Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection.
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.
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.
Patrick
P
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.).
Sara
S
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
C
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
M
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
S
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
S
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
M
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
EC
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
P
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
J
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
S
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
H
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
M
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
L
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
A
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
E
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
S
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
K
Pryor
D002545:Brain Ischemia / Q000188:drug therapy / Q000628:therapy*; D002985:Clinical Protocols; D002986:Clinical Trials as Topic / Q000592:standards*; D004311:Double-Blind Method; D006801:Humans; D061185:Mechanical Thrombolysis; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018579:Patient Selection; D011486:Protein C / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D020521:Stroke / Q000188:drug therapy / Q000628:therapy*; D015912:Thrombolytic Therapy
C000591161:3K3A-APC protein; D018696:Neuroprotective Agents; D011486:Protein C; D011994:Recombinant Proteins
activated protein C; clinical trial; neuroprotective agents; thrombectomy; thrombolysis