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Ongoing Clinical Trials Posters II Thursday, February 10, 2011, 6:15 pm - 6:45 pm Presentation Number: CT P1 PI Coordinator Affiliation: University of California, San Francisco PI Coordinator Name: S. Claiborne Johnston Trial Abbreviation: The POINT Trial Trial Contact Information: Mary Farrant, MBA BSN RN, University of California San Francisco Stroke Sciences Group, San Francisco, California, United States, 94143, Phone 1-415-502-2096, E-mail [email protected] Trial Email: [email protected] Trial Name: Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial Trial Registry Number ID: NCT00991029 Trial Sponsor: University of California, San Francisco, National Institute of Neurological Disorders and Stroke (NINDS) Trial Web Site: http://pointtrial.org/ Publishing Title: The POINT Trial Author Block: S. Claiborne Johnston, J Donald Easton, Univ of California San Francisco, San Francisco, CA Abstract Body: Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) Trial, is a prospective, randomized, double-blind, multicenter trial with the primary null hypothesis that, in patients with TIA or minor ischemic stroke treated with aspirin 50-325 mg/day, there is no difference in survival free of ischemic stroke, myocardial infarction, and ischemic vascular death at 90 days in those treated with clopidogrel (600 mg loading dose then 75 mg/day) compared to placebo when therapy is initiated within 12 hours of onset. Subjects are over 18 years of age with high-risk TIA (defined as an ABCD2 score > 4) or minor ischemic stroke (with NIHSS < 3) and each subject is followed for 90 days from randomization. A total of 4,150 patients will be recruited and the trial will be completed in 7 years. The first subject was enrolled on May 28, 2010. Principal Investigator: S. Claiborne Johnston, MD, PhD, University of California, San Francisco Co-Principal Investigator: J. Donald Easton, MD, University of California, San Francisco Contact: Mary Farrant, MBA BSN RN, University of California San Francisco Stroke Sciences Group, San Francisco, California, United States, 94143, Phone 1-415-502-2096, E-mail [email protected]. Number of Centers: 150 Sponsor: University of California, San Francisco, National Institute of Neurological Disorders and Stroke (NINDS) Collaborators: Neurological Emergencies Treatment Trials Network (NETT), Medical University of South Carolina, The EMMES Corporation Dates of Study: October 2009 - September 2016 ClinicalTrials.gov Identifier: NCT00991029 Characters: 1670; Words: 243 Author Disclosure Block: S. Johnston: None. J. Easton: None. Presentation Number: CT P2 PI Coordinator Affiliation: Hospital Germans Trias i Pujol, Badalona (Spain) PI Coordinator Name: Antoni Dávalos Trial Abbreviation: ICTUS Trial Contact Information: Julio J Secades, [email protected] Trial Email: [email protected] Trial Name: International Citicoline Trial on acUte Stroke Trial Registry Number ID: NCT00331890 Trial Sponsor: Ferrer Group Trial Web Site: www.ferrergrupo.com Publishing Title: ICTUS Study: International Citicoline Trial on acUte Stroke (update 2011) Author Block: Antoni Dávalos, Hosp Germans Trias i Pujol, Badalona, Spain; José Alvarez-Sabín, Hosp de la Vall d'Hebron, Barcelona, Spain; José Castillo, Hosp Clínico Univrio de Santiago, Santiago de Compostela, Spain; Erik Cobo, Univ Politècnica de Catalunya, Barcelona, Spain; Exuperio Díez-Tejedor, Hosp Univrio La Paz, Madrid, Spain; Jose Ferro, Hosp de Santa Maria, Lisbon, Portugal; Eduardo Martínez-Vila, Clínica Univria de Navarra, Pamplona, Spain; Julio J Secades, Ferrer Group, Barcelona, Spain; for the ICTUS Trial Investigators Abstract Body: Background: Citicoline is a safe drug approved in some countries for the treatment of acute ischemic stroke. The drug has shown some evidence of efficacy in a data pooled analysis, based on four clinical trials performed in USA with oral citicoline given within 24 hours from symptoms onset. Trial Steering Committee: Antoni Dávalos (Chairman), José Alvarez-Sabín, José Castillo, Erik Cobo (Statistician), Exuperio Díez-Tejedor, Jose Ferro, Savion Gropper, Eduardo Martínez-Vila, Julio J Secades. Data Safety Monitoring Board: Kennedy R Lees (Chairman), Steve Warach, John Whitehead (Statistician). Purpose: To confirm the results obtained in the data pooled analysis. Design: Multicenter, randomized (under minimization), double-blind, placebo-controlled trial, based on a sequential analysis (triangular model). Sample Size: The study will follow a sequential analysis, with the first approach to test the efficacy with 1000 patients, and the second one, with 1533 patients. The upper limit has been established in 2600 patients. This design has 80% power to establish a treatment effect of 1.26 (common odds ratio). Centers: 26 centers in Spain, 8 in Portugal and 10 in Germany Study Population: Male or female, ≥ 18 years old, treated within 24 hours of symptoms onset, with a measurable focal neurological deficit lasting for a minimum of 60 minutes. Baseline NIHSS score ≥ 8, with a neuroimage compatible with the diagnosis of acute ischemic stroke and symptoms referable to MCA territory. Pre-stroke mRS ≤ 1. Signed informed consent is mandatory. Interventions: Patients will be randomized in a 1:1 ratio to receive either citicoline or placebo. Citicoline forms: 1000 mg ampoules (4 cc) and 500 mg tablets. Daily dosage: 1000 mg/12 h i.v. during the first three days and orally from the fourth day until the end of the 6 weeks treatment period. Outcome Endpoints: Primary end-point will consist in a global score test combining three measures of success evaluated 12 weeks after treatment on the basis of intention-to-treat criteria: neurological (NIHSS) ≤ 1), disability (MRS ≤ 1), and activities of daily life (BI ≥ 95), averaged using a Global Test. Secondary endpoints: Results of the single scales at week 12. Formal training and certification in the use of mRS and NIHSS are mandatory. Safety Endpoints: Vital signs, adverse events, symptomatic hemorrhagic transformation in patients treated with rTPA (ECASS criteria), neurological deterioration, mortality, and concomitant medication records Statistical Analysis: The main analysis will consist of a Global Test combining the three measures of success on the basis of intention-to-treat criteria applying LOCF. A patient who dies before 12 weeks will be considered to have failed on all three measures. Trial Status: All the centers are open. Close to 1900 patients are expected to be included by February 2010. The second interim analysis on 1533 patients will be completed before the conference. Registers:EudraCT Nº 2005-004825-25; ClinicalTrials.gov NCT00331890; Stroke Trials Registry Author Disclosure Block: A. Dávalos: Research Grant; Modest; Ferrer Group. Speakers; Modest; Ferrer Group. Honoraria; Modest; Ferrer Group. Consultant/Advisory Board; Modest; Ferrer Group. J. Alvarez-Sabín: Research Grant; Modest; Ferrer Group. Consultant/Advisory Board; Modest; Ferrer Group. J. Castillo: Research Grant; Modest; Ferrer Group. Honoraria; Modest; Ferrer Group. Consultant/Advisory Board; Modest; Ferrer Group. E. Cobo: Other Research Support; Modest; Ferrer Group. Honoraria; Modest; Ferrer Group. Consultant/Advisory Board; Modest; Ferrer Group. E. Díez-Tejedor: Research Grant; Modest; Ferrer Group. Honoraria; Modest; Ferrer Group. Consultant/Advisory Board; Modest; Ferrer Group. J. Ferro: ; Ferrer Group. E. Martínez-Vila: ; Ferrer Group. J.J. Secades: Employment; Significant; Ferrer Group. Presentation Number: CT P3 PI Coordinator Affiliation: University of Pennsylvania; Haukeland University Hospital - Bergen, Norway; Duke University; Rigshospitalet - Copenhagen, Denmark PI Coordinator Name: Scott E. Kasner, Lars Thomassen, John F. Rhodes, Lars Søndergaard Trial Abbreviation: REDUCE Trial Contact Information: Erin McDowell W.L. Gore & Associates, Inc. Medical Products Division 4250 West Kiltie Lane Flagstaff, AZ 86001 USA US Telephone: 928-864-4214 US Facsimile: 928-864-4952 EU Telephone: 011-928-864-4214 EU Facsimile: 011-928-864-4952 Trial Email: [email protected] Trial Name: GORE HELEX™ Septal Occluder and Antiplatelet Medical Management for Reduction of Recurrent Stroke or Imaging-Confirmed TIA in Patients with Patent Foramen Ovale (PFO) - The Gore REDUCE Study Trial Registry Number ID: NCT00738894 Trial Sponsor: W.L. Gore & Associates, Inc. Trial Web Site: http://clinicaltrials.gov/ct2/show/NCT00738894 Publishing Title: GORE HELEX Septal Occluder and Antiplatelet Medical Management for Reduction of Recurrent Stroke or Imaging-Confirmed TIA in Patients with Patent Foramen Ovale (PFO) - The Gore REDUCE Study Author Block: Scott E Kasner, Univ of Pennsylvania, Philadelphia, PA; The Gore REDUCE Study Investigators Abstract Body: Rationale: The relationships between cryptogenic stroke and patent foramen ovale (PFO) are complex, and the role of percutaneous closure for prevention for recurrent stroke remains promising but uncertain. Objective: The REDUCE Study is designed to demonstrate that PFO closure with the GORE HELEX Septal Occluder plus antiplatelet medical management is safe and effective and reduces the risk of recurrent stroke or imaging-confirmed transient ischemic attack (TIA) when compared to antiplatelet medical management alone in patients with a PFO and history of cryptogenic stroke or imaging-confirmed TIA. Design: Multicenter, multinational, randomized clinical trial. Population: • 664 men and Women, age 18 - 60 years • Cryptogenic ischemic stroke or imaging-confirmed TIA • Presence of Patent Foramen Ovale (PFO) confirmed by transesophageal echocardiography (TEE) • No evidence of an alterative etiology for stroke Intervention: Participants will be randomized 2:1 to PFO closure with the GORE HELEX Septal Occluder plus antiplatelet medical management vs. antiplatelet medical management alone. Patients will be followed to 2 years for the primary endpoint, and up to 5 years for secondary endpoints. Primary Outcome: Time to recurrent stroke or imaging-confirmed TIA, or death due to stroke through 24 months post-randomization. All events will be adjudicated by a blinded clinical events committee. Secondary Outcomes: Proportion of participants with new ischemic lesions on MRI at 2 years compared to MRI obtained at baseline; systemic embolic events; PFO closure in device-arm subjects by transthoracic echocardiography (TTE); device- and procedure-related adverse events; time to recurrent stroke or imagingconfirmed TIA, or death due to stroke through 60 months post-randomization. Statistical Analysis: Time to recurrent stroke or imaging-confirmed TIA will be compared using an unadjusted log-rank test and presented using Kaplan-Meier methods. The primary analysis will be by intention-to-treat. Trial Status: Enrollment is ongoing at a maximum of 50 investigational sites in the United States, Denmark, Finland, Sweden, and Norway with no per-site subject limit. Author Disclosure Block: S.E. Kasner: Research Grant; Significant; Gore PI grant to the Univ of Penn. Presentation Number: CT P4 PI Coordinator Affiliation: U of Cinti, Mayo, Cleveland Clinic, Columbia, GCB&S, U of Maryland, U of Florida, Notre Dame, NW U, Stanford, Brigham & Women's, USCF, U of Virginia, U of Washington, U of Alabama, Mass Gen'l, U. of Michigan, Johns Hopkins, Wash. U. STL, Allegheny PI Coordinator Name: J. Broderick MD; L. Sauerbeck, RN, MS Trial Abbreviation: FIA II Trial Contact Information: 800-503-3427 Trial Email: [email protected] Trial Name: The Familial Intracranial Aneurysm Study II Trial Registry Number ID: NCT00071565 Trial Sponsor: NIH Division of Neurological Disorders and Stroke Trial Web Site: www.FIAStudy.org Publishing Title: The Familial Intracranial Aneurysm Study II Author Block: Laura Sauerbeck, Univ of Cincinnati, Cincinnati, OH; FIA Investigators Abstract Body: Background: Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms (IAs) occurs in about 30,000 people per year in the United States. Unruptured IAs are estimated to be present in at least 1.0% of the population. The goal of this National Institutes of Health funded, multi-center study is to identify genes that increase the risk of developing saccular IAs. During the first phase of the FIA study we identified COL9A1 (collagen 9A1 gene) and PDE1A (phosphodiesterase 1A gene) as high priority candidate genes based not only the strength of the association with FIA but also on their biological function. Phase II of the study will collect families and sporadic cases of IA for replication of these findings, as well as genes identified by other studies. Subjects: 200 families with multiple family members diagnosed with IA, along with 1800 sporadic cases of IA will be enrolled as a replication data set through August 31, 2011. Families that qualify include: 1. Two or > alive affected siblings. 2. At least 2 affected siblings, one of who is alive and the other whose genotype can be reconstructed. 3. > three affected family members, two of who are both alive and have living connecting relatives. 4. > three affected family members, one of whom alive, at least one who can be reconstructed and there are living connecting relatives. Exclusion Criteria for both family and sporadic cases: 1. Fusiform-shaped or IAs which are part of an arteriovenous malformation. 