Bozik Michael E, Mitsumoto Hiroshi, Brooks Benjamin R, Rudnicki Stacy A, Moore Dan H, Zhang Bing, Ludolph Albert, Cudkowicz Merit E, van den Berg Leonard H, Mather James, Petzinger Thomas, Archibald Donald
Knopp Biosciences LLC , Pittsburgh, Pennsylvania , USA.
Amyotroph Lateral Scler Frontotemporal Degener. 2014 Sep;15(5-6):406-13. doi: 10.3109/21678421.2014.943672. Epub 2014 Aug 15.
Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.
我们的目标是比较右普拉克索在肌萎缩侧索硬化症（ALS）中的II期和III期（EMPOWER）研究，并基于研究间显著的人群差异评估潜在的EMPOWER应答亚组和生物标志物。在一项事后分析中，我们比较了两项右普拉克索研究的基线人群特征，并分析了由研究间显著差异定义的亚组中的EMPOWER疗效结果和实验室指标。结果显示，与II期相比，EMPOWER研究中符合埃尔埃斯科里亚尔标准（EEC）确诊的参与者比例下降（p = 0.005），利鲁唑的使用增加（p = 0.002），且平均症状持续时间显著增加（p = 0.037）。在EMPOWER研究中，基线肌酐水平（p < 0.001）和研究期间肌酐变化（p < 0.001）与肌萎缩侧索硬化功能评定量表修订版（ALSFRS-R）显著相关。在由EEC确诊的ALS、利鲁唑使用情况和<中位数症状持续时间（15.3个月）定义的EMPOWER亚组中，接受右普拉克索治疗的参与者的ALSFRS-R斜率下降减少（p = 0.015），死亡率降低（p = 0.011），肌酐损失减少（p = 0.003）。总之，在右普拉克索治疗ALS的临床试验中，II期和EMPOWER研究人群之间存在显著差异。在对由这些差异定义的EMPOWER亚组进行的事后分析中，在接受利鲁唑治疗、症状持续时间短、EEC确诊的ALS参与者亚组中发现了右普拉克索潜在的临床益处。肌酐损失与疾病进展相关，且在接受右普拉克索治疗的参与者中减少，表明其为候选生物标志物。
