Long-term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS.
Long-term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS.
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DOI：
10.1002/acn3.567
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发表时间：
2018-06
影响因子：
5.3
通讯作者：
Feldman EL
中科院分区：
文献类型：
--
作者：
Goutman SA;Brown MB;Glass JD;Boulis NM;Johe K;Hazel T;Cudkowicz M;Atassi N;Borges L;Patil PG;Sakowski SA;Feldman EL
椎管内人脊髓源性神经干细胞（HSSC）移植是肌萎缩侧索硬化症（ALS）的潜在治疗方法;然而，以前的试验缺乏对照。这项事后分析比较了I期和II期（Ph 1/2）开放标签脊柱内HSSC移植研究中移植后长达3年的非卧床肢体发作ALS受试者与合并资源开放获取ALS临床试验（PRO-ACT）和头孢曲松数据集中的匹配受试者，以提供所需的分析，为未来的临床试验设计提供信息。对匹配的受试者亚组的生存率、ALSFRS-R和结合生存率和ALS功能评定量表修订版（ALSFRS-R）功能状态的复合统计量（ALS/SURV）进行了评估：PRO-ACT n = 1108，Ph 1/2 n = 21和头孢曲松n = 177，Ph 1/2 n = 20。两个队列之间的生存期无显著差异：1/2期中位生存期为4.7年，95% CI（1.2，∞）vs PRO‐ACT为2.3年（1.9，2.5），P = 1.0; 1/2期为3.0年（1.2，5.6）vs头孢曲松为2.3年（1.8，2.8），P = 0.88。第1/2阶段和两个比较队列之间24个月时的平均ALSFRS-R存在显著差异（第1/2阶段30.1 ± 8.6 vs. PRO-ACT 24.0 ± 10.2，P = 0.048;第1/2阶段30.7 ± 8.8 vs.头孢曲松19.2 ± 9.5，P = 0.0023）。使用ALS/SURV，中位PRO‐ACT和头孢曲松受试者在24个月时死亡，而在PRO‐ACT和头孢曲松比较中，中位1/2期受试者ALSFRS‐ R在24个月时分别为23（P = 0.0038）和19（P = 0.14），支持1/2期研究中改善的功能结局。Ph 1/2研究与历史数据集的比较显示，使用ALS/SURV与PRO‐ACT对照相比，生存率和功能显著改善。虽然结果令人鼓舞，但与历史人群的比较显示了非对照研究的局限性。这些发现支持持续评价ALS患者的HSSC移植，支持对照人群的获益，并能够进行必要的把握度计算，以设计一项随机、假手术对照的疗效研究。
Intraspinal human spinal cord‐derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb‐onset ALS participants in Phase 1 and 2 (Ph1/2) open‐label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs. Survival, ALSFRS‐R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS‐R) functional status were assessed for matched participant subsets: PRO‐ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20. Survival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO‐ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS‐R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO‐ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO‐ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS‐Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO‐ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study. Comparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO‐ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery‐controlled efficacy study.
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影响因子：
15.8
作者：
Yan J;Xu L;Welsh AM;Hatfield G;Hazel T;Johe K;Koliatsos VE
通讯作者：
Koliatsos VE
影响因子：
3.7
作者：
Sims-Robinson C;Bakeman A;Bruno E;Jackson S;Glasser R;Murphy GG;Feldman EL
通讯作者：
Feldman EL
影响因子：
11.2
作者：
Chen KS;Sakowski SA;Feldman EL
通讯作者：
Feldman EL
影响因子：
6.2
作者：
Xu, Leyan;Yan, Jun;Koliatsos, Vassilis E.
通讯作者：
Koliatsos, Vassilis E.
影响因子：
9.9
作者：
Atassi, Nazem;Berry, James;Leitner, Melanie
通讯作者：
Leitner, Melanie