Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials
Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials
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DOI：
10.1093/cid/ciaa016
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发表时间：
2020-10-01
影响因子：
11.8
通讯作者：
Boulware, David R.
中科院分区：
文献类型：
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作者：
Pullen, Matthew F.;Hullsiek, Katherine Huppler;Boulware, David R.
背景。在隐球菌性脑膜炎 2 期临床试验中，从脑脊液 (CSF) 中清除隐球菌的早期杀菌活性 (EFA) 被用作全因死亡率的替代终点。美国食品和药物管理局允许使用替代终点来加速监管审批，但全民教育作为替代终点需要进一步验证。我们研究了 18 周内脑脊液隐球菌清除率 (EFA) 与死亡率之间的关系。方法。我们汇集了 2010-2017 年期间进行的 3 项连续隐球菌性脑膜炎临床试验的个体水平 CSF 数据。所有 738 名受试者均接受两性霉素+氟康唑诱导治疗，并进行连续定量脑脊液培养。通过一般线性回归与前 10 天的培养天数来分析每 mL CSF 的 log(10) 转化菌落形成单位 (CFU)。结果。 EFA > = 0.60 (n = 170) 的死亡率为 37%，EFA 0.40-0.59 (n = 182) 的死亡率为 36%，0.30-0.39 (n = 112) 的死亡率为 39%，0.20-0.29 (n = 87) 的死亡率为 35%，EFA < 的死亡率为 50% 0.20 CFU/mL/天 (n = 187)。将 EFA < 0.20 的患者与 EFA > = 0.20 的患者进行比较，18 周死亡率的风险比为 1.60（95% 置信区间，1.25，2.04；P = .002）。 EFA 最低的组具有较低的中位 CD4 T 细胞计数 (P < .01) 和脑脊液细胞增多症患者比例较低 (P < .001)。结论。 EFA 与隐球菌性脑膜炎的全因死亡率相关。 EFA 阈值 > = 0.20 log(10) CFU/mL/天与相似的 18 周死亡率 (37%) 相关，而 EFA < 0.20 的死亡率为 50%。该 EFA 阈值可被视为替代终点的目标。这建立在现有研究的基础上，以验证全民教育作为替代终点。
Background. In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks.Methods. We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010-2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log(10)-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days.Results. Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40-0.59 (n = 182), 39% for 0.30-0.39 (n = 112), 35% for 0.20-0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001).Conclusions. EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log(10) CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.