2. Family history of polycycstic kidney disease, Ehlers Danlos Syndrome, Marfan’s Syndrome, Fibromuscular Dysplasia, or Moya-Moya. 3. Failure to obtain informed consent (IC). Methods: After obtaining an IC each subject is administered questionnaires covering medical history, environmental risk factors, and demographics. A blood specimen is also obtained from each subject. DNA extraction and immortalization of cell lines occurs at the NINDS repository located at Coriell Institute for Medical Research. Performance of GWAS of these subjects will take place when collection is completed. We plan to compare these IA cases with age and gender-matched controls with available genotype data from collaborating databases such as ARIC. The final step will be a comparison of genotypic and phenotypic data from all approximately 2400 white IA familial and non-familial cases from FIA I & II with 5000+ age and gender matched stroke/IA free controls form collaborating databases. SNPs and gene regions that are replicated in white populations will be tested in our 600+ families as well as minority populations of IA cases from FIA I and II and minority controls from FIA I/II and ARIC. Results: During FIA I 441 families (2800 subjects) were completely characterized. To-date in FIA II ~ 1230 sporadic subjects and 54 families has been enrolled. Study Centers: UC (Coordinating/Recruiting Ctr); (PI) J Broderick, Study Manager: L. Sauerbeck, CO-PI D Woo (C) K. Franklin; Statisical Center: Indiana University: T Foroud: NINDS Repository (PI) M. D’Andrea; UC Genotyping Center (PI) R. Deka: Recruiting Centers: Mayo Clinic (PI) R. Brown Jr (Cs) L Jaeger, D Gravenhof; Cleveland Clinic (PI) P. Rassmussen (Cs) D Andrews-Hinders, L. Strozniak; Columbia Univ. (PI) E.S. Connolly (C) L Lewis; Univ. of Florida (PI) S. Lewis (C) T. Sheehan; Goodman Campbell Brain& Spine. (PI) T. Payner, (C) N Miracle; Univ. of Maryland (PI) F. Aldrich (Cs) C. Aldrich, K Booker; Notre Dame (PI) G Rouleau (C) K. Boisvert; Northwestern Univ. (PI) H Batjer (C) S. Thompson; Stanford Unvi. (PI) G Steinberg (Cs) M Coburn, S Dunn; Brigham & Women’s (PI) R Du(C) R Brach; UCSF (PI) N Ko, (C) P Buekea; Univ of Virginia (PIs) K Lui, B Worrall (C) E. Rost Ruffner, S Raja; Univ of Washington (PI) D. Tirschell (C) P Tanzi; Univ. of Alabama (PI) W. Fisher (C) K Lamb; Massachusetts General (PI) C. Ogilvy (C) M Whalen; Univ. of Michigan (PI) A Pandey (C) K Maddox; Johns Hopkins (PI) D Gandhi (C) A Jones; Washington Univ. STL (PI) C Derdeyn (C) L Shinawi; Allegheny Gen. (PI) K Aziz (C) L Fletcher Author Disclosure Block: L. Sauerbeck: Research Grant; Significant; Salary Support. Presentation Number: CT P5 PI Coordinator Affiliation: University of Cincinnati Academic Health Center PI Coordinator Name: Joseph P. Broderick; Joyce Zeigler Trial Abbreviation: IMS III Trial Contact Information: Program Manager, Judith Spilker, [email protected], 513-558-4350. Administrative Coordinator, Rose Beckmann, [email protected], 513-558-3907. http://www.ims3.org Trial Email: [email protected] Trial Name: The Interventional Management of Stroke (IMS) III Trial Trial Registry Number ID: NCT00359424 Trial Sponsor: NINDS/University of Cincinnati Trial Web Site: www.ims3.org Publishing Title: The Interventional Management of Stroke (IMS) III Trial: An Ongoing Phase III Trial Author Block: Thomas A. Tomsick, Joseph P. Broderick, Univ of Cincinnati, Cincinnati, OH; for the IMS III Investigators Abstract Body: BACKGROUND AND PURPOSE: The IMS I and II pilot trials showed that the combined intravenous (IV) and intra-arterial (IA) approach to recanalization may be more effective than standard IV rt-PA (Activase®) alone for moderate-to-large (NIHSSS ≥10 or 8-9 with positive CTA) strokes, and with a similar safety profile. Therefore, the primary objective of this NIH-funded, Phase III, randomized, multi-center, open-label clinical trial is to determine whether a combined IV/IA approach to recanalization is superior to standard IV rt-PA alone when initiated within three hours of acute ischemic stroke onset. METHODS: A projected 900 subjects with moderate-to-large ischemic strokes between ages 18-82 will be enrolled at 50+ centers in the United States, Canada, Australia and Europe. Both approaches must have IV treatment initiated within three hours of stroke onset. Subjects will be randomized in a 2:1 ratio with more subjects enrolled in the combined IV/IA group. The IV rt-PA alone group will receive the full standard dose (0.9 mg/kg, 90 mg max [10% as bolus]) of rt-PA intravenously over an hour. The combined IV/IA group will receive a lower dose of rt-PA (~ 0.6 mg/kg, 60 mg max) over 40 minutes followed by immediate angiography. If a treatable thrombus is not demonstrated, no IA therapy will be administered. If an appropriate thrombus is identified, treatment will continue with either the Concentric Merci® Retriever, the Penumbra System™ thrombus-removal device, infusion of rt-PA and delivery of low-intensity ultrasound at the site of the occlusion via the EKOS® Micro-Infusion Catheter (in US only), or infusion of rt-PA via a standard micro-catheter. New devices will be evaluated as they become clinically available. The choice of IA strategy will be made by the treating neurointerventionalist. IA treatment must begin within 5 hours and be completed within 7 hours of stroke onset. The primary outcome measure is a favorable clinical outcome, defined as a modified Rankin Score (mRS) of 0-2 at 3 months. The primary safety measure is mortality at 3 months and symptomatic ICH within the first 36 hours after onset. Finally, a secondary objective of the IMS III Trial is to determine the costeffectiveness of the combined IV/IA approach as compared to standard IV rt-PA. CONCLUSIONS: The IMS III Trial will develop and maintain a network of interventional centers to test the safety, feasibility, and potential efficacy of a combined IV/IA approach to recanalization using intra-arterial infusion of rt-PA and/or FDA-approved catheter devices. As of October 11, 2010, 434 subjects had been randomized. Author Disclosure Block: T.A. Tomsick: Research Grant; Significant; Neurointerventional PI NINDS funded IMS III. J.P. Broderick: ; PI NINDS funded SPOTRIAS Center, includes CLEAR-ER, STOP-IT clinical trials, PI NINDS funded IMS III, PI NINDS funded FIA, PI NINDS funded T-32 Cerebrovascular Fellowship Training Program for Cerebrovascular Disease, Co-Investigator NINDS funded GERFHS, Co-Investigator NINDS funded IRIS, Co-Investigator NINDS funded CREST, Co-Investigator NINDS funded COSS, Co-Investigator NINDS funded SWISS. Other Research Support; Significant; Genentech supplies study drug to IMS III/CLEARER, EKOS Corp. supplies catheter devices for IMS III, Schering Plough supplies drug for CLEAR-ER. Honoraria; Modest; Genentech, Inc., stroke advisory board, PhotoThera, stroke advisory board, Oakstone Medical Publishing, speaker. Presentation Number: CT P6 PI Coordinator Affiliation: Yale School of Medicine PI Coordinator Name: Walter N. Kernan Trial Abbreviation: IRIS Trial Contact Information: [email protected] Trial Email: [email protected] Trial Name: Insulin Resistance Intervention after Stroke Trial Trial Registry Number ID: NCT00091949 Trial Sponsor: National Institutes of Neurological Disorders and Stroke Trial Web Site: www.iristrial.org Publishing Title: The Insulin Resistance Intervention after Stroke (IRIS) Trial Author Block: Walter Kernan, Yale Schoool of Med, New Haven, CT; Karen L Furie, Massachusetts General Hosp, Boston, MA; Mark Gorman, Univ of Vermont, Burlington, VT; Peter Guarino, Yale Sch of Med, New Haven, CT; Ralph I Horwitz, Stanford Univ, Palo Alto, CA; Silvio Inzucchi, Anne M Lovejoy, Catherine M Viscoli, Lawrence H Young, Yale Schoool of Med, New Haven, CT Abstract Body: RATIONALE: Among persons who survive an ischemic stroke or TIA, a major source of morbidity and mortality is recurrent stroke and myocardial infarction. Even with current therapies, within 5 years 18-25% of patients will have a recurrent stroke and 10-12% will have a myocardial infarction. The IRIS trial will test the effectiveness of pioglitazone as a new potential preventive therapy. Pioglitazone, a thiazolidinedione, increases insulin sensitivity by activating the nuclear transcription factor PPARγ. In addition to decreasing insulin resistance, pioglitazone improves dyslipidemia and endothelial function, reduces vascular inflammation, promotes fibrinolysis, and slows carotid atherosclerosis. In clinical trials among diabetic patients, it reduced the risk for stroke, MI, or death. AIMS: To determine if pioglitazone, compared with placebo, is effective in lowering the risk for stroke or myocardial infarction among men and women with a recent ischemic stroke or TIA. Secondary aims involve prevention of diabetes and cognitive decline. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SAMPLE SIZE: 3136 participants will be recruited during 6 years and followed for an average of 4 years. POPULATION: - Non-diabetic men & women - Ischemic stroke or TIA within 6 months of enrollment - At least 40 years of age - Able to give informed consent - Insulin resistant (by HOMA-IR index from fasting insulin and glucose values). INTERVENTION: Potential participants are tested for insulin resistance soon after the index stroke or TIA. Those found to have insulin resistance are randomized to placebo or pioglitazone 15 mg tablets. The medication dose is increased each month to a final dose of 3 tablets daily. Thereafter, participants will receive tablets containing placebo or 45 mg pioglitazone for once daily use. After dose escalation, participants will be followed with scheduled telephone calls and annual in-person visits. Blood is drawn annually for safety and efficacy measures. PRIMARY OUTCOMES: Stroke and myocardial infarction. STATISTICAL ANALYSIS: Time to first event by intention to treat. STATUS: Currently recruiting participants. PROGRESS REPORT: 160 centers are actively recruiting participants. Among 5131 patients who have had screening blood work, 3207 (63%) were insulin resistant; of these 3207, 144 (5%) had unrecognized diabetes. A total of 2581 participants had been randomized as of October 1, 2010. STEERING COMMITTEE: Arizona: B. Coull; California: R. Horwitz; Colorado: Greg Schwartz; Connecticut: W. Kernan (PI, Chair), P. Guarino, S. Inzucchi, A. Lovejoy, P. Peduzzi, C. Viscoli, L. Young; Iowa: H. Adams; Maryland: R. Conwit; Massachusetts: K. Furie; Ohio: D. Kleindorfer; Ontario: D. Spence; Oregon: W. Clark; Vermont M. Gorman. Tel Aviv: D. Tanne. Australia: M. Parsons. UK: G. Ford. Germany: P. Ringleb. Italy: A. Carolei. SPONSOR: NINDS. Drug donated by Takeda Pharmaceuticals North America, Inc. CONTACT: [email protected] WEBSITE: iristrial.org Author Disclosure Block: W. Kernan: Other Research Support; Significant; Takeda Pharmaceuticals North America, Inc provides placebo tablets and active pioglitazone tablets to support the IRIS trial. In addition, the company has provided a grant to support storage of blood. K.L. Furie: None. M. Gorman: None. P. Guarino: None. R.I. Horwitz: None. S. Inzucchi: Consultant/Advisory Board; Modest; Intermittent consultation for Takeda Pharmaceuticals North America. A.M. Lovejoy: None. C.M. Viscoli: None. L.H. Young: None. Presentation Number: CT P7 PI Coordinator Affiliation: Newcastle University PI Coordinator Name: Professor A D Mendelow Trial Abbreviation: STICH II Trial Contact Information: Dr Barbara A Gregson; [email protected]; Fax: +44 191 256 3268; Phone: +44 191 256 3139 Trial Email: [email protected] Trial Name: Surgical Trial in Lobar Intracerebral Haemorrhage Trial Registry Number ID: ISRCTN22153967 Trial Sponsor: Newcastle upon Tyne Hospitals NHS Foundation Trust Trial Web Site: www.research.ncl.ac.uk/stich Publishing Title: Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) Author Block: Barbara A Gregson, Newcastle Univ, Newcastle Upon Tyne, United Kingdom; STICH II Investigators Abstract Body: Background Spontaneous superficial intracerebral haemorrhage (ICH) accounts for 20% of all stroke-related sudden neurological deficits and has the highest morbidity and mortality of all strokes. The role of surgery remains controversial following the report of the international STICH trial which was neutral. Further analyses and metaanalysis have suggested that patients with lobar haemorrhage may benefit from early surgery. Objective STICH II aims to establish whether a policy of earlier surgical evacuation of haematomas in selected patients with spontaneous lobar ICH will improve outcome compared to a policy of initial conservative treatment. Design STICH II is an international multicentre randomised parallel group trial. Population Patients for whom the treating neurosurgeon is in equipoise about the benefits and risks of early craniotomy are eligible for the trial. Inclusion criteria include superficial, spontaneous lobar ICH on CT scan, best motor score on the Glasgow Coma Score (GCS) of 5 or 6 and best eye score on the GCS of 2 or more, and volume of haematoma between 10 and 100m. Patients are ineligible if the haemorrhage is due to an aneurysm or angiographically proven arteriovenous malformation, is secondary to tumour or trauma or extends into the basal ganglia, thalamic, cerebellar or brain stem. Patients are also ineligible if there is any Intraventricular haemorrhage or hydrocephalus or if there is severe, pre-existing physical or mental disability or severe comorbidity which might interfere with assessment of outcome. Six hundred patients will be recruited to the trial. Intervention The trial intervention is early evacuation of the haematoma, by craniotomy, within 12 hours of randomisation combined with appropriate best medical treatment versus best medical treatment, combined with delayed evacuation only if it becomes necessary later. Outcome measures Outcome is measured at six months via a structured postal questionnaire including the Glasgow Outcome scale, Modified Rankin Scale and EuroQol. Analysis Analysis will be on an “intention to treat” basis. The primary analysis will be a simple categorical frequency comparison using the chi-squared test for prognosis based favourable and unfavourable outcome at six months. Trial status The STICH II trial is funded by the UK MRC and NIHR EME and sponsored by Newcastle upon Tyne Hospitals NHS Trust. (ISRCTN22153967) Centre and patient recruitment are ongoing. At 15 October 101 centres from 32 countries had been recruited and 360 patients recruited from those 61 of those centres. Current details at 31 January 2011 of recruiting centres and recruited patients will be presented. Author Disclosure Block: B.A. Gregson: Research Grant; Significant; Medical Research Council, NIHR HTA, NIHR EME. Presentation Number: CT P8 PI Coordinator Affiliation: University of Michigan PI Coordinator Name: Lewis B. Morgenstern Trial Abbreviation: NA Trial Contact Information: Lewis B. Morgenstern, [email protected] Trial Email: [email protected] Trial Name: Outcomes of Intracerebral Hemorrhage without Early Do-Not-Resuscitate orders Trial Registry Number ID: NA Trial Sponsor: none Trial Web Site: NA Publishing Title: Outcomes of Intracerebral Hemorrhage without Early Do-Not-Resuscitate Orders: A Multicenter Observational Registry Author Block: Darin B Zahuranec, Univ of Michigan, Ann Arbor, MI; J Claude Hemphill III, Univ of California San Francisco, San Francisco, CA; Kyra J Becker, Univ of Washington, Seattle, WA; Madeleine C Geraghty, Providence Sacred Heart Medical Ctr, Spokane, WA; Brisa N Sanchez, Lewis B Morgenstern, Univ of Michigan, Ann Arbor, MI Abstract Body: Rationale: Traditional outcome prediction models suggest that patients with severe intracerebral hemorrhage (ICH) have a high risk of death. However, early do-not-resuscitate (DNR) orders and withdrawal or limitation of life sustaining treatment (LST) are common after ICH. Predictions from prognostic models and clinical experience assessing outcome are therefore confounded by the intensity of treatment provided. More data are needed on the survival and functional outcome of ICH cases treated with full modern neurocritical care and without early limitations of LST. Study Goal: To compare the 30-day mortality and 90-day functional outcome of patients with severe ICH and without early DNR orders to the predicted outcome based on a published ICH prognostic model. Eligibility and Design: This is an observational study ongoing at 4 centers (University of Michigan, San Francisco General Hospital, University of Washington, and Providence Sacred Heart Medical Center) where the standard care pattern is to avoid early DNR orders or limitations of LST for ICH. Eligibility criteria include: 1) Age ≥ 18 years; 2) Spontaneous ICH; 3) Initial GCS of ≤ 12; and 4) No plans for DNR orders or withdrawal of LST in the first 5 days of hospitalization. Patients with pre-existing DNR orders or clear prior wishes to refuse aggressive treatment for severe illness are excluded. The patient’s legally authorized representative is approached to consent for observational data collection only if they have already agreed to a plan of full supportive treatment as part of regular clinical care. No specific treatments are mandated by the study, and the patient or family may request a DNR order or withdrawal of LST at any time. Data on ICH characteristics and inpatient treatment patterns are collected. Patients are contacted at 30 and 90 days to determine vital status and functional outcome (modified Rankin Scale). The predicted probability of death at 30 days for each patient will be calculated based on the ICH Score, and the average predicted mortality for the cohort will be compared to the observed mortality. The planned sample size of 105 cases study will provide 80% power to detect a 15% absolute difference between observed and predicted mortality. An interim analysis is planned at 61 cases to screen for early evidence of a large effect (absolute mortality difference of 20%). For the analysis of functional outcome, the observed proportion of cases with severe disability (modified Rankin Scale of 5) will be compared to the proportion predicted from prior ICH outcome studies. Pre-defined criteria for a positive study are a 15% absolute reduction in predicted mortality with a less than 10% increase in the proportion of cases with severe disability. Enrollment Progress: As of October 2010, 33 patients have been enrolled at the 4 centers. Any centers wishing to participate should contact Dr. Morgenstern at [email protected]. Future Directions: This study will provide information on the outcome of severe ICH patients treated without early DNR orders or withdrawal of LST. If there is a reduction in mortality without an increase in severe disability, future educational intervention studies designed to reduce use of early treatment limitations after ICH should follow. Author Disclosure Block: D.B. Zahuranec: None. J. Hemphill: None. K.J. Becker: None. M.C. Geraghty: None. B.N. Sanchez: None. L.B. Morgenstern: None. Presentation Number: CT P9 PI Coordinator Affiliation: Georgetown University/UCLA Stroke Center PI Coordinator Name: Chelsea Kidwell, MD/Judy Guzy, RN Trial Abbreviation: MR RESCUE Trial Contact Information: Gina Ramirez, [email protected], 202-687-5396 Trial Email: [email protected] Trial Name: Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy Trial Registry Number ID: NCT00389467 Trial Sponsor: NIH-NINDS Trial Web Site: No website Publishing Title: Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy Author Block: Chelsea S. Kidwell, Georgetown Univ, Washington, DC; Reza Jahan, Sidney Starkman, Jeffry R. Alger, Judy Guzy, UCLA Stroke Ctr, Los Angeles, CA; Gina Ramirez, Georgetown Univ, Washington, DC; Timothy Schaewe, Jeffrey L. Saver, UCLA Stroke Ctr, Los Angeles, CA; MR RESCUE Investigators Abstract Body: Background and Objective: The general aim of the MR RESCUE Trial is to investigate whether multimodal imaging can identify patients who will benefit substantially from mechanical embolectomy with the Concentric Clot Retriever device or the Penumbra System for the treatment of acute ischemic stroke up to 8 hours from symptom onset. Design: MR RESCUE is a randomized, controlled, blinded-outcome phase IIB clinical trial. Population Studied: Acute ischemic stroke patients with large vessel ICA or MCA occlusion enrolled within 8 hours of symptom onset. 120 patients will be enrolled. Intervention: Patients are randomized to embolectomy (employing the Concentric Retriever or Penumbra System) or standard medical care, with randomization stratified by penumbral pattern. Outcome Measures: The primary outcome measure is the day 90 modified Rankin Score. Additional clinical, angiographic, and MRI/CT radiographic outcome measures will also be assessed. Analysis: The primary hypothesis is that the presence of substantial ischemic penumbral tissue on multimodal imaging identifies patients most likely to respond to mechanical embolectomy for acute ischemic stroke. The primary endpoint analyzed will be the distribution of scores on the modified Rankin Scale of global handicap at 90 days. Nested hypotheses test for 1) treatment efficacy in patients with penumbral regions pretreatment, and 2) absence of treatment benefit (equivalency) in patients without penumbral regions pretreatment. Trial Status: Actively recruiting. 84 patients have been enrolled and 27 total sites are participating. Author Disclosure Block: C.S. Kidwell: Research Grant; Significant; NINDS Grant Number P50 NS44378. R. Jahan: ; NINDS Grant Number P50 NS44378. S. Starkman: ; NINDS Grant Number P50 NS44378. J.R. Alger: ; NINDS Grant Number P50 NS44378. J. Guzy: ; NINDS Grant Number P50 NS44378. G. Ramirez: ; NINDS Grant Number P50 NS44378. T. Schaewe: ; NINDS Grant Number P50 NS44378. J.L. Saver: ; NINDS Grant Number P50 NS44378. Presentation Number: CT P10 PI Coordinator Affiliation: Dept. of Neurology, Univ. of Heidelberg PI Coordinator Name: Prof. Dr. Werner Hacke Trial Abbreviation: SPACE2 Trial Contact Information: Dr. Peter Ringleb, [email protected]; fax +49 6221 56 8243 Trial Email: [email protected] Trial Name: Stent-protected Angioplasty in Asymptomatic Trial Registry Number ID: ISRCTN 78592017 Trial Sponsor: DFG/BMBF Trial Web Site: www.space-2.de Publishing Title: SPACE-2: Stent-protected Angioplasty in Asymptomatic Carotid Artery Stenosis vs. Endarterectomy. A three-arm Clinical Trial Author Block: Peter A Ringleb, Tilman Reiff, Hemasse Amiri, Univ hospital Heidelberg, Heidelberg, Germany; SPACE 2 Collaborators Abstract Body: Current recommendations for treatment of asymptomatic carotid stenosis are essentially still based on data from clinical trials performed at the end of the last century. There is increasing evidence of an improved of upto-date best-medical treatment to prevent cerebro- and cardiovascular risk as compared to a decade ago. Considering a low risk rate with up-to-date pharmacotherapy, interventional therapies such as CEA and, in particular, CAS need their specific justification because they are associated with considerable periinterventional risks. SPACE-2 is a three-armed study with a randomized, controlled, open, multi-centre design comparing best medical treatment with CEA and CAS. A hierarchical study protocol has been developed with a superiority design of interventional vs. conservative treatment. In case superiority for CAS and CEA is established vs best medical treatment alone, a non-inferiority comparison between the two interventions will be performed. All patients are treated in accordance with their individual risk factor profile and risk factors.. Primary safety endpoint is assessed as the rate of any stroke and death from any cause within 30 days of treatment. The primary efficacy endpoint is the cumulative rate of any stroke or death from any cause within 30 days plus ipsilateral ischemic stroke within 5 years of follow up. Secondary endpoints also include myocardial infarction. 3,640 subjects are envisaged to be enrolled in the clinical trial. Randomization has started in Juli 2009. Currently, 34 centers in Germany, Austria and Switzerland are participating. The study is funded by the German Research Foundation (DFG) and the Federal Ministry of Education and Research (BMBF). The results of this trial are expected to be important for defining a proven standard for the best possible treatment of asymptomatic carotid artery stenosis and would have wide impact on managing this disease. Author Disclosure Block: P.A. Ringleb: None. T. Reiff: None. H. Amiri: None. Presentation Number: CT P11 PI Coordinator Affiliation: MUSC/Emory PI Coordinator Name: Chimowitz/Lane Trial Abbreviation: SAMMPRIS Trial Contact Information: Bethany Lane, [email protected], 866-767-4594 (fax) Trial Email: NA Trial Name: Stenting versus Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis Trial Registry Number ID: NCT00576693 Trial Sponsor: NIH/NINDS Trial Web Site: http://www.sammpris.org/ Publishing Title: Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) Author Block: Colin Derdeyn, Washington Univ Sch of Med, St. Louis, MO; Marc Chimowitz, Medical Univ of South Carolina, Charleston, SC; David Fiorella, State Univ of New York, Stony Brook, Stony Brook, NY; Tanya Turan, Medical Univ of South Carolina, Charleston, SC; Bethany Lane, Michael Lynn, Emory Univ Sch of Med, Atlanta, GA; Scott Janis, Natl Inst of Neurological Disorders and Stroke, Bethesda, MD Abstract Body: Background: Atherosclerotic stenosis of the major intracranial arteries is an important cause of ischemic stroke. In the USA, intracranial stenosis causes approximately 50,000 strokes per year. The recently concluded Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial provided key information regarding the risk of future stroke in this population. Patients with severe stenosis (70%-99%), recent TIA or stroke, female gender, and baseline NIH stroke scale > 1 were at highest risk of stroke in the territory of the stenotic artery. Patients with severe stenosis (70% - 99%) and TIA or stroke within 30 days prior to enrollment had a 22.9% rate of ischemic stroke in the territory of the symptomatic artery at one year ((5% CI 15.4% - 30.4%). In addition, patients with poorly controlled blood pressure and elevated low denisty lipoprotein (LDL) during follow-up had a significantly higher rate of stroke, myocardial infarction (MI), or vascular death, compared with patients with good control of these risk factors. Stenting has emerged as a promising treatment for intracranial stenosis that is increasingly being used in clinical practice in the USA and other developed countries. The efficacy of this procedure remains to be proven. Given the clear impact of poorly controled risk factors on outcome, proof of efficacy will require a randomized clinical trial comparing stenting and aggresive medical therapy vs. aggressive medical therapy alone in patients with symptomatic intracranial arterial stenosis. Objective and Primary Endpoints: To determine whether intracranial stenting (using the Wingspan selfexpanding nitinol stent) and intensive medical therapy is superior to intensive medical therapy alone for preventing the primary endpoint (any stroke or death within 30 days after enrollment, any stroke or death within 30 days of re-angioplasty of symptomatic restenosis of the qualifying lesion, or stroke in the territory of the symptomatic intracranial artery beyond 30 days) during a mean follow-up of two years in high-risk patients with symptomatic stenosis of a major intracranial artery (MCA, carotid, vertebral, basilar). Design: SAMMPRIS is an investigator-initiated, Phase III, multi-center, randomized, blindly-adjudicated clinical trial of angioplasty and stenting with aggressive medical management versus medical management alone. The anticipated sample size is 764 subjects. The primary inclusion criteria include recent ischemic symptoms (within 30 days of enrollment) and a 70 to 99% atherosclerotic stenosis of a major intracranial artery amenable to angioplasty and stenting. The aggressive medical therapy regimen consists of aspirin 325 mg per day for entire follow-up, clopidogrel 75mg per day for 90 days after enrollment and aggressive risk factor management primarily targeting blood pressure < 140 / 90 mm Hg (< 130 / 80 if diabetic) and LDL < 70mg/dl. . Risk factor management will be performed by the study neurologist at each site who will be assisted by an innovative, evidence-based, educational, lifestyle modification program (INTERxVENT). Trial Status: Sixty sites (the maximum allowed under the FDA IDE for the Wingspan stent) have been selected. Site selection was a two step process involving credentialing of the study interventionalists by the SAMMPRIS Interventional Credentialing Committee and a separate evaluation of the clinical site, based on the experience and availability of a neurologist and study coordinator from the site, and a favorable review of the site by the 3rd party monitor performing the qualifying site visit. The study began actively enrolling subjects November 18th, 2008. As of October 30th, 2010, 386 subjects have been randomized at 43 active sites. Author Disclosure Block: C. Derdeyn: Consultant/Advisory Board; Significant; W.L. Gore and Associates. M. Chimowitz: None. D. Fiorella: ; Microvention/Terumo; Codman. T. Turan: None. B. Lane: None. M. Lynn: None. S. Janis: None. Presentation Number: CT P12 PI Coordinator Affiliation: Washington University School of Medicine PI Coordinator Name: Derdeyn/Hantler Trial Abbreviation: NA Trial Contact Information: Nancy Hantler, CCRC Trial Email: [email protected] Trial Name: The Role of Cerebral Hemodynamics in Moyamoya Disease Trial Registry Number ID: NCT00629915 Trial Sponsor: NINDS Trial Web Site: http://neuro.wustl.edu/patientcare/clinicalservices/moyamoyacenter.htm Publishing Title: The Role of Cerebral Hemodynamics in Moyamoya Disease Author Block: Colin Derdeyn, Washington Univ Sch of Med, St. Louis, MO; Patricia