Review

. 2021 Mar;52(3):1154-1161.

doi: 10.1161/STROKEAHA.120.031939. Epub 2021 Feb 10.

The Utility of Domain-Specific End Points in Acute Stroke Trials

Steven C Cramer^{1

2}, Steven L Wolf³, Jeffrey L Saver¹, Karen C Johnston⁴, J Mocco⁵, Maarten G Lansberg⁶, Sean I Savitz⁷, David S Liebeskind¹, Wade Smith⁸, Max Wintermark⁹, Jordan J Elm¹⁰, Pooja Khatri¹¹, Joseph P Broderick¹², Scott Janis¹³; NIH StrokeNet Recovery and Rehabilitation Group and the Acute Stroke Group*

Collaborators, Affiliations

Collaborators

NIH StrokeNet Recovery and Rehabilitation Group and the Acute Stroke Group*:
Daofen Chen, Alexander Dromerick, Kari Dunning, Andrew W Grande, Randolph S Marshall, Caitlyn Meinzer, Stephen Page, Aimee Reiss, Lorie Richards, Lawrence Wechsler, Carolee Winstein, Cheryl Bushnell, Dorothy Edwards, Warren Lo, Jin-Moo Lee, Catherine M Amlie-Lefond, Gregory W Albers, Robert Dempsey, Toby I Gropen, Edward C Jauch, Enrique C Leira, Renee Martin, Brett C Meyer, Kiva Schindler, Phillip Scott, Aneesh B Singhal, Claudia S Moy

Affiliations

¹ Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles (S.C.C., J.L.S., D.S.L.).
² California Rehabilitation Institute, Los Angeles (S.C.C.).
³ Division of Physical Therapy, Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, GA (S.L.W.).
⁴ Department of Neurology, University of Virginia, Charlottesville (K.C.J.).
⁵ Department of Neurosurgery, Mt. Sinai, New York (J.M.).
⁶ Department of Neurology, Stanford University, CA (M.G.L.).
⁷ Institute for Stroke and Cerebrovascular Disease, University of Texas Health Science Center, Houston (S.I.S.).
⁸ Department Neurology, University of California, San Francisco (W.S.).
⁹ Department of Radiology, Stanford University, CA (M.W.).
¹⁰ Department of Public Health Sciences, Medical University of South Carolina, Charleston (J.J.E.).
¹¹ Department of Neurology, University of Cincinnati (P.K.).
¹² Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, University of Cincinnati Academic Health Center, OH (J.P.B.).
¹³ Division of Clinical Research, The National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (S.J.).

PMID: 33563009
PMCID: PMC7902441
DOI: 10.1161/STROKEAHA.120.031939

Review

The Utility of Domain-Specific End Points in Acute Stroke Trials

Steven C Cramer et al. Stroke. 2021 Mar.

. 2021 Mar;52(3):1154-1161.

doi: 10.1161/STROKEAHA.120.031939. Epub 2021 Feb 10.

Authors

Collaborators

NIH StrokeNet Recovery and Rehabilitation Group and the Acute Stroke Group*:
Daofen Chen, Alexander Dromerick, Kari Dunning, Andrew W Grande, Randolph S Marshall, Caitlyn Meinzer, Stephen Page, Aimee Reiss, Lorie Richards, Lawrence Wechsler, Carolee Winstein, Cheryl Bushnell, Dorothy Edwards, Warren Lo, Jin-Moo Lee, Catherine M Amlie-Lefond, Gregory W Albers, Robert Dempsey, Toby I Gropen, Edward C Jauch, Enrique C Leira, Renee Martin, Brett C Meyer, Kiva Schindler, Phillip Scott, Aneesh B Singhal, Claudia S Moy

Affiliations

¹ Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles (S.C.C., J.L.S., D.S.L.).
² California Rehabilitation Institute, Los Angeles (S.C.C.).
³ Division of Physical Therapy, Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, GA (S.L.W.).
⁴ Department of Neurology, University of Virginia, Charlottesville (K.C.J.).
⁵ Department of Neurosurgery, Mt. Sinai, New York (J.M.).
⁶ Department of Neurology, Stanford University, CA (M.G.L.).
⁷ Institute for Stroke and Cerebrovascular Disease, University of Texas Health Science Center, Houston (S.I.S.).
⁸ Department Neurology, University of California, San Francisco (W.S.).
⁹ Department of Radiology, Stanford University, CA (M.W.).
¹⁰ Department of Public Health Sciences, Medical University of South Carolina, Charleston (J.J.E.).
¹¹ Department of Neurology, University of Cincinnati (P.K.).
¹² Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, University of Cincinnati Academic Health Center, OH (J.P.B.).
¹³ Division of Clinical Research, The National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (S.J.).

PMID: 33563009
PMCID: PMC7902441
DOI: 10.1161/STROKEAHA.120.031939

Abstract

Domain-specific endpoints are assessments that correspond to the output of individual neural systems and are useful for capturing treatment effects on specific behaviors. By contrast, global endpoints combine several attributes into a single score and are useful for capturing broad treatment effects in a summary way. While global endpoints have become the de facto mechanism required to define benefit in stroke trials, they also have important limitations, some of which might be addressed by simultaneously measuring domain-specific endpoints. Substantial opportunity remains to identify quantifiable patient benefit that would otherwise not be captured by global endpoints. Potential advantages of incorporating domain-specific endpoints in acute stroke trials are discussed, such as increased granularity of measurement, improved understanding of how therapies affect the brain between acute treatment and day 90, and optimized therapeutic translation. Potential disadvantages are also considered, including time and cost of administering domain-specific endpoints, as well as statistical implications. Domain-specific endpoints and global endpoints are not mutually exclusive, and both capture clinical benefits to patients. Incorporating a broader set of outcome assessments in stroke trials, including both global and domain-specific endpoints, is warranted.

Keywords: brain; infarction; neurons; outcome assessment; reperfusion.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest

Dr. Cramer has served as a consultant for Constant Therapeutics, MicroTransponder, Neurolutions, SanBio, Fujifilm Toyama Chemical Co., Medtronic, and TRCare. Dr. Saver co-created the Rankin Focused Assessment (RFA) while a University of California employee, and Dr. Saver, collaborators, and the University of California Regents have made the RFA freely and permanently available as a no-fee public resource under a Creative Commons, use-freely-with-attribution license. Dr. Saver also co-created a written vignette rater certification program for the RFA while a University of California employee. The written vignettes are an optional system for training and certifying raters in the use of the free RFA resource. The University of California Regents, along with Dr. Saver and collaborators, hold a copyright for the written vignette rater certification system. Any revenues received under that copyright are used to support the training of Vascular Neurology Fellows at UCLA. Dr. Wolf has served as a consultant for SAEBO, Inc., Motus Nova, MicroTransponder, and Fujifilm Toyama Chemical Co. Dr Lansberg has served as a consultant for Biogen, Nektar Therapeutics, and Roche/Genentech. Dr. Khatri’s department has received funds for her efforts from Cerenovus (Investigator-Initiated Study), Nervive (NIH SBIR co-investigator), Lumosa (consultant), and Diamedica (Scientific Advisory Board). She has also received funds from Bayer (National Trial PI) and UpToDate, Inc. (royalties). Dr. Broderick’s department received funds from Genentech for his role on steering committee of TIMELESS Trial, and from Ono Pharmaceuticals for consulting work. Dr. Lansberg reports consultancy for NuvOx Pharma. Dr. Smith reports other from MindRhythm, Inc

References

1. European Medicines Agency. Points to consider on clinical investigation of medicinal products for the treatment of acute stroke. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin.... 2001. Last accessed November 24, 2020.
1. Savitz SI, Cramer SC, Wechsler L. Stem cells as an emerging paradigm in stroke 3: Enhancing the development of clinical trials. Stroke. 2014;45:634–639 - PMC - PubMed
1. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11–20 - PubMed
1. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, Albers GW, Cognard C, Cohen DJ, Hacke W, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285–2295 - PubMed
1. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–1030 - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions

Grants and funding

U01 NS086872/NS/NINDS NIH HHS/United States

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The Utility of Domain-Specific End Points in Acute Stroke Trials

Collaborators

Affiliations

The Utility of Domain-Specific End Points in Acute Stroke Trials

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical