Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 May 2;5(6):730-740.
doi: 10.1002/acn3.567. eCollection 2018 Jun.

Long-term Phase 1/2 Intraspinal Stem Cell Transplantation Outcomes in ALS

Affiliations
Free PMC article

Long-term Phase 1/2 Intraspinal Stem Cell Transplantation Outcomes in ALS

Stephen A Goutman et al. Ann Clin Transl Neurol. .
Free PMC article

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Interpretation: 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.

Figures

Figure 1
Figure 1
Kaplan–Meier survival curves. (A) Matched PROACT (n = 1108) versus Ph1/2 (n = 21) participants: during follow‐up, 239 deaths were observed in the PROACT group, 11 in the Ph1/2 group (Wilcoxon P = 0.996, log‐rank 0.203). (B) Matched ceftriaxone (n = 177) versus Ph1/2 (n = 20) participants: during follow‐up, 84 deaths were observed in the ceftriaxone group, 11 in the Ph1/2 group (Wilcoxon P = 0.877, log‐rank 0.297). PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials.
Figure 2
Figure 2
ALS/SURV outcomes for matched Ph1/2 versus PRO‐ACT and ceftriaxone cohorts: ALS/SURV outcomes are plotted by time. Each marker represents the median measure (from Table 2). The bars encompass the 25th and 75th percentile. Values above the horizontal line reflect ALSFRS‐R whereas values below reflect survival. Graphs represent absolute measures for Ph1/2 versus PRO‐ACT without losses to follow‐up (A) or with losses to follow‐up (B), and absolute measures for Ph1/2 versus ceftriaxone without losses to follow‐up (C) or with losses to follow‐up (D). For the Ph1/2 cohort, the lower quartile limit fell between a subject who was alive and a subject who had died; therefore, no value could be estimated (open circle/†; B and D). ALS, amyotrophic lateral sclerosis; ALSFRS‐R, ALS Functional Rating Scale revised; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials.

Similar articles

See all similar articles

Cited by 9 articles

See all "Cited by" articles

References

    1. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688–1700. - PubMed
    1. Lunn JS, Sakowski SA, Hur J, Feldman EL. Stem cell technology for neurodegenerative diseases. Ann Neurol 2011;70:353–361. - PMC - PubMed
    1. Chen KS, Sakowski SA, Feldman EL. Intraspinal stem cell transplantation for amyotrophic lateral sclerosis. Ann Neurol 2016;79:342–353. - PMC - PubMed
    1. Goutman SA, Chen KS, Feldman EL. Recent advances and the future of stem cell therapies in amyotrophic lateral sclerosis. Neurotherapeutics 2015;12:428–448. - PMC - PubMed
    1. Hefferan MP, Galik J, Kakinohana O, et al. Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation. PLoS One 2012;7:e42614. - PMC - PubMed

Grant support

This work was funded by National Institute of Neurological Disorders and Stroke grant 1R01NS077982; ALS Association, Neuralstem, Inc. grant ; A. Alfred Taubman Medical Research Institute grant ; philanthropic sources grant .
Feedback