Davis, Univ of Iowa Sch of Med, Iowa City, IA; Shyam Prabhakaran, Rush Univ Sch of Med, Chicago, IL; Venkatesh Aiyagari, Univ of Illinois at Chicago, Chicago, IL; Christina Ivan, Indiana Univ Sch of Med, Indianapolis, IN; Allyson Zazulia, Tom Videen, Nancy Hantler, John Lee, Robert Grubb Jr, Gregory Zipfel, Phil Miller, Washington Univ Sch of Med, St. Louis, MO Abstract Body: Background: Moyamoya phenomenon is secondary response to an obliterative vasculopathy involving the large arteries at the base of the brain (Figure 1). The nature of this vasculopathy is unknown and may be multifactorial. In the United States, moyamoya phenomenon most commonly affects women in their third and fourth decades of life, and is frequently associated with ischemic stroke (1,2). The natural history of this disorder is not known, nor is the benefit of surgical revascularization procedures. The mechanism of stroke in these patients is not known, but hemodynamic factors are likely to play a major role. Severe hemodynamic impairment has been shown to predict the risk of future stroke in patients with atherosclerotic carotid artery occlusion (Figure 2) (3). Objectives: The primary objective (Aim 1) is to test the hypothesis that increased oxygen extraction in the cerebral hemisphere beyond the occlusive lesion is a predictor of subsequent risk of ipsilateral stroke. Secondary aims are (2A) to determine other predictive factors for stroke in this population; (2B) to obtain preliminary estimates of the effects of different medical treatment regimens in this population; (2C) to determine the temporal changes in hemodynamic impairment in medically treated patients; (2D) to obtain determine the effects of surgery on hemodynamic impairment in the subset of patients that undergo surgical revascularization; (2E) to obtain estimates of surgical complication rates for patients with and without hemodynamic impairment. Study Design: This is a prospective, blinded (to hemodynamic status), independently-adjudicated natural history study 4. Some patients may undergo surgical revascularization procedures, based on the discretion of treating physicians. The outcome of these patients will also be determined. On enrollment, all patients will undergo regional measurements of cerebral oxygen extraction fraction (OEF) with positron emission tomography (PET, Figure 2). Information on baseline clinical, laboratory, epidemiologic, and angiographic risk factors will be obtained at the time of the PET study. Patients will be followed at six-month intervals to determine the subsequent risk of ipsilateral stroke. All patients will return at one and three years for repeat PET studies. We anticipate 50 patients will be enrolled over the next five years (10 per year). Each involved hemisphere will be treated separately, for a total of 100 cerebral hemispheres at risk. Treating physicians and patients will be blinded to the results of the PET scan. The primary objective (Aim 1) is to test the hypothesis that increased oxygen extraction in the cerebral hemisphere beyond the occlusive lesion is a predictor of subsequent risk of ipsilateral stroke. Inclusion/Exclusion Criteria: Inclusion criteria: . Adult > 18 years of age . Capable of informed consent . Clinical: Both asymptomatic and symptomatic patients will be included. . Anatomic: Unilateral or bilateral imaging findings consistent with moyamoya collaterals (Suzuki stages 3 and 4) on digital subtraction, computed tomographic, or magnetic resonance angiography (after Suzuki and Kodama, 1983, 5) Exclusion criteria: . Any other disease that might be responsible for the vasculopathy, including atherosclerosis, neurofibromatosis, meningitis, sickle cell disease, skull base radiation therapy. . Pregnancy: All women of child-bearing potential will be tested for pregnancy using a urine b-HCG test on the day of the enrollment and follow up PET scans. Data Analysis: Medically-treated hemispheres will be followed over the 5 - year study for the occurrence of ipsilateral ischemic stroke, the primary endpoint. End point assessment will be made blind to PET data. The threshold for abnormal OEF will be set prospectively as > 0.44. The primary statistical analysis will be a comparison on the survival distribution of the time to stroke occurrence in hemispheres with increased OEF versus those with normal OEF on initial PET studies. This analysis will be done using a log-rank test (Aim 1). Cox’s proportional hazards models will be used to perform the comparison after adjusting the effect of other covariates (Aim 2A). Depending on the variability of medical treatment, the treatment regimen may be added as a variable (Aim 2B). Repeat PET measurements of OEF in medically and surgically treated hemispheres will be compared to baseline measurements to determine if OEF improves over time in either group (Aims 2C and 2D). Trial Status: Trial is ongoing. Funding was received from the NIH in September 2006 (RO1 NS051631). Enrollment is proceeding at target pace, with 46 subjects enrolled to date. Participating Sites: Washington University, St Louis; University of Illinois-Chicago, Rush University, Indiana University, University of Iowa Author Disclosure Block: C. Derdeyn: None. P. Davis: None. S. Prabhakaran: None. V. Aiyagari: None. C. Ivan: None. A. Zazulia: None. T. Videen: None. N. Hantler: None. J. Lee: None. R. Grubb: None. G. Zipfel: None. P. Miller: None. Presentation Number: CT P13 PI Coordinator Affiliation: The George Institute for Global health, Royal Prince Alfred Hospital, University of Sydney PI Coordinator Name: ANDERSON CRAIG Trial Abbreviation: INTERACT2 Trial Contact Information: Craig Anderson [email protected] Trial Email: [email protected] Trial Name: The second Intensive Blood Pressure Reduction in Intracerebral Hemorrhage Trial Trial Registry Number ID: ACTRN1260800036239, NCT00716079, ISRCTN73916115 Trial Sponsor: NHMRC Trial Web Site: https://studies.thegeorgeinstitute.org.au/interact2 Publishing Title: Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2): progress update on the largest clinical trial in ICH Author Block: Craig Anderson, The George Inst for Global Health, Royal Prince Alfred Hosp, Sydney Univ, Sydney, Australia; Yining Huang, Peking Univ First Hosp, Beijing, China; Jiguang Wang, Ctr for Epidemiological Studies and Clinical Trials, Rui Jin Hosp, Shanghai, China; Emma Heeley, Candice Delcourt, Richard Lindley, The George Inst for Global Health, Royal Prince Alfred Hosp, Sydney Univ, Sydney, Australia; Christian Stapf, Lariboisiere Hosp, Paris, France; Christophe Tzourio, INSERM Unit 708, Paris, France; Hisatomi Arima, The George Inst for Global Health, Royal Prince Alfred Hosp, Sydney Univ, Sydney, Australia; Mark Parsons, John Hunter Hosp and Hunter Medical Res Unit, Newcastle, Australia; Bruce Neal, John Chalmers, The George Inst for Global Health, Royal Prince Alfred Hosp, Sydney Univ, Sydney, Australia; The INTERACT2 Investigators Abstract Body: Background: INTERACT2, an open, randomised, multicentre study, aims to establish the effectiveness of early intensive blood pressure (BP) lowering treatment in acute ICH, the most serious and least treatable form of stroke. Methods A total of 2800 patients with ICH and elevated systolic BP (150-220 mmHg) and capacity to receive intensive BP lowering treatment <6 hours of onset are to be included from ~140 sites worldwide. Simple electronic data collection procedures are used and patients are centrally randomly assigned to intensive (target systolic <140 mmHg) or conservative (target systolic <180 mmHg) BP management using routine intravenous agents. Vital status and disability is assessed at 28 and 90 days. CT digital images are analysed centrally. The trial is registered (ACTRN1260800036239, NCT00716079, ISRCTN73916115). Results Since launch of the study in October 2008, 1400 patients have been randomised from China (46 sites), Australia (8), Europe (3 Austria, 1 Belgium, 11 France, 6 Germany, 3 Italy, 1 Portugal, 3 Spain). India (5), Pakistan (1), and Chile (1). Preliminary data indicates similar patient and clinical characteristics to INTERACT1, and good BP separation between groups. The clinical network has expanded to include sites additional non-Asian sites. Conclusions: Recruitment and quality parameters indicate INTERACT2 is on schedule to achieve the study goals. Author Disclosure Block: C. Anderson: None. Y. Huang: None. J. Wang: None. E. Heeley: None. C. Delcourt: None. R. Lindley: None. C. Stapf: None. C. Tzourio: None. H. Arima: None. M. Parsons: None. B. Neal: None. J. Chalmers: None. Presentation Number: CT P14 PI Coordinator Affiliation: University of Minneosta PI Coordinator Name: Adnan I. Qureshi Trial Abbreviation: ATACH-II Trial Contact Information: Bo Connelly, [email protected], (612) 625-6974 Trial Email: [email protected] Trial Name: Antihypertensive Treatment of Acute Cerebral Hemorrhage II Trial Registry Number ID: NCT01176565 Trial Sponsor: University of Minnesota - Clinical and Translational Science Institute Trial Web Site: www.atach-2.com Publishing Title: Antihypertensive Treatment of Acute Cerebral Hemorrhage II Author Block: Adnan I. Qureshi, Univ of Minnesota, Minneapolis, MN; ATACH-II Investigators Abstract Body: The December 2003 report from a National Institute of Neurological Disorders and Stroke (NINDS)Workshop on priorities for clinical research in intracerebral hemorrhage (ICH) recommended clinical trials for evaluation of blood pressure (BP) management in acute ICH as a leading priority. The Special Writing Group of the Stroke Council of the American Heart Association in 1999 and 2007 emphasized the need for clinical trials to ensure evidence-based treatment of acute hypertension in ICH. To address important gaps in current knowledge, we propose to conduct a five-year multi-center, randomized, controlled, Phase III trial with blinded outcome ascertainment to determine the efficacy of early, intensive antihypertensive treatment using intravenous nicardipine for acute hypertension in subjects with spontaneous supratentorial ICH. The primary hypothesis of this large, streamlined, focused trial is that intensive systolic blood pressure (SBP) reduction (SBP less than or equal to 140mmHg -- hereafter referred to as the intensive treatment) using intravenous (IV) nicardipine with treatment initiated within 3 hours of onset of ICH and continued for the next 24 hours reduces the likelihood of death or disability at 3months after ICH (defined by modified Rankin scale [mRS] score of 46)by 10% or greater (absolute difference) compared with standard SBP reduction (SBP less than or equal to 180mmHg -- hereafter referred to as the standard treatment). The underlying mechanism for this expected beneficial effect of intensive treatment is presumably mediated through reduction of the rate and magnitude of hematoma expansion observed in approximately 73% of patients with acute ICH. The trial will recruit a maximum of 1,280 subjects with ICH who meet the eligibility criteria. The proposed clinical trial is a natural extension of numerous case series, a subsequent pilot trial funded by NINDS, and a preliminary randomized controlled trial in this patient population funded by the Australian National Health and Medical Research Council. Both trials recently confirmed the safety and tolerability of both the regimen and goals of antihypertensive treatment in acutely hypertensive patients with ICH, as proposed in the present trial. The Australian trial provided preliminary evidence of attenuation of hematoma expansion with intensive SBP reduction. The proposed trial will have important public health implications by providing necessary information regarding the efficacy and safety of antihypertensive treatment of acute hypertension in subjects with ICH. BP treatment represents a strategy that can be made widely available without the need of specialized equipment and personnel and therefore can make a major impact upon outcome in patients with ICH. Author Disclosure Block: A.I. Qureshi: Research Grant; Significant; National Institutes of Health, American Heart Association. Other Research Support; Significant; Minnesota Medical Foundation, ESP Pharma, EKR Therapeutics. Presentation Number: CT P15 PI Coordinator Affiliation: Rush University Medical Center and University of Miami PI Coordinator Name: Shyam Prabhakaran, MD, MS and Jose G. Romano, MD Trial Abbreviation: MoSIS Trial Contact Information: Iszet Campo-Bustillo, MPH, Phone: (305) 243-8018, Fax: (305) 243-7081, Email: [email protected] Trial Email: [email protected] Trial Name: Mechanisms of Stroke in Intracranial Stenosis Trial Registry Number ID: NCT01152944 Trial Sponsor: National Institute of Neurologic Disorders and Stroke Trial Web Site: http://clinicaltrials.gov/ct2/show/NCT01152944 Publishing Title: Mechanisms of Stroke in Intracranial Stenosis (MoSIS - NCT01152944) Author Block: Shyam Prabhakaran, Rush Univ Medical Ctr, Chicago, IL; David S Liebeskind, Univ of California Los Angeles, Los Angeles, CA; Iszet Campo-Bustillo, Tatjana Rundek, Sebastian Koch, Univ of Miami, Miller Sch of Med, Miami, FL; Miral D. Jhaveri, Rush Univ Medical Ctr, Chicago, IL; Michael Lynn, Emory Univ, Atlanta, GA; Colin P. Derdeyn, Washington Univ Sch of Med, St. Louis, MO; Marc I. Chimowitz, Medical Univ of South Carolina, Charleston, SC; Jose G. Romano, Univ of Miami, Miller Sch of Med, Miami, FL Abstract Body: Background: Intracranial atherosclerotic disease causes up to 10% of strokes in the United States and may be the most important cause of ischemic stroke worldwide. The risk of recurrent stroke is as high as 25% over 2 years in those with stenosis 70-99%. The mechanisms for recurrent stroke remain unclear, however. Progressive arterial narrowing, plaque instability (thrombo-embolism), and/or exhausted vasomotor reactivity with impaired collateral flow are potential mechanisms that may elevate stroke risk. Objective: Understand the mechanisms that underlie ischemic stroke in high-grade intracranial atherosclerotic disease in order to determine predictors of recurrent stroke Design: Prospective investigator-blinded ancillary study to the ongoing Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial Study population: 100 medically-treated patients in SAMMPRIS trial with recently symptomatic (< 30 days) high grade (70-99%) intracranial stenosis of the carotid, middle cerebral, vertebral, or basilar arteries. Besides SAMMPRIS