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

Background and Purpose— 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. Methods— 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. Results— 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. Conclusions— 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. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.

[1]  P. Meyers,et al.  Multisociety consensus quality improvement guidelines for intraarterial catheter-directed treatment of acute ischemic stroke, from the American Society of Neuroradiology, Canadian Interventional Radiology Association, Cardiovascular and Interventional Radiological Society of Europe, Society for Card , 2013, Journal of vascular and interventional radiology : JVIR.

[2]  Gerhard Schroth,et al.  National Institutes of Health Stroke Scale Score and Vessel Occlusion in 2152 Patients With Acute Ischemic Stroke , 2013, Stroke.

[3]  J. Griffin,et al.  Activated Protein C Analog Protects From Ischemic Stroke and Extends the Therapeutic Window of Tissue-Type Plasminogen Activator in Aged Female Mice and Hypertensive Rats , 2013, Stroke.

[4]  J. Saver,et al.  Statistical Analysis of the Primary Outcome in Acute Stroke Trials , 2012, Stroke.

[5]  V. Aiyagari,et al.  The Failure of Neuronal Protective Agents Versus the Success of Thrombolysis in the Treatment of Ischemic Stroke , 2001, Annals of the New York Academy of Sciences.

[6]  M. Chopp,et al.  An Activated Protein C Analog With Reduced Anticoagulant Activity Extends the Therapeutic Window of Tissue Plasminogen Activator for Ischemic Stroke in Rodents , 2012, Stroke.

[7]  P. Lyden,et al.  Revisiting Cerebral Postischemic Reperfusion Injury: New Insights in Understanding Reperfusion Failure, Hemorrhage, and Edema , 2015, International journal of stroke : official journal of the International Stroke Society.

[8]  A. Demchuk,et al.  Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials , 2016, The Lancet.

[9]  G. Albers,et al.  Reperfusion versus recanalization: the winner is…. , 2015, Stroke.

[10]  E. López‐Cancio,et al.  Time to recanalization and risk of symptomatic intracerebral haemorrhage in patients treated with intravenous thrombolysis , 2012, European journal of neurology.

[11]  M. Mokin,et al.  Randomized trials of endovascular therapy for stroke — impact on stroke care , 2016, Nature Reviews Neurology.

[12]  Roland Bammer,et al.  Ischemic core and hypoperfusion volumes predict infarct size in SWIFT PRIME , 2016, Annals of neurology.

[13]  G. Donnan,et al.  1,026 Experimental treatments in acute stroke , 2006, Annals of neurology.

[14]  Brett C Meyer,et al.  An ethical hierarchy for decision making during medical emergencies , 2010, Annals of neurology.

[15]  Christopher S Coffey,et al.  2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association , 2015, Stroke.

[16]  J. Griffin,et al.  Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. , 2014, Current pharmaceutical design.

[17]  Patricia D. Williams,et al.  Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein C for ischemic stroke. , 2012, Current pharmaceutical design.

[18]  Geoff Cohen,et al.  The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial , 2012, The Lancet.

[19]  A. Messori,et al.  Stent-Retriever Thrombectomy for Stroke. , 2015, The New England journal of medicine.

[20]  J. Griffin,et al.  Activated Protein C Mutant with Minimal Anticoagulant Activity, Normal Cytoprotective Activity, and Preservation of Thrombin Activable Fibrinolysis Inhibitor-dependent Cytoprotective Functions* , 2007, Journal of Biological Chemistry.

[21]  M. Kaste,et al.  Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. , 2008, The New England journal of medicine.

[22]  J. Grotta,et al.  Early stroke treatment associated with better outcome: the ninds rt-pa stroke study , 2000, Neurology.

[23]  Joanna M. Wardlaw,et al.  Recommendations on Angiographic Revascularization Grading Standards for Acute Ischemic Stroke: A Consensus Statement , 2013, Stroke.

[24]  Hester F. Lingsma,et al.  A randomized trial of intraarterial treatment for acute ischemic stroke. , 2015, The New England journal of medicine.

[25]  M. Krause,et al.  Endovascular therapy for ischemic stroke with perfusion-imaging selection. , 2015, The New England journal of medicine.

[26]  S. Goodman,et al.  Some practical improvements in the continual reassessment method for phase I studies. , 1995, Statistics in medicine.

[27]  Joseph P. Broderick,et al.  Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. , 1995 .

[28]  Michael D Hill,et al.  Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial , 2014, The Lancet Neurology.

[29]  J. Griffin,et al.  Protein C anticoagulant and cytoprotective pathways , 2012, International Journal of Hematology.

[30]  J. Grotta,et al.  Reperfusion Injury: Demonstration of Brain Damage Produced by Reperfusion after Transient Focal Ischemia in Rats , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  Anil Kumar,et al.  A review on animal models of stroke: An update , 2016, Brain Research Bulletin.

[32]  Eric E. Smith,et al.  Randomized assessment of rapid endovascular treatment of ischemic stroke. , 2015, The New England journal of medicine.

[33]  Gillian L. Currie,et al.  Systematic reviews and meta-analysis of preclinical studies: why perform them and how to appraise them critically , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[34]  Niaz Ahmed,et al.  Neuroprotection in Cerebral Ischaemia: Facts and Fancies – The Need for New Approaches , 2003, Cerebrovascular Diseases.

[35]  L. Caplan How well does "evidence-based" medicine help neurologists care for individual patients? , 2007, Reviews in neurological diseases.

[36]  G. Salvioli,et al.  Hyperhomocysteinemia and Other Newly Recognized Inherited Coagulation Disorders (Factor V Leiden and Prothrombin Gene Mutation) in Patients with Idiopathic Cerebral Vein Thrombosis , 2003, Cerebrovascular Diseases.

[37]  Jane C Khoury,et al.  Revascularization End Points in Stroke Interventional Trials: Recanalization Versus Reperfusion in IMS-I , 2005, Stroke.

[38]  O. Berkhemer,et al.  Stent-Retriever Thrombectomy for Stroke. , 2015, The New England journal of medicine.

[39]  D. Pelz,et al.  Catheter based selective hypothermia reduces stroke volume during focal cerebral ischemia in swine , 2015, Journal of NeuroInterventional Surgery.

[40]  P. Sandercock,et al.  Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials | NOVA. The University of Newcastle's Digital Repository , 2014 .

[41]  Werner Hacke,et al.  Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study , 2007, The Lancet.