Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection

Patrick Lyden; Sara Weymer; Chris Coffey; Merit Cudkowicz; Samantha Berg; Sarah O'Brien; Marc Fisher; E Clarke Haley; Pooja Khatri; Jeff Saver; Steven Levine; Howard Levy; Marilyn Rymer; Lawrence Wechsler; Ashutosh Jadhav; Elizabeth McNeil; Salina Waddy; Kent Pryor

doi:10.1161/STROKEAHA.116.013881

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Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection

Journal article

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Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection

Patrick Lyden, Sara Weymer, Chris Coffey, Merit Cudkowicz, Samantha Berg, Sarah O'Brien, Marc Fisher, E Clarke Haley, Pooja Khatri, Jeff Saver, …

Stroke (1970), Vol.47(12), pp.2979-2985

12/2016

DOI: 10.1161/STROKEAHA.116.013881

PMCID: PMC5134840

PMID: 27803392

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https://doi.org/10.1161/STROKEAHA.116.013881View

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Abstract

The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment. It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.

Double-Blind Method

Brain Ischemia - therapy

Humans

Clinical Protocols

Stroke - drug therapy

Recombinant Proteins - adverse effects

Recombinant Proteins - pharmacology

Protein C - pharmacology

Recombinant Proteins - administration & dosage

Patient Selection

Neuroprotective Agents - pharmacology

Brain Ischemia - drug therapy

Thrombolytic Therapy

Protein C - administration & dosage

Clinical Trials as Topic - standards

Neuroprotective Agents - adverse effects

Neuroprotective Agents - administration & dosage

Mechanical Thrombolysis

Protein C - adverse effects

Stroke - therapy

Details

Title: Subtitle: Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection
Creators: Patrick Lyden - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.). lydenp@cshs.org
Sara Weymer - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Chris Coffey - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Merit Cudkowicz - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Samantha Berg - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Sarah O'Brien - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Marc Fisher - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
E Clarke Haley - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Pooja Khatri - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Jeff Saver - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Steven Levine - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Howard Levy - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Marilyn Rymer - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Lawrence Wechsler - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Ashutosh Jadhav - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Elizabeth McNeil - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Salina Waddy - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Kent Pryor - From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.)
Resource Type: Journal article
Publication Details: Stroke (1970), Vol.47(12), pp.2979-2985
Publisher: United States
DOI: 10.1161/STROKEAHA.116.013881
PMID: 27803392
PMCID: PMC5134840
ISSN: 0039-2499
eISSN: 1524-4628
Grant note: U01 NS077179 / NINDS NIH HHS U01 NS077352 / NINDS NIH HHS U01 NS088312 / NINDS NIH HHS
Language: English
Date published: 12/2016
Academic Unit: Biostatistics
Record Identifier: 9983997446002771

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