Abstract TMP115: Technical Feasibility and Protocol Compliance in the Second Stroke Pre-Clinical Assessment Network
Authors: Lyden Patrick , Johnson Jenny , Unger Evan , Hagg Theo , van Leyen Klaus , Alkayed Nabil , Goforth Robyn , Diniz Marcio , Lynch Kirsten , Bedirian Karni , Lamb Jessica , Nagarkatti Karisma , Hu Bingren , Olivas Garcia Yamileck , Chen Yingxin , Liu Chunli , Sheng Huaxin , zhang shasha , Wang Haichen , Austin Wyatt , Flores Cynthia , Yang Wei , Hess David , Khan Mohammad B. , Kamat Pradip , Siddiqui Shahneela , DHANDAPANI Krishnan , Arbab Ali , Ayata Cenk , Morais Andreia , Imai Takahiko , JIN XUYAN , Sansing Lauren , Braga Boisserand Ligia , Mishra Sandeep Kumar , Caglayan Pinar , Guan Stacy , Sanganahalli Basavaraju , Hyder Fahmeed , Leira Enrique , Chauhan Anil , Patel Rakeshkumar , Kumskova Mariia , Jha Abhishek , Jain Aditi , Kuznetsov Vitalii 
Published: January 2025

Background/Aims:
The Stroke Preclinical Assessment Network (SPAN) is a randomized, placebo-controlled, blinded, multi-laboratory preclinical study using a Multi-Arm Multi-Stage statistical design to select one or more putative stroke treatments with an implied high likelihood of success in future human clinical stroke trials.

Methods:
Through a rigorous NIH-managed peer review process, six independent research laboratories were selected for testing five promising cerebrovascular interventions. A Coordinating Center at the University of Southern California leads the trial. The Interventions, also selected through an NIH peer review process, included NanO2 (NuvOx) an oxygen delivery emulsion, tatCN19o (Neurexis) a CaM-kinase II inhibitor, GSK2256098 (GlaxoSmithKline/ETSU) a focal adhesion kinase inhibitor, GSK2256294 (GlaxoSmithKline/OHSU) a soluble epoxide hydrolase inhibitor, and BPN-27332 (Loxagen/MGH) a lipoxygenase inhibitor. After a pilot trial to evaluate several behavioral measures, we designated the primary endpoint for SPAN 2 to be a multi-item functional test battery, the Simplified SPAN Score. All other procedures, including behavior tests and magnetic resonance imaging were performed as they were in SPAN 1. Per the SPAN 2 pre-specified protocol, an interim analysis was performed after Stage 1, aka, SPAN 2.1.

Results:
SPAN 2.1 enrolled 774 subjects, divided among 4 animal co-morbid models in whom a transient filament MCAo was performed: young healthy mice (n=193), diet-induced obese mice (n=197), aged mice (n=192), and spontaneously hypertensive rats (192). Nine subjects were found ineligible, leaving an ITT population of 765, of whom 13 were dropped during the stroke procedure—the primary analysis population (mITT) included 751 subjects. Protocol compliance was evaluated: over 99% of subjects received the correct assigned intervention, but dose timing was protocol adherent in only 61%. Animals who did not receive all assigned doses (n=100) were excluded, leaving a Full Treatment population of 651. Mortality after treatment included 158 subjects, 21% of the mITT group. Among the animal comorbid models, mortality was greatest (40%) in aged mice.

Conclusions:
The feasibility and protocol compliance seen in SPAN 1 have been replicated in stage 1 of the second trial, SPAN 2.1. Mortality resembles previous experience, with an improved survival in aged mice. SPAN 2 has advanced to Stage 2 where improved dose timing is implemented.