测。如果检测到病毒，则停止研究药物给药并开始先发制人的抗巨细胞病毒治疗。主要终点是移植后6个月内的巨细胞病毒病。本研究注册于ClinicalTrials.gov，NCT 00411645。结果在2006年12月至2008年5月期间，681例患者入组并分配接受Maribavir（454例）或安慰剂（227例）。Maribavir组6个月内巨细胞病毒疾病的发生率为20/454（4%），安慰剂组为11/227（5%）（OR 0.90; 95% CI 0.42-1.92）。在移植后100天内，Maribavir组中通过pp 65抗原血症测量的巨细胞病毒感染率较低（26.4%）比安慰剂组（34.8%; OR 0.67; 0.47-0-95），但血浆巨细胞病毒DNA PCR检测时则无（27- 8%vs30.4%，OR0.88; 0.62-1.25），也不受抗巨细胞病毒治疗的影响（30.6%vs37.4%，OR0.73，0.52 -1.03）。Maribavir耐受性良好：除了味觉障碍（Maribavir组15%，安慰剂组6%）外，大多数不良事件（包括急性移植物抗宿主病和中性粒细胞减少症）对两组的影响相同。解释与安慰剂相比，Maribavir预防在移植后开始时不能预防巨细胞病毒病。巨细胞病毒疾病作为主要终点可能不足以显示在预防性抗病毒治疗的背景下，异基因干细胞移植受者中巨细胞病毒预防的改善。临床和病毒学复合终点应在未来的试验中使用。
Background Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients.Methods In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645.Findings Between December, 2006, and May, 2008,681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0.90; 95% CI 0.42-1.92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26.4%) than in the placebo group (34.8%; OR 0.67; 0.47-0-95), but not when measured by plasma cytomegalovirus DNA PCR (27-8% vs 30.4%; OR 0.88; 0.62-1.25), nor by initiation of treatment against cytomegalovirus (30.6% vs 37.4%; OR 0.73,0.52-1.03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo).Interpretation Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials.