A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke

Patrick D Lyden^{1

2}, Márcio A Diniz³, Francesca Bosetti⁴, Jessica Lamb¹, Karisma A Nagarkatti¹, André Rogatko³, Sungjin Kim³, Ryan P Cabeen⁵, James I Koenig⁴, Kazi Akhter⁶, Ali S Arbab⁷, Brooklyn D Avery⁸, Hannah E Beatty⁹, Adnan Bibic⁶, Suyi Cao⁸, Ligia Simoes Braga Boisserand⁹, Angel Chamorro^{10

11}, Anjali Chauhan¹², Sebastian Diaz-Perez¹³, Krishnan Dhandapani¹⁴, Nirav Dhanesha¹⁵, Andrew Goh¹², Alison L Herman⁹, Fahmeed Hyder^{16

17}, Takahiko Imai¹⁸, Conor W Johnson⁹, Mohammad B Khan¹⁹, Pradip Kamat¹⁹, Senthilkumar S Karuppagounder²⁰, Mariia Kumskova¹⁵, Jelena M Mihailovic¹⁶, Joseph B Mandeville¹⁸, Andreia Morais¹⁸, Rakesh B Patel¹⁵, Basavaraju G Sanganahalli¹⁶, Cameron Smith¹⁹, Yanrong Shi⁸, Brijesh Sutariya¹⁵, Daniel Thedens²¹, Tao Qin¹⁸, Sofia E Velazquez^{9

13}, Jaroslaw Aronowski¹², Cenk Ayata²², Anil K Chauhan¹⁵, Enrique C Leira^{10

23

24}, David C Hess¹⁹, Raymond C Koehler⁸, Louise D McCullough¹², Lauren H Sansing^{9

13}

Affiliations

¹ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
² Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
³ Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Laboratory of Neuro Imaging, USC Mark and Mary Stevens Imaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
⁶ Department of Radiology, Johns Hopkins University, Baltimore, MD 21218-2625, USA.
⁷ Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912-0004, USA.
⁸ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21218-2625, USA.
⁹ Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁰ Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
¹¹ Department of Neurology, Hospital Clinic, University of Barcelona, Barcelona 08036, Spain.
¹² Department of Neurology, McGovern Medical School, University of Texas HSC, Houston, TX 77030, USA.
¹³ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁴ Department Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
¹⁵ Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
¹⁶ Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT 06520, USA.
¹⁷ Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
¹⁸ Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USA.
¹⁹ Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
²⁰ Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
²¹ Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
²² Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
²³ Department of Neurosurgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
²⁴ Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA.

PMID: 37729432
DOI: 10.1126/scitranslmed.adg8656

Randomized Controlled Trial

A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke

Patrick D Lyden et al. Sci Transl Med. 2023.

. 2023 Sep 20;15(714):eadg8656.

doi: 10.1126/scitranslmed.adg8656. Epub 2023 Sep 20.

Authors

Affiliations

¹ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
² Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
³ Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Laboratory of Neuro Imaging, USC Mark and Mary Stevens Imaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
⁶ Department of Radiology, Johns Hopkins University, Baltimore, MD 21218-2625, USA.
⁷ Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912-0004, USA.
⁸ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21218-2625, USA.
⁹ Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁰ Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
¹¹ Department of Neurology, Hospital Clinic, University of Barcelona, Barcelona 08036, Spain.
¹² Department of Neurology, McGovern Medical School, University of Texas HSC, Houston, TX 77030, USA.
¹³ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁴ Department Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
¹⁵ Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
¹⁶ Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT 06520, USA.
¹⁷ Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
¹⁸ Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USA.
¹⁹ Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
²⁰ Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
²¹ Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
²² Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
²³ Department of Neurosurgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
²⁴ Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA.

PMID: 37729432
DOI: 10.1126/scitranslmed.adg8656

Abstract

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.

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Preclinical multi-center trial for assessment of stroke treatment in rodents.
Heinke L. Heinke L. Nat Cardiovasc Res. 2023 Oct;2(10):860. doi: 10.1038/s44161-023-00359-y. Nat Cardiovasc Res. 2023. PMID: 39196258 No abstract available.

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A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke

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A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke

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