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Clinical Trial
. 2024 Feb 1;81(2):154-162.
doi: 10.1001/jamaneurol.2023.5200.

Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial

Kiyohiro Houkin  1 , Toshiya Osanai  2 , Shinichiro Uchiyama  3   4 , Kazuo Minematsu  5 , Akihiko Taguchi  6 , Katsuhiko Maruichi  7 , Yoshimasa Niiya  8 , Katsuyuki Asaoka  9 , Yoshihiro Kuga  10 , Katsumi Takizawa  11 , Koichi Haraguchi  12 , Shinichi Yoshimura  13 , Kazumi Kimura  14 , Koji Tokunaga  15 , Atsuo Aoyama  16 , Fusao Ikawa  17 , Chikanori Inenaga  18 , Tatsuya Abe  19 , Atsushi Tominaga  20 , Shinichi Takahashi  21 , Kohsuke Kudo  22 , Miki Fujimura  2 , Taku Sugiyama  2 , Masaki Ito  2 , Masahito Kawabori  2 , David C Hess  23 , Sean I Savitz  24 , Teruyuki Hirano  25 ; TREASURE Study Investigators
Collaborators, Affiliations
Clinical Trial

Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial

Kiyohiro Houkin et al. JAMA Neurol. .

Abstract

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke.

Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset.

Design, setting, and participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022.

Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset.

Main outcomes and measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test.

Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups.

Conclusions and relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study.

Trial registration: ClinicalTrials.gov Identifier: NCT02961504.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Houkin reported receiving personal fees from Healios KK during the conduct of the study and from Bayer Yakuhin, Idorsia Japan, and Daiichi Sankyo Co Ltd outside the submitted work. Dr Osanai reported receiving meeting and travel support from Healios KK outside the submitted work. Dr Uchiyama reported receiving personal fees from Healios KK during the conduct of the study and from Bayer and Boehringer Ingelheim outside the submitted work. Dr Minematsu reported receiving personal fees from Healios KK during the conduct of the study and lecture fees from Pfizer, Bristol Myers Squibb, Takeda, Bayer Yakuhin, Daiichi Sankyo Co Ltd, and Nippon Chemiphar outside the submitted work. Dr Hess reported receiving personal fees from Athersys Inc for advisory board service during the conduct of the study. In addition, Dr Hess reported holding a patent for multipotent progenitor cells in neurological disease with Augusta University and Athersys Inc, with royalties paid from St Marys on the Hill. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Profile
aOther indicates that the participant became a welfare recipient during the study and withdrew prematurely because the hospital policy prohibits welfare recipients from participating in clinical trials.
Figure 2.
Figure 2.. Distribution of Modified Rankin Scale Score on Days 90 and 365
A and B, Modified Rankin Scale scores on days 90 (A) and 365 (B). Scores range from 0 to 6, with 0 indicating no symptoms; 1, symptoms without clinical disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death. Imputation was performed by last postrandomization primary efficacy assessment carried forward.
Figure 3.
Figure 3.. Subgroup Analyses of Modified Rankin Scale Score Scores of 0 to 2 at Day 90 Stratified by Age and Ischemic Core Volume
Risk differences and corresponding 2-sided 95% CIs in the MultiStem and placebo groups adjusted using the same factors in the Cochran-Mantel-Haenszel (CMH) test were calculated using the Mantel-Haenszel method by Sato T. aTreatments were compared after categorizing patients by age at baseline using the CMH test adjusted for baseline National Institutes of Health Stroke Scale (NIHSS) score (≤12 or ≥13) and receipt of concomitant reperfusion therapy (yes or no). There were 97 patients in the MultiStem group and 95 in the placebo group. bTreatments were compared after stratifying patients by diffusion-weighted imaging (DWI) ischemic core volume at baseline using the CMH test adjusted for baseline NIHSS score (≤12 or ≥13), receipt of concomitant reperfusion therapy (yes or no), and age (20-74 or ≥75 years) There were 94 patients in the MultiStem group and 91 in the placebo group.
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