eligibility criteria and randomization to medical arm, MoSIS requires informed consent and excludes patients with documented magnetic resonance imaging and/or transcranial Doppler (TCD) contraindications. Intervention: Baseline TCD with emboli detection and vasomotor reactivity, quantitative magnetic resonance angiography (QMRA), post-processing perfusion angiography, and serial single-vessel TCD every four months Outcome measure: Ischemic stroke in the territory of the stenotic artery Analysis: The relationship between the time to ischemic stroke in the territory and each of the imaging measurement variables (TCD, QMRA, and perfusion angiography) will be assessed using the log-rank test. Using Cox-proportional hazards models, the hazard ratio for each imaging parameter will be calculated with multivariable adjustments for relevant risk factors. Status: Up to 15 sites in SAMMPRIS will participate in MoSIS Principal Investigators: Shyam Prabhakaran, MD, MS and Jose Romano, MD Affiliations: Rush University Medical Center and University of Miami Coordinator: Iszet Campo-Bustillo, MPH, University of Miami Sponsor: National Institute of Neurologic Disorders and Stroke Contact: Iszet Campo-Bustillo, MPH, Clinical Research Building (C215), 1120 NW 14th St. Suite# 1361-1, Miami, FL 33136, Phone: (305) 243-8018, Fax: (305) 243-7081, email: [email protected] Website: http://clinicaltrials.gov/ct2/show/NCT01152944 Author Disclosure Block: S. Prabhakaran: None. D.S. Liebeskind: None. I. Campo-Bustillo: None. T. Rundek: None. S. Koch: None. M.D. Jhaveri: None. M. Lynn: None. C.P. Derdeyn: None. M.I. Chimowitz: None. J.G. Romano: None. Presentation Number: CT P16 PI Coordinator Affiliation: Stanford University Stroke Center PI Coordinator Name: Gregory W. Albers Trial Abbreviation: DIAS-3 and DIAS-4 Trial Contact Information: H. Lundbeck A/S Trial Email: [email protected] Trial Name: Desmoteplase in Acute Ischemic Stroke Trial Registry Number ID: NCT00790920 and NCR0085661 Trial Sponsor: H. Lundbeck A/S, Copenhagen, Denmark Trial Web Site: www.lundbeck-dias.com Publishing Title: Desmoteplase in Acute Ischemic Stroke: Status Update on the DIAS Clinical Trial Program Author Block: Gregory W Albers, Stanford Univ Stroke Ctr, Palo Alto, CA; Rüdiger von Kummer, Univ of Technology, Dresden, Germany; on behalf of the DIAS-3 and DIAS-4 Study Group Abstract Body: Desmoteplase is a novel, highly fibrin-specific thrombolytic agent in Phase III of clinical development. The structure of desmoteplase is similar to rt-PA (alteplase), but it does not contain the plasmin-sensitive cleavage site and the lysine-binding Kringle 2 domain. As a result, desmoteplase, compared with rt-PA, has high fibrin selectivity, an absence of neurotoxicity, and no apparent negative effect on the blood-brain barrier. Evidence of safety and efficacy of desmoteplase was obtained in the Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS) and Desmoteplase in Acute Ischemic Stroke (DIAS) Phase II trials. The DIAS2 Phase III trial supported the safety profile of desmoteplase but did not replicate the positive efficacy findings of DEDAS and DIAS. Post hoc analyses of patients with TIMI scores 0-1 revealed lower response rates in the placebo group (18%) and higher response rates in the desmoteplase groups (36% and 27% for desmoteplase 90 µg/kg and 125 µg/kg, respectively). Therefore, in 2009, 2 large, randomized, double-blind, placebocontrolled, multinational Phase III trials were initiated (DIAS-3 and DIAS-4, n=800: NCT00790920 and NCT00856661) to evaluate the efficacy and safety of a single intravenous bolus of 90 µg/kg desmoteplase given 3-9 hours after onset of ischemic stroke (NIHSS score 4-24, age 18-85 y). Patients are selected with occlusion or high-grade stenosis (TIMI 0-1) in proximal cerebral arteries as assessed by magnetic resonance or computed tomography angiography. Whenever possible, additional perfusion-weighted imaging and diffusion-weighted imaging assessments are done. Further trial information will be presented at this congress. In support of the program, a DIAS trial network (hub-spoke model) has been implemented in the United States that consists of both tertiary and community-based acute stroke centers managed by regional hub directors, representing standard clinical practice for a majority of potential stroke patients. The initiative will provide an opportunity to extend medical treatment to patients who would ordinarily not have access to thrombolytic therapy. In 2009, a Phase I desmoteplase trial was completed in healthy Japanese and Caucasian men, assessing the safety, tolerability, and pharmacokinetics of desmoteplase at doses up to 90 µg/kg. The results of this study were presented at the 2010 World Stroke Conference in Seoul. Subsequently, a randomized, double-blind, placebo-controlled, dose-escalation Japanese Phase II trial was initiated in September 2010 (DIAS-J; NCT01104467). The primary objective of DIAS-J is to evaluate the safety and tolerability of desmoteplase 70 and 90 µg/kg 3-9 hours after onset of ischemic stroke in Japanese patients (n=48). Secondary objectives are to evaluate clinical improvement up to day 90; recanalization and change in infarct size 18±6 hours after start of treatment; and to study pharmacokinetics, pharmacodynamics and immunogenicity. Desmoteplase is the only thrombolytic agent in late-stage development despite the high unmet treatment need in acute ischemic stroke. Therefore, the results of the DIAS clinical trial program will be important for physicians and patients in need of a safer, effective treatment for acute ischemic stroke. Author Disclosure Block: G.W. Albers: Honoraria; Modest; H. Lundbeck A/S, Boerhinger Ingelheim. R. von Kummer: ; H. Lundbeck A/S. Presentation Number: CT P17 PI Coordinator Affiliation: David Geffen School of Medicine at UCLA PI Coordinator Name: Jeffrey Saver, MD / Fiona Chatfield, RN Trial Abbreviation: FAST-MAG Trial Contact Information: Jeffrey Saver, MD / [email protected] Trial Email: [email protected] Trial Name: Field Administration of Stroke Therapy - Magnesium Phase 3 Clinical Trial Trial Registry Number ID: NCT00059332 Trial Sponsor: NIH-NINDS Trial Web Site: www.fastmag.info Publishing Title: The Field Administration of Stroke Therapy - Magnesium (FAST-MAG) Phase 3 Clinical Trial Author Block: Jeffrey L Saver, Geffen Sch of Med at UCLA, Los Angeles, CA; Marc Eckstein, Los Angeles Fire Dept EMS and USC, Los Angeles, CA; Sam Stratton, OC EMS Agency and Harbor-UCLA Medical Ctr, Los Angeles, CA; Frank Pratt, LA County Fire EMS, Los Angeles, CA; Scott Hamilton, Stanford, San Francisco, CA; Robin Conwit, NIH-NINDS, Bethesda, MD; David S Liebeskind, Geffen Sch of Med at UCLA, Los Angeles, CA; Gene Sung, Nerses Sanossian, Univ of Southern California, Los Angeles, CA; for the FASTMAG Investigators and Coordinators Abstract Body: BACKGROUND: Magnesium is neuroprotective in preclinical models of stroke and has been safe and shown signals of potential efficacy when delivered early after onset of human cerebral ischemia. Delayed initiation of neuroprotective agents has hindered past phase 3 neuroprotective agent trials. OBJECTIVE: To demonstrate that paramedic initiation of intravenous magnesium sulfate within 2 hours ofsymptom onset improves the longterm functional outcome of hyperacute stroke patients. DESIGN: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial. POPULATION STUDIED: 1700 patients (850 in each arm) with acute stroke, including both cerebral infarction and intracerebral hemorrhage patients. Inclusion criteria: 1) likely stroke as identified by the Los Angeles Prehospital Stroke Screen (LAPSS), 2) age 40-95, 3) symptom onset within 2 hours of treatment initiation, 4) deficit present ≥ 15 minutes. INTERVENTION: Paramedics administer a loading dose of magnesium sulfate (Mg) or matched placebo in the field, 4 grams over 15 minutes. In the ED, a maintenance infusion follows, 16 grams Mg or matched placebo over 24 hours. OUTCOME MEASURE(S): The primary endpoint is the modified Rankin Scale global measure of functional outcome, assessed 90 days after treatment. Secondary endpoints include NIHSS (neurologic deficit), Barthel Index (disability), and Stroke Impact Scale (quality of life). ANALYSIS: The primary analysis will assess the difference in the distribution of mRS scores between treated and placebo groups, employing the Cochran-Mantel-Haenszel test statistic (shift analysis). TRIAL SITES: The trial is being conducted in two regional stroke systems: 1) Los Angeles County EMS, including 31 EMS provider agencies, 41 stroke receiving hospitals, 228 ambulances, and 2200 paramedics; and 2) Orange County EMS, including 13 EMS provider agencies, 9 stroke receiving hospitals, 125 ambulances, and 1250 paramedics. Site investigators include over 400 emergency physicians and over 150 neurologists, neurosurgeons, and hospitalists. TRIAL STATUS: Through 11/1/2010, 1126 patients had been enrolled. Median interval from last known well to start of study agent is 46 minutes. Treatment was initiated within 1 hour of onset in 73% and between 1-2 hours in 25%. Median pretreatment stroke severity on the Los Angeles Motor Scale (LAMS) is 4. Adjudicated final diagnoses are acute cerebral ischemia in 73%, intracerebral hemorrhage in 24%, and stroke mimic in 3%. Author Disclosure Block: J.L. Saver: None. M. Eckstein: None. S. Stratton: None. F. Pratt: None. S. Hamilton: None. R. Conwit: None. D.S. Liebeskind: None. G. Sung: None. N. Sanossian: None. Presentation Number: CT P18 PI Coordinator Affiliation: Mayo Clinic Florida/UMDNJ-New Jersey Medical School PI Coordinator Name: Thomas G. Brott, MD/Alice J. Sheffet, Ph.D. Trial Abbreviation: CREST Trial Contact Information: Alice J Sheffet, [email protected], www.cresttrial.org, fax=973-972-8383, phone=973-972-7718 Trial Email: [email protected] Trial Name: Carotid Revascularization Endarterectomy versus Stenting Trial (CREST): Long Term Follow-up Trial Registry Number ID: NCT00004732 Trial Sponsor: NINDS/NIH Trial Web Site: www.cresttrial.org Publishing Title: Carotid Revascularization Endarterectomy versus Stenting Trial (CREST): Long Term Follow-up Author Block: Alice J Sheffet, Susan E Hughes, MeeLee Tom, UMDNJ NJ MEDICAL SCHOOL, Newark, NJ; Donald V Heck, Forsyth Radiological Associates, Winston-Salem, NC; Bart Demaerschalk, Mayo Clinic Arizona, Scottsdale, AZ; Irfan Altafullah, Minneapolis Clinic of Neurology, Golden Valley, MN; David Chiu, The Methodist Hosp, Houston, TX; Jenifer H Voeks, Jason Avery, Univ of Alabama at Birmingham, Birmingham, AL; Mary E Longbottom, Thomas G Brott, for the CREST Investigators, Mayo Clinic Florida, Jacksonville, FL Abstract Body: BACKGROUND: Multisite clinical trials currently support guidelines for carotid treatment based on 2-4 years of follow-up for patients living decades after revascularization. Designed to establish the relative efficacy of carotid endarterectomy (CEA) versus carotid stenting (CAS), the NINDS-funded Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), completed enrollment July 18, 2008. Randomization of 2502 symptomatic (1321) and asymptomatic (1181) patients occurred at 117 North American sites. Primary results were published July 1, 2010 for periprocedural and midterm outcomes with a median follow-up of 2.5 years. The risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly for CEA and CAS. OBJECTIVE: Extension of CREST follow-up for up to ten years to evaluate the clinical and anatomic durability of CAS versus CEA (as assessed by ipsilateral stroke and recurrent stenosis > 50%). DESIGN: CREST (ClinicalTrials.gov NCT00004732) is an NINDS-funded, randomized, two-arm, multicenter clinical trial with blinded endpoint adjudication. Extended follow-up of CREST CAS and CEA subjects includes annual clinic visits and midpoint telephone visits (maximum 10 years follow-up; average 7.5 years). POPULATION: Active post-procedure symptomatic and asymptomatic CREST subjects (n=2000) reconsented for up to 10 years of follow-up. OUTCOMES: The primary aim is to assess CEA versus CAS in the prevention of ipsilateral stroke. Secondary aims will 1) assess if there are effect modifiers of the long-term durability of the two procedures, such as age, sex, pre-procedural degree of stenosis and symptomatic status, 2) assess if there is a temporal change or pattern in the relative efficacy of the two procedures, 3) assess differences between groups in the rates of restenosis or revascularization, 4) link Medicare-eligible CREST participants with inpatient and outpatient CMS data files to assess patient outcomes and utilization of healthcare services. ANALYSIS: Statistical analysis of the primary aim (time-to-event modeling with adjustment for major baseline covariates) will assess post-procedural treatment differences from Day 31 up to ten years, providing 90% power to detect a hazard ratio of 1.67. TRIAL STATUS: On February 5, 2010, NINDS Council approved the extension of CREST long-term follow-up through 2015. Protocol Amendment VI, approved by the DSMB, FDA, and UMDNJ IRB of Record (May 21 to August 26, 2009) extends ongoing follow-up for up to 10 years. The visit schedule and forms have been streamlined for efficient reporting of events and data collection necessary for the assessment of the longerterm differential effectiveness of CAS versus CEA. With the focus on long-term clinical outcomes, simplification of the follow-up protocol will result in reduced patient/clinic burden and reduced cost. To date, 111 site IRBs have approved long-term follow-up with 1064 CREST subjects re-consented for extended follow-up. Top reconsenting sites are: Central Baptist Hospital, Lexington, KY; CHA Hospital L’Enfant Jesus, Quebec City, Canada; Oregon Health Science University, Portland, OR; University of Calgary, Calgary, Canada; and Heritage Valley Health Systems, Beaver, PA. Continuing CREST follow-up will allow comparative assessment of clinical and anatomical durability of CEA and CAS in symptomatic and asymptomatic patients for the longest period in any carotid trial. Author Disclosure Block: A.J. Sheffet: None. S.E. Hughes: None. M. Tom: None. D.V. Heck: Other Research Support; Modest; Local Site PI on SAPPHIRE-WW, CHOICE, CABANA and ACT I trials. B. Demaerschalk: None. I. Altafullah: ; Local Site PI of the CHOICE registry that is sponsored by Abbott. D. Chiu: None. J.H. Voeks: None. J. Avery: None. M.E. Longbottom: None. T.G. Brott, for the CREST Investigators: Honoraria; Modest; Sahs Memorial Lecture University of Iowa, VEITH Symposium, American Academy of Neurology 62nd Annual Meeting, Heritage Valley Health System, American Society of Neuroradiology 48th Annual Meeting, Massachusetts General Hospital, Pennsylvania Advances in Stroke. Presentation Number: CT P19 PI Coordinator Affiliation: University of British Columbia/University of Texas Health Science Center at San Antonio PI Coordinator Name: Oscar Benavente/Robert Hart/Ana Roldan/Marie Benavente Trial Abbreviation: SPS3 Trial Contact Information: Oscar Benavente, MD/[email protected]/604-822-1789 Trial Email: [email protected] Trial Name: Secondary Prevention of Small Subcortical Strokes Trial Registry Number ID: NCT00059306 Trial Sponsor: NIH/NINDS Trial Web Site: www.sps3.org Publishing Title: Secondary Prevention of Small Subcortical Strokes (SPS3) Author Block: Ana Roldan, Marie Benavente, UNIVERSITY OF BRITISH COLUMBIA, VANCOUVER, BC, Canada; Pablo Pergola, Gabriela Pergola, UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO, SAN ANTONIO, TX; Leslie McClure, Jeff Szychowski, UNIVERSITY OF ALABAMA, Birmingham, AL; Christopher Coffey, UNIVERSITY OF IOWA, Iowa, IA; Robin Conwit, NIH/NINDS, Bethesda, MD; Robert Hart, UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO, San Antonio, TX; Oscar Benavente, UNIVERSITY OF BRITISH COLUMBIA, VANCOUVER, BC, Canada Abstract Body: Background Small subcortical strokes(S3) account for about 25% of all brain infarcts, are very frequent among Hispanic Americans(HA) and are usually due to cerebral small artery disease which predisposes to vascular dementia. Over 2 million S3 survivors are at high risk of stroke recurrence and subsequently vascular dementia; millions more suffer subclinical S3 and cognitive decline caused by the intrinsic disease of the small penetrating cerebral arteries. No previous randomized trials have focused on secondary prevention after S3 or subcortical TIA, optimal target levels of BP control after stroke and their relationship to cognitive decline, or prevention of stroke and dementia in HA. Objectives Determine: if the combination of Aspirin 325 mg/d+Clopidogrel 75 mg/d is more efficacious than Aspirin 325 mg/d alone AND whether intensive BP lowering (systolic <130 mmHg) is superior to usual hypertension management (systolic between 130-149 mmHg) in reducing stroke recurrence, cognitive decline and major vascular events in patients with symptomatic S3 or subcortical Transit Ischemic Attack (TIA). Methods SPS3 is a randomized multicenter clinical trial . Patients are assigned in a factorial design to 2 interventions: a. Aspirin 325 mg/d vs. Aspirin 325 mg/d+Clopidogrel 75 mg/d. (double-blinded). b. Two targets of systolic BP, “usual” (130-149 mmHg) vs.“intensive” (<130 mmHg). (open-label with blinded event assessment). Will include 3000 participants with symptomatic, MRI documented S3/subcortical TIA within the prior 6 months and without carotid stenosis or major cardiac sources of embolism. Follow-up every 3 months for a mean of 3.5 yrs. Outcomes Recurrent stroke (primary), cognitive decline, major vascular events and death. Trial Status 2865 patients from 8 countries are currently participating. The study will be completed on April 2012. Mean age is 63 yrs old; 63% Male; 25% Hispanics. Author Disclosure Block: A. Roldan: None. M. Benavente: None. P. Pergola: None. G. Pergola: None. L. McClure: None. J. Szychowski: None. C. Coffey: None. R. Conwit: None. R. Hart: None. O. Benavente: None. Presentation Number: CT P20 PI Coordinator Affiliation: RESPECT Steering Committee PI Coordinator Name: RESPECT Steering Committee Trial Abbreviation: RESPECT Trial Trial Contact Information: Kristine Veltum [email protected] Trial Email: [email protected] Trial Name: Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment Trial Trial Registry Number ID: NCT00465270 Trial Sponsor: AGA Medical Corporation Trial Web Site: www.respectstudy.com Publishing Title: Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) Trial. Author Block: David Thaler, Tufts Medical Ctr, Boston, MA; John Carroll, Univ of Colorado, Denver, CO; Jeffrey Saver, UCLA, Los Angeles, CA; Richard Smalling, Univ of Texas, Houston, Houston, TX; Brian van Dorn, AGA Medical Corp, Plymouth, MN Abstract Body: PURPOSE: To investigate whether percutaneous PFO closure is superior to current standard of care medical treatment in the prevention of recurrent embolic stroke. DESIGN: Multicenter, randomized, active control, blinded adjudicated outcome, clinical trial. SAMPLE SIZE: 900 patients (450 per study arm). POPULATION STUDIED: Patients age 18-60 with patent foramen ovale who have had a cryptogenic stroke due to presumed paradoxical embolism within the last 270 days. INTERVENTIONS: Patients are randomly assigned to medical therapy or PFO closure with the AMPLATZER PFO Occluder. Medical therapy options include aspirin alone, coumadin alone, clopidogrel alone, or aspirin combined with extended-release dipyridamole. OUTCOME MEASURES: The primary endpoint is recurrent nonfatal stroke, all-cause post-randomization death within 45 days of randomization or 30 days after implant whichever occurs last, or fatal ischemic stroke. The secondary efficacy endpoints are complete closure of the defect at the six-month follow-up, time to recurrent symptomatic cryptogenic nonfatal stroke or cardiovascular death, and TIA. STATISTICAL ANALYSIS: The superiority of the device will be tested by using an exact binomial test of the proportion of device primary endpoint events to primary endpoint events across both arms of the study, conditioned on the total number of events. CURRENT STATUS AND BASELINE DEMOGRAPHICS: 807 patients have been enrolled as of October 31, 2010. The graph below depicts progressive enrollment. Index strokes were located in the cerebral cortex (43%), deep white matter [centrum semiovale and internal capsule] (3%), deep grey matter [basal ganglia and thalamus] (10%), brain stem/cerebellum (13%) and in multiple territories (19%). Large infarcts (>3cm) occurred in 22% of the patients. Most subjects (85%) showed PFO-shunting at rest, i.e. without Valsalva. Atrial septal aneurysms (≥10mm) are present in 35%. Updated data will be presented. Author Disclosure Block: D. Thaler: Consultant/Advisory Board; Modest; Consulting for AGA Medical. Consultant/Advisory Board; Significant; minimal. J. Carroll: Consultant/Advisory Board; Modest; Consulting for AGA Medical. Consultant/Advisory Board; Significant; minimal. J. Saver: Consultant/Advisory Board; Modest; Consulting for AGA Medical. Consultant/Advisory Board; Significant; minimal. R. Smalling: Consultant/Advisory Board; Modest; Consulting for AGA Medical. Consultant/Advisory Board; Significant; minimal. B. van Dorn: Employment; Modest; Employee of AGA Medical - Statistician. Employment; Significant; Employee. Presentation Number: CT P21 PI Coordinator Affiliation: University of Cincinnati PI Coordinator Name: Matthew Flaherty, MD / Traci Doellman, RN Trial Abbreviation: STOP-IT Study Trial Contact Information: Project Manager: Janice Carrozzella, RN, BA, CCRA; [email protected]; 513-4758797 / 513-475-8793 Trial Email: [email protected] Trial Name: The Spot Sign for Predicting & Treating ICH Growth Study Trial Registry Number ID: NCT00810888 Trial Sponsor: NIH / NINDS Trial Web Site: www.STOPITSTUDY.org Publishing Title: The Spot Sign for Predicting and Treating ICH Growth (STOP-IT) Study Author Block: Matthew Flaherty, Univ of Cincinnati, Cincinnati, OH; The STOP-IT Study Investigators Abstract Body: Background: Intracerebral hemorrhage (ICH) is estimated to affect 67,000 persons in the United States and 5,000 persons in Canada annually and is associated with a 40-50% case-fatality rate. There are no proven treatments for ICH. The demonstration that hematoma growth after ictus is common and associated with neurological decline has spurred research into early hemostatic therapy to potentially improve patient outcomes. Recombinant activated factor VII (rFVIIa) was proven to significantly reduce hematoma growth when administered within four hours of symptom onset in two placebo-controlled, blinded, randomized clinical trials. Because rFVIIa works to stop bleeding but should not otherwise affect the natural history of ICH, only patients destined to have hematoma growth will benefit from this therapy. Ideally, clinicians will be able to identify patients who will have significant hematoma growth regardless of their time of presentation and administer hemostatic therapy to this group. CT angiography (CTA) is a widely available, fast, non-invasive tool that has shown promise for predicting hematoma growth. In multiple, recent retrospective case series patients with contrast extravasation within their hematomas (the spot sign) had greater risk of subsequent hematoma growth and worse outcomes than patients without extravasation. The next step in this treatment paradigm is to confirm the ability of CTA to predict hematoma growth and to explore the role CTA may play in the administration of hemostatic therapy. Objectives: • Determine the sensitivity and specificity of the CTA spot sign for hematoma growth. o Working hypothesis: For patients scanned within five hours of stroke onset, the spot sign will have a high sensitivity and specificity for hematoma growth. • Determine the feasibility of using CTA to identify ICH patients at high risk of hematoma growth and to select patients for randomization to treatment with rFVIIa or placebo. o Working Hypothesis #1: Site investigators will determine the presence or absence of a spot sign in the acute setting with a high degree of accuracy as compared to blinded over-read by a study neuroradiologist. o Working Hypothesis #2: Use of CTA to identify candidates for randomization to rFVIIa versus placebo can be done in a time-efficient manner • Randomize ICH patients who present within five hours of symptom onset and have a spot sign to treatment with rFVIIa versus placebo, in order to (a) determine if rFVIIa is effective at reducing hematoma growth among patients with a spot sign and (b) provide preliminary efficacy data for this treatment paradigm. o Working Hypothesis: Spot-positive patients treated with rFVIIa will have less hematoma growth than spotpositive patients treated with placebo. Design: STOP-IT will enroll patients with acute ICH less than five hours from symptom onset. Patients will be included in one of two study arms. The first arm will be a multicenter, randomized, double-blind, placebo-controlled trial comparing rFVIIa to placebo for treatment of patients with acute ICH and a spot sign on CTA. The second arm will be a multicenter, prospective observational study of hematoma growth among patients without a spot sign on CTA. Comparisons will be made between 1) patients with a spot sign randomized to placebo and patients without a spot sign, in order to determine the value of the spot sign for predicting hematoma growth and 2) patients who have a spot sign and are randomized to rFVIIa or placebo in order to determine the effect of study drug upon hematoma growth. Population: Approximately 184 subjects with intracerebral hemorrhage fulfilling inclusion and failing no exclusion criteria will be enrolled into one of two study arms at twelve clinical sites across the United States and Canada. Interventions: Eligible, consented subjects presenting within five hours of ICH onset will be qualified for enrollment into one of two study arms in this multicenter phase II study. Patients who have a spot sign present on CTA will be randomized 1:1 to treatment with either rFVIIa (80 mcg/kg - maximum dose volume 10.0 mL, equivalent to maximum weight of 125 kg) or placebo. Patients without a spot sign will be enrolled in a prospective observational arm and their data will be compared to spot-positive patients treated with placebo to determine the sensitivity and specificity of the CTA spot sign for hematoma growth. Outcome Measures: Primary Outcome: Clinical • Safety: Life-threatening thromboembolic complications defined as development of (1) acute myocardial ischemia; (2) acute cerebral ischemia; and (3) acute pulmonary embolism through day 4 following completion of study drug administration. • The rate of hematoma growth among spot sign positive subjects at 24 hours, comparing subjects treated with rFVIIa to those treated with placebo. Hematoma growth will be defined as a > 33% or > 6 cc increase in volume. Secondary Outcome: Clinical • Incidence of other potentially study drug related thromboembolic complications such as deep venous thrombosis and elevations in troponin not associated with ECG evidence of acute coronary syndrome through day 90 following completion of study drug administration. • The rate of total hemorrhage volume growth (hematoma plus IVH) among spot-positive subjects and ninety day outcomes among spot positive subjects, dichotomized as modified Rankin Scale score of 0-4 versus 5-6, comparing subjects treated with rFVIIa to those treated with placebo Primary Outcome: Test Performance: • The sensitivity and specificity of the spot sign for predicting hematoma growth. Secondary Outcome: Test Performance: • The positive and negative predictive values of the spot sign and the accuracy of the site investigators for correct identification of the spot sign as compared to a blinded study neuroradiologist. Analysis (Imaging): The local investigator will use the baseline CT as part of the screening process for eligibility. Baseline hematoma volume for study screening will be calculated by the ABC/2 method. De-identified baseline and 24hour CTs will be provided to the University of Calgary via the Clinical Coordinating Center for subsequent interpretation by a blinded clinician. Hematoma volumes for study endpoints will be calculated by volumetric analysis. Scans will also be analyzed for the location of hemorrhage, the presence and volume of IVH, the presence or absence of hydrocephalus, edema volume, mass effect, prior infarction(s) (baseline CT) and acute infarction(s). Local investigators will interpret the CTA for the presence or absence of the spot sign in the acute setting. Digital, de-identified copies of the CTAs will be provided to Sunnybrook Health Sciences Centre via the Clinical Coordinating Center for subsequent interpretation by a blinded neuroradiologist. All CTAs will also be subsequently reviewed for the presence or absence of the spot sign by a blinded study neurologist and a blinded study emergency medicine physician. Measures of inter-rater reliability will be determined among the evaluators, with the neuroradiologist’s reading considered the gold-standard. Author Disclosure Block: M. Flaherty: Other Research Support; Significant; Novo Nordisk is supplying study drug for this trial. Presentation Number: CT P22 PI Coordinator Affiliation: University of Illinois at Chicago PI Coordinator Name: Epideh Amin-Hanjani, MD FACS FAHA Trial Abbreviation: VERiTAS Trial Contact Information: Linda Rose-Finnell, [email protected], 312-355-2050 Trial Email: [email protected] Trial Name: Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke Trial Registry Number ID: NCT00590980 Trial Sponsor: NIH/NINDS Trial Web Site: http://veritas.neur.uic.edu Publishing Title: Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS) Study Author Block: Sepideh Amin Hanjani, Keith Thulborn, Sean Ruland, Dilip Pandey, DeJuran Richardson, Univ of Illinois at Chicago, Chicago, IL; Gregory J. Zipfel, Washington Univ Sch of Med at St. Louis, St. Louis, MO; Mitchell S. Elkind, Columbia Univ, New York, NY; David S. Liebeskind, Univ of California at Los Angeles, Los Angeles, CA; Jeffrey Kramer, Mercy Hosp and Medical Ctr, Chicago, IL; Frank Silver, Univ of TorontoToronto Western Hosp, Toronto, ON, Canada; Scott Kasner, Univ of Pennsylvania, Philadelphia, PR; Colin Derdeyn, Washington Univ Sch of Med at St. Louis, St. Louis, MO; Philip B. Gorelick, Fady T. Charbel, Univ of Illinois at Chicago, Chicago, IL Abstract Body: Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS) Study Background: Over one third of ischemic strokes occur in the posterior circulation, a leading cause of which is vertebrobasilar occlusive disease secondary to atherosclerosis. Symptomatic vertebrobasilar disease (VBD) carries a high annual risk of stroke, averaging 10-15% per year. Advances in endovascular angioplasty and stenting have created new treatment options, but these interventions carry significant risks, and the selection criteria for appropriate candidates remain uncertain. Determining predictors of stroke in this population is an important step toward identifying those high risk patients most suitable for consideration of intervention. Preliminary studies suggest that the risk of stroke in VBD is strongly related to the extent to which intracranial blood flow is compromised. Objective: To test the hypothesis that among patients with symptomatic VBD, those with distal blood flow compromise, as determined by magnetic resonance (MR) blood flow imaging, are at higher risk of subsequent posterior circulation stroke than those with normal flow. Design: VERiTAS is a 5 year multicenter, prospective, observational cohort study, with a recruitment goal of 80 patients. Population Studied: The target population is patients with symptomatic VBD. Inclusion criteria: stroke or transient ischemic attack (TIA) in the vertebrobasilar territory; ≥ 50% stenosis or occlusion of extracranial or intracranial vertebral or basilar arteries; symptoms within 60 days of enrollment; ≥ 18 years of age and ability to provide informed consent. Exclusion criteria: major disabling stroke prohibiting the ability to return for follow-up assessment; limited life expectancy; known cardiac disease associated with cardioembolic risk (e.g. atrial fibrillation and prosthetic valves); blood dyscrasias; non-atherosclerotic vertebrobasilar disease (e.g. dissection); unilateral vertebral stenosis or occlusion; inability to undergo MRI or cerebral angiography. Study Procedures: Patients will undergo blinded hemodynamic assessment with MR based imaging, consisting of quantitative MR angiography and MR perfusion, at enrollment and at 6 month intervals for at least one year. Clinical assessments to identify recurrent ischemic events will be performed at routine intervals up to two years maximum. Outcome Measures: The primary endpoint is fatal and nonfatal ischemic stroke in the vertebrobasilar territory. Analysis: Analysis of the primary endpoint will consist of time-to-event comparison using the log-rank test between patients designated as 'low flow' versus 'normal flow' based upon the enrollment MR imaging. Trial status: The study is open for enrollment at 6 sites (UIC, UCLA, Washington University, Columbia, Mercy, UHN-Toronto Western Hospital). As of October 20, 2010, 40 subjects have been enrolled. PI/Coordinator name: Sepideh Amin-Hanjani, MD PI/Coordinator Affiliation(s): University of Illinois at Chicago Trial Sponsor: NIH/NINDS Trial Contact information: Linda Finnell, MPA, CCRA; 312-355-2050; [email protected] Trial Email: [email protected] Trial web site: http://veritas.neur.uic.edu Author Disclosure Information: Trial Name: Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke Trial Abbreviation: VERiTAS Study Trial Registry Number or 10: NCT00590980 PI/Coordinator Name(s): Sepideh Amin-Hanjani, MD PI/Coord. Affiliation(s): University of Illinois at Chicago Trial Sponsor(s): NINDS Trial E-mail: [email protected] Trial Web Site: http://veritas.neur.uic.edu Trial Contact Information: Linda Rose-Finnell, [email protected], 312-355-2050 Author Disclosure Block: S. Amin Hanjani: Research Grant; Significant; NIH/NINDS. Other Research Support; Modest; GE Healthcare, VasSol, Inc. K. Thulborn: Ownership Interest; Significant; Thulborn Associates, Inc. (owner). S. Ruland: None. D. Pandey: None. D. Richardson: None. G.J. Zipfel: Research Grant; Significant; NIH. Other Research Support; Modest; AHA, Brain Aneurysm Foundation, American Health Assistance Foundation, Washington University ADRC. M.S. Elkind: None. D.S. Liebeskind: None. J. Kramer: None. F. Silver: None. S. Kasner: None. C. Derdeyn: Research Grant; Significant; NIH/NINDS. Honoraria; Modest; Synthes. Ownership Interest; Modest; nFocus, Inc.. Consultant/Advisory Board; Modest; Pulse Therapeutics. Consultant/Advisory Board; Significant; W.L.Gore and Associates. P.B. Gorelick: Other Research Support; Significant; Lundbeck, Inc. F.T. Charbel: Ownership Interest; Significant; VasSol, Inc.. Presentation Number: CT P23 PI Coordinator Affiliation: University of Edinburgh, University of Sydney PI Coordinator Name: Peter Sandercock, Richard Lindley, Joanna Wardlaw Trial Abbreviation: IST-3 Trial Contact Information: Peter sandercock: [email protected] Trial Email: [email protected] Trial Name: Third International Stroke Trial Trial Registry Number ID: ISRCTN25765518 Trial Sponsor: University of Edinburgh and Lothian Health Board Trial Web Site: http://www.ist3.com Publishing Title: Third International Stroke Trial (IST-3) a Large-scale Randomised Controlled Trial Of Thrombolytic Therapy For Patients With Acute Ischaemic Stroke ISRCTN ISRCTN25765518 Author Block: Peter A Sandercock, Univ of Edinburgh, Edinburgh, United Kingdom; Richard I Lindley, Univ of Sydney, Sydney, Australia; Joanna Wardlaw, Univ of Edinburgh, Edinburgh, United Kingdom; The IST-3 collaborative group Abstract Body: Background. Current regulatory approvals permit the use of thrombolysis in a highly selected subset of patients with acute ischaemic stroke. Objective. To determine whether a wider variety of patients can benefit from treatment than is possible under the current approvals. Design. IST-3 is a randomised controlled, trial of iv rtPA (0.9mg/kg), with a PROBE (Prospective, Randomised, Open, Blinded Endpoint) design. Eligibility. acute ischaemic stroke, assessed and able to start treatment within 6 hours of onset, CT (or MR) scan has excluded intracranial haemorrhage. Details at www.ist3.com. Patient inclusion is by (telephone or a secure website to) a rapid centralised randomisation system balancing on key prognostic factors. Treatment is allocated after the baseline data have been recorded and cross-checked. Brain imaging (CT or MR) must be repeated after treatment (at 24-48hrs). In centres where pre-treatment perfusion or angiography are routine, these scans are collected as well the plain CT or MR scans. Baseline and follow-up CT/MR images reviewed by 'blinded' expert panel. Perfusion and angiography data are processed centrally. In all centres, follow-up is conducted by centralised (blinded) postal or telephone questionnaire, independently of the clinician treating the patient. Outcome measures: primary outcome is survival free of death or dependence at six months. Planned subgroup analyses: effect of: age, stroke severity, time to randomisation, blood pressure, CT appearances, perfusion or angiographic findings (where available) on the risks and benefits of treatment. Sample size With 3100 patients, the trial could detect a 4.7% absolute difference in the primary outcome. Trial Status: A total of 2444 patients had been recruited by 13th October 2010. Results will be reported in May 2012. Author Disclosure Block: P.A. Sandercock: Other; Modest; Member of independent DSMB for RELY trial. R.I. Lindley: Speakers; Modest; Richard Lindley was supported to attend a national stroke meeting by Boehringer Ingelheim and has also received honoraria for services as Scientific Committee member from the company. J. Wardlaw: None. Presentation Number: CT P24 PI Coordinator Affiliation: University of California, Irvine PI Coordinator Name: Steven C. Cramer, MD Trial Abbreviation: --Trial Contact Information: Steven C. Cramer, MD; [email protected]; FAX 714 456-8805; PHONE 714 4566876 Trial Email: [email protected] Trial Name: A Single-Blind Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients With Ischemic Stroke Trial Registry Number ID: Clinicaltrials.gov ID # NCT00833989 Trial Sponsor: GlaxoSmithKline Trial Web Site: --Publishing Title: A Single-Blind Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients With Ischemic Stroke Author Block: Steven C. Cramer, UC IRVINE MEDICAL CENTER, Orange, CA; On behalf of the GSK249320 Study Investigators Abstract Body: BACKGROUND: There are no approved therapies for improving recovery post-stroke that are initiated beyond the first few hours. Furthermore, in most studies where patients do receive an approved hyperacute stroke therapy, most patients are left with significant disability despite overall efficacy. Therapies based on brain repair have the potential to improve outcomes with a relatively wide time window. One such approach revolves around promoting axon outgrowth and plasticity to augment brain repair. This is supported by studies that indicate blocking myelin inhibitory proteins, such as myelin associated glycoprotein (MAG), improves outcome. GSK249320 is a humanized IgG1 monoclonal antibody to MAG that has a disabled Fc region; these features mitigate concerns related to (a) anti-MAG neuropathy, which is due to IgM-type antibodies, and (b) toxicity caused by activation of Fc-effector functions for example, activation of the complement system due to C1q binding. Studies in rodents and primates indicate that intravenous administration of GSK249320 beginning 24 hours after experimental stroke improves behavioral outcome, without changing infarct volume. GSK249320 appeared well-tolerated when administered to 31 healthy human subjects. OBJECTIVE: The objective of this study is to evaluate the safety, pharmacokinetics, and pharmacodynamics of various doses of GSK249320 in patients with recent stroke. DESIGN: This is a placebo-controlled, randomized, single-blind, multicenter, international study. POPULATION STUDIED: A total of 40 patients are planned for enrollment. Inclusion criteria include stroke onset 24-72 hours prior to therapy initiation; the stroke must be radiologically confirmed to be either (a) ischemic, supratentorial, and with diameter >15mm or volume >4cc, or (b) hemorrhagic, supratentorial, and with an ICH score of 0-2; NIHSS score = 3-21; weakness in arm or leg or both; age 18-90 years; and reasonable likelihood of receiving standard physical, occupational and speech rehabilitation therapy. Exclusion criteria include previous symptomatic stroke within 3 months prior to study entry; significant disability prior to the current stroke; depression; significant aphasia; peripheral neuropathy; presence of neurological or psychiatric disease likely to confound clinical evaluations; presence of a demyelinating disease; other major chronic co-morbid conditions; contraindication to transcranial magnetic stimulation or MRI; participation in any investigational rehabilitation paradigm targeting stroke recovery; or pregnancy or lactation. INTERVENTION: Each patient will be randomized to receive 2 IV doses of either GSK249320 or placebo. Dose 1 will be given 24-72 hr after stroke onset, and Dose 2 will be given 9+/- 1 days after Dose 1. There will be three dose escalation cohorts (1, 5 and 15 mg/kg per dose), with 8 patients on placebo and 8 on active in cohort 1 and 8 patients on active and 4 on placebo in cohorts 2 and 3. Doses will be given in a blinded fashion; however study site pharmacy staff preparing infusions will be unblinded to patient treatment assignment. OUTCOME MEASURES: The primary outcome measure is safety, as determined from adverse events, vital signs, physical exam, ECG, nerve conduction tests, MRI, behavioral assessments, and laboratory testing. Secondary outcome measures include immunogenicity, based on serum Ab measures; pharmacokinetics, based on blood draws; function, based on behavioral assessments, both global and domain specific; and neurophysiology, based on transcranial magnetic stimulation findings. ANALYSIS: Adverse events and safety findings will be tabulated and examined. Estimates of the effect of GSK249320 at each dose relative to placebo will be calculated for behavioral measures. The relationship between GSK249320 plasma exposures and any markers of safety or biological activity will be subjected to exploratory pharmacokinetic/pharmacodynamic analyses. TRIAL STATUS: Fifteen sites in the US, Germany, and Canada are participating. As of October 13, 2010, enrollment has completed with 42 patients enrolled. Follow up visits are ongoing. Author Disclosure Block: S.C. Cramer: Research Grant; Significant; This study was supported by a grant from GlaxoSmithKline. Consultant/Advisory Board; Significant; Dr. Cramer serves as a consultant to GlaxoSmithKline. Presentation Number: CT P25 PI Coordinator Affiliation: The NIHR Stroke Research Network PI Coordinator Name: Prof Gary A. Ford Trial Abbreviation: The NIHR Stroke Research Network Clinical Trials Portfolio Trial Contact Information: [email protected] Trial Email: n/a Trial Name: The NIHR Stroke Research Network Clinical Trials Portfolio Trial Registry Number ID: n/a Trial Sponsor: n/a Trial Web Site: n/a Publishing Title: The National Institute of Health Research Stroke Research Network Clinical Trials Portfolio Author Block: Gary A Ford, NIHR Stroke Res Network, Newcastle upon Tyne, United Kingdom; Philip M Bath, Univ of Nottingham, Nottingham, United Kingdom; Martin M Brown, Univ Coll London, London, United Kingdom; Ian Ford, Univ of Glasgow, Glasgow, United Kingdom; Anne Forster, Univ of Leeds, Leeds, United Kingdom; Martin James, Royal Devon & Exeter Hosp, Exeter, United Kingdom; Kennedy R Lees, Matthew Walters, Univ of Glasgow, Glasgow, United Kingdom; Sine Littlewood, NIHR Stroke Res Network, Newcastle Univ, Newcastle upon Tyne, United Kingdom; Jonathan Mant, Univ of Cambridge, Cambridge, United Kingdom; Hugh S Markus, St George's Univ of London, London, United Kingdom; Bogdan Milojkovic, NIHR Stroke Res Network, Newcastle Univ, Newcastle upon Tyne, United Kingdom; Michael J Power, Ulster Hosp, Belfast, United Kingdom; Sheila Lennon, Univ of Ulster, Co Antrim, United Kingdom; Chris Price, Wansbeck General Hosp, Ashington, United Kingdom; Tom Robinson, Univ Hosp of Leicester NHS Trust, Leicester, United Kingdom; Helen Rodgers, NIHR Stroke Res Network, Newcastle Univ, Newcastle upon Tyne, United Kingdom; Christine Roffe, Keele Univ, Stoke-on-Trent, United Kingdom; Christopher R Burton, Bangor Univ, Gwynedd, United Kingdom; Pippa Tyrrell, Univ of Manchester, Salford, United Kingdom; Marion F Walker, Univ of Nottingham, Nottingham, United Kingdom Abstract Body: Background: The National Institute for Health Research (NIHR) Stroke Research Network (SRN) was established in England in June 2005 to provide world-class health service infrastructure to support clinical stroke research and remove barriers to its conduct. NIHR SRN facilitates stroke research through investment in a national coordinating centre, 8 English local stroke research networks ($7 million funding in 2008), and works closely with stroke research networks and structures in Scotland, Northern Ireland and Wales to enhance clinical stroke research infrastructure, clinical co-ordination, research nursing staff, imaging and pharmacy. In 2010 funding was provided to 8 Hyperacute Stroke Research Centres across England to support the delivery of hyperacute stroke studies ($6 million funding over 3 years). NIHR SRN aims to increase collaborative working between academics, stroke clinicians, patients and research funders. Support is provided to academic studies funded through peer review and open national competition and commercial studies. International studies funded in open national competition are potentially eligible for NIHR SRN support. The UK wide study portfolio consisted of 88 open studies (51 randomized clinical trials, RCTs) in October 2010 with a further 11 studies in set-up. Patients recruited into stroke studies increased from 2598 (1941 in RCTs) in 2006/07 to 8734 (4893 in RCTs) in 2009/10 with patient recruitment from 191 hospitals. Increased recruitment occurred in both academic and commercial funded studies and in all three areas of acute, rehabilitation and prevention research. The NIHR SRN portfolio includes the following academic and industry sponsored multi-centre international trials open to recruitment: CEPO, DIAS-4, SISTERS, T05018-1001, ACST-2, ARUBA, AVERT, CADISS, CLEAR III, CLOTS-3, ENOS, EUPACT, INTERACT II, IRIS, IST-3, MASH-II, MISTIE, PODCAST, PRET, STASH, STICH II, VIST. Investment in stroke clinical research infrastructure has had a major impact on UK stroke research activity. Current activity suggests 5-6% of the incident UK stroke population participate in clinical stroke trials. The future aims of SRN are to increase the number of patients participating in stroke studies in the UK to 10,000 each year with 7000 participating in randomised controlled trials. NIHR SRN welcomes applications from academic chief investigators and commercial companies seeking support for UK patient recruitment to ongoing clinical trials. Author Disclosure Block: G.A. Ford: None. P.M. Bath: None. M.M. Brown: None. I. Ford: None. A. Forster: None. M. James: None. K.R. Lees: None. M. Walters: None. S. Littlewood: None. J. Mant: None. H.S. Markus: None. B. Milojkovic: None. M.J.P. Power: None. S. Lennon: None. C. Price: None. T. Robinson: None. H. Rodgers: None. C. Roffe: None. C.R. Burton: None. P. Tyrrell: None. M.F. Walker: None. Presentation Number: CT P26 PI Coordinator Affiliation: Columbia University PI Coordinator Name: Shunichi Homma Trial Abbreviation: WARCEF Trial Contact Information: Vilma Mejia (Asst. Project Manager), 630 West 168 St Mail Code 44, New York, NY 10032 Tel # 212-305-3033 Trial Email: [email protected] Trial Name: Warfarin versus Aspirin in Reduced Ejection Fraction Trial Registry Number ID: NCT00041938 Trial Sponsor: NIH-NINDS Trial Web Site: www.warcef.org Publishing Title: Update on Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial Author Block: J.L.P. Thompson, Shunichi Homma, Columbia Univ, New York, NY Abstract Body: Rationale and Design: Warfarin Aspirin Reduced Cardiac Ejection Fraction study (WARCEF) is a randomized, double-blind, controlled trial comparing warfarin (INR= 2.75) and ASA (325mg) in patients with reduced left ventricular ejection fraction (LVEF) in sinus rhythm. Background: Patients with heart failure (HF) in sinus rhythm are at high risk of death, and have a 1.6%/ year rate of stroke and 8-10% rate of recurrent stroke. Up to 28% of these patients are anticoagulated with warfarin although no conclusive evidence identifies a preferred therapy. WARCEF is designed to assess whether warfarin or ASA, in combination with current standard HF regimen, is superior for reducing the risk of death or stroke in patients with reduced LVEF. Methods: WARCEF is an NIH/NINDS-funded, NIH/NHLBI-endorsed multicenter randomized double-blind trial involving 176 sites in11 countries. Patients in sinus rhythm with LVEF <35% (or wall motion index < 1.2) are eligible. The target is 20% enrollment of patients with prior (<365 days) ischemic stroke or TIA. A maximum of 20% of enrolled patients may be NYHA Class I. The composite primary outcome is time to the first to occur of death, ischemic stroke, or intracerebral hemorrhage (ICH). The trial was designed with 80% power with two sided α=0.05 for any combination of the 3 component event rates that achieves the design hazard rate reduction of 17.82% or more for either medication. Given recruitment curtailment, power for the primary outcome is ≈65% for the design hazard rate reduction, and > 80% for the most important secondary outcome, the first to occur of death, ischemic stroke, ICH, MI, or HF hospitalization. Safety is evaluated by assessing the risk of major hemorrhagic and other serious adverse events. Given the greater costs and demands of warfarin therapy, ASA will be declared preferable unless warfarin is found to be significantly superior on the primary outcome. Results: Recruitment ended in March 2010 with 2,305 patients randomized. Follow-up phase is ongoing until May 2011. Conclusions: No conclusive evidence identifies a preferred antithrombotic regimen for patients with low LVEF in sinus rhythm. WARCEF is the only trial directly comparing anticoagulant and antiplatelet therapies in this population. Any of the three possible outcomes (warfarin superior; ASA superior; neither superior) will lead to an important treatment recommendation for patient care. Author Disclosure Block: J. Thompson: None. S. Homma: None. Presentation Number: CT P27 PI Coordinator Affiliation: University of California, San Diego PI Coordinator Name: Patrick D. Lyden, MD Trial Abbreviation: ICTuS 2/3 Trial Contact Information: [email protected] Trial Email: [email protected] Trial Name: The Intravascular Cooling in the Treatment of Stroke 2/3 Trial Registry Number ID: NCT01123161 Trial Sponsor: NINDS SPOTRIAS P50NS044148 Trial Web Site: http://clinicaltrials.gov/ct2/show/NCT01123161?term=ictus&rank=2 Publishing Title: Phase 2/3 Study of Intravenous Thrombolysis and Hypothermia for Acute Treatment of Ischemic Stroke Author Block: Thomas M Hemmen, Rema Raman, UCSD MEDICAL CENTER, San Diego, CA; David Brown, Hoag Memorial Hosp Presbyterian, Newport Beach, CA; Fen-Lei Chang, Parkview Hosp, Fort Wayne, IN; Gregor Broessner, Medische Univ Innsbruck, Innsbruck, Austria; Salvador Cruz-Florez, St Louis Univ, St Louis, MO; Rainer Kollmar, Univsklinikum Erlangen, Erlangen, Germany; Gilda M Tafreshi, Scripps Mercy Hosp, San Diego, CA; Mauricio Concha, Sarasota Memorial Hosp, Sarasota, FL; Irfan Altafullah, North Memorial Hosp, Robbinsdale, MN; Patrick Michel, Univ de Lausanne, Lausanne, Switzerland; Sven Poli, UnivsKlinikum Heidelberg, Heidelberg, Germany; Andrei V Alexandrov, Univ of Alabama, Birmingham, AL; Karen S Rapp, UCSD MEDICAL CENTER, San Diego, CA; George A Lopez, James C Grotta, Univ of Texas Medical Sch, Houston, TX; Patrick D Lyden, Cedars-Sinai Medical Ctr, Los Angeles, CA Abstract Body: Introduction: The purpose of this study is to determine whether the combination of thrombolysis and hypothermia is superior to thrombolysis alone for the treatment of acute ischemic stroke. The study will be conducted in two stages: a Phase 2 study to assess the safety of various protocol changes, to demonstrate sufficient recruitment, and to allow an interim analysis for futility; a Phase 3 efficacy study will follow if prespecified milestones are achieved. Methods: This is a prospective, randomized, single-blind, multi-center Phase 2/3 study. We aim to include 1600 ischemic stroke patients (400 in phase 2, 1200 in phase 3) treated within 3 hours of symptom onset with IV tPA (according to FDA or EMEA protocol), NIHSS ≥7 and ≤20, age 22-80. Patients will be randomly assigned to either hypothermia permissively targeted to 33ºC or normothermia. Favorable outcome is defined as a 90-day Modified Rankin score (mRS) of 0 or 1. Secondary outcome measures are: 90-day NIHSS, Barthel Index (BI), mortality, shift analysis of the mRS, global odds ratio of mRS, BI, NIHSS, incidence of symptomatic intracranial hemorrhage and 90-day Montreal Cognitive Assessment. Interim analyses for futility are planned after phase 2 and 800 patients, which include frequency of target temperature reached within 6 hours from symptom, pneumonia rate, safety profile of iced saline infusion and study-wide average enrollment of at least 0.4 patients/site/month. Status: The study team obtained a conditional IDE from the FDA. The sponsor, NINDS constituted a Data Safety Monitoring Board and a study-wide safety physician was recruited to assist in study oversight. First subject enrolment is planned for December 2010. Sponsor: NINDS SPOTRIAS 3P50NS044227 and 5P50NS044148 Clinicaltrials.gov ID: NCT01123161 Cooling systems and catheters are provided by Philips/Innercool. Author Disclosure Block: T.M. Hemmen: None. R. Raman: None. D. Brown: None. F. Chang: None. G. Broessner: None. S. Cruz-Florez: None. R. Kollmar: None. G.M. Tafreshi: None. M. Concha: None. I. Altafullah: None. P. Michel: None. S. Poli: None. A.V. Alexandrov: None. K.S. Rapp: None. G.A. Lopez: None. J.C. Grotta: None. P.D. Lyden: None. Presentation Number: CT P28 PI Coordinator Affiliation: University of Miami Miller School of Medicine PI Coordinator Name: Myron D. Ginsberg, MD Trial Abbreviation: ALIAS - Part 2 Trial Contact Information: ALIAS Part 2 Trial, [email protected], 305-243-6449 Trial Email: [email protected] Trial Name: Albumin in Acute Stroke - Part 2 Trial Registry Number ID: NCT00235495 Trial Sponsor: NIH Trial Web Site: https://webdcu.musc.edu/alias2/ Publishing Title: ALIAS-Part 2 Phase III Multicenter Clinical Trial of Albumin Therapy for Neuroprotection in Acute Ischemic Stroke Author Block: Myron D. Ginsberg, Univ of Miami Miller Sch of Med, Miami, FL; Michael D. Hill, Univ of Calgary, Calgary, AB, Canada; Yuko Y. Palesch, Renee H. Martin, Sharon Yeatts, Medical Univ of South Carolina, Charleston, SC; Claudia S. Moy, Natl Inst of Neurological Disorders and Stroke, Rockville, MD; Diego Tamariz, Univ of Miami Miller Sch of Med, Miami, FL; Karla J. Ryckborst, Univ of Calgary, Calgary, AB, Canada Abstract Body: Background In extensive preclinical studies, human albumin conferred high-grade neuroprotection in focal cerebral ischemia, with a therapeutic window extending to four hours. An NIH-supported pilot-phase clinical trial of 25% human albumin (ALB) therapy in subjects with acute ischemic stroke (duration =<16 h) was subsequently completed (Stroke 37:2100-6 and 37:2107-14, 2006). This was a multiple-tier, dose-escalation safety trial comprising a standard-of-care IV tPA cohort (<3 h) and a nontPA cohort. Results: 82 subjects were enrolled (mean age 65 years; 52% male; 51% received tPA). Safety: The only adverse event related to ALB therapy was mild-moderate pulmonary edema in 13% of subjects; this was readily managed by furosemide, which was recommended prophylactically at the higher ALB dose-tiers. Probing for efficacy: In the tPA cohort, 72% of subjects receiving ALB at dose-tiers IV-VI (average time 6.6 h after stroke onset) had a favorable outcome at 3 months (defined as NIH Stroke Scale 0-1 and/or modified Rankin Scale 0-1), compared to 36% of historical subjects who received tPA (but not ALB) in the NINDS tPA Trial. The NIH-funded ALIAS Phase III Multicenter Trial began subject enrollment in 2005. As of December 2007, 434 subjects had been enrolled at ~60 North American clinical sites. Mean age was 70 (SD 14, maximum 97); mean time from stroke onset to study drug, 3.4 h (SD 0.7 h). Baseline NIHSS score was 13 (SD 6). Of these subjects, 349 received thrombolysis. Neurological deterioration within 48 h occurred in 15%; death from any cause within 90 days occurred in 17%; and pulmonary edema in 7.6%. In December, 2007, the DSMB placed the trial on hold to review a safety concern. Revisions were then made to the protocol and analysis plan, and a comprehensive site-training plan was constructed. The DSMB and NINDS then gave permission to re-start the trial as “ALIAS Trial Part 2”. Objective The primary objective of ALIAS is to ascertain whether high-dose human ALB therapy (2.0 g/kg) increases the proportion of acute ischemic stroke patients with favorable outcome compared to placebo