Journal article
Multicenter SPAN Trial of Fasudil in Ischemic Stroke
Stroke (1970), Vol.56(8), pp.2306-2317
08/2025
DOI: 10.1161/STROKEAHA.125.050977
PMCID: PMC12407252
PMID: 40421536
Abstract
The SPAN (Stroke Preclinical Assessment Network) is a confirmatory multicenter trial network to test cerebroprotective interventions in experimental acute stroke. In a first-of-its-kind trial, SPAN tested 6 interventions in a rodent model of transient focal ischemic stroke. Here, we report the efficacy of fasudil, an isoform-nonselective rho-associated kinase inhibitor, on primary and secondary outcomes in the SPAN trial.
Fasudil was administered at 10 mg/kg intraperitoneally every 12 hours for 6 doses starting 5 minutes before reperfusion in a 60-minute endovascular filament middle cerebral artery occlusion model. The active treatment arm (n=345) was compared with the pooled intraperitoneal and intravenous vehicle arms (n=344). In addition to healthy young mice, the trial included aging mice (16±1 months), diet-induced obese mice, and spontaneously hypertensive rats. The a priori fasudil substudy design stipulated the modified corner test performance on day 28 as the primary end point and separate analyses for mice and spontaneously hypertensive rats using the modified intention-to-treat cohort.
Fasudil improved the primary outcome end point in mice (probabilistic index point estimate, 0.57;
=0.022). The effect appeared stronger in aging mice and when ischemia was induced during the active circadian stage. Fasudil did not show any benefit in the spontaneously hypertensive rats. Alternative analyses using the per-protocol population and imputation generally yielded similar conclusions.
Our results reveal a favorable therapeutic profile for fasudil, supporting future translational development of rho-associated kinase inhibitors in ischemic stroke.
Details
- Title: Subtitle
- Multicenter SPAN Trial of Fasudil in Ischemic Stroke
- Creators
- Takahiko Imai - Massachusetts General HospitalAndreia Lopes de Morais - Harvard Medical SchoolXuyan Jin - Massachusetts General HospitalTao Qin - Massachusetts General HospitalJessica Lamb - Department of Neurology, Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA (J.L., K.N., P.D.L.)Karisma Nagarkatti - Department of Neurology, Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA (J.L., K.N., P.D.L.)Mu-Hsun Chen - Icahn School of Medicine at Mount SinaiLigia S B Boisserand - Yale UniversityRakesh B Patel - University of IowaMariia Kumskova - University of IowaAnjali Chauhan - The University of Texas Health Science Center at HoustonKrishnan M Dhandapani - Augusta UniversityMohammad B Khan - Augusta UniversityPradip K Kamat - Augusta UniversityYanrong Shi - Johns Hopkins MedicineSuyi Cao - Johns Hopkins UniversityBasavaraju G Sanganahalli - Yale UniversityJoseph B Mandeville - Massachusetts General HospitalPatrick D Lyden - Department of Neurology, Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA (J.L., K.N., P.D.L.)David C Hess - Augusta UniversityEnrique C Leira - University of IowaAnil K Chauhan - University of IowaJaroslaw Aronowski - The University of Texas Health Science Center at HoustonLouise D McCullough - The University of Texas Health Science Center at HoustonRaymond Koehler - Johns Hopkins MedicineLauren H Sansing - Yale UniversityMárcio A Diniz - Icahn School of Medicine at Mount SinaiCenk Ayata - Massachusetts General HospitalStroke Preclinical Assessment Network (SPAN) Investigators
- Resource Type
- Journal article
- Publication Details
- Stroke (1970), Vol.56(8), pp.2306-2317
- DOI
- 10.1161/STROKEAHA.125.050977
- PMID
- 40421536
- PMCID
- PMC12407252
- NLM abbreviation
- Stroke
- ISSN
- 0039-2499
- eISSN
- 1524-4628
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS; PHILADELPHIA
- Grant note
- National Institutes of Health: U01NS113388, R35HL139926 University of Southern California: U24NS113452 Yale University School of Medicine: U01NS113445 Johns Hopkins University: U01NS113444, R01NS102583, R01NS105894 Augusta University: R01NS099455, U01NS113356, R01NS112511 Massachusetts General Hospital: U01NS113443, U01NS130588 University of Texas: U01NS113451
Supported by National Institutes of Health funding to the University of Iowa (U01NS113388 and R35HL139926 to Dr Chauhan and U01NS113388 to Dr Leira), the University of Southern California (U24NS113452 to Dr Lyden), the Yale University School of Medicine (U01NS113445 to Dr Sansing), the Johns Hopkins University (U01NS113444, R01NS102583, and R01NS105894 to Dr Koehler), the Augusta University (R01NS099455, U01NS113356, and R01NS112511 to Dr Hess), the Massachusetts General Hospital (U01NS113443 and U01NS130588 to Dr Ayata), and the University of Texas (U01NS113451 to Dr McCullough and Dr Aronowski).
- Language
- English
- Electronic publication date
- 05/27/2025
- Date published
- 08/2025
- Academic Unit
- Neurology; Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
- Record Identifier
- 9984825534302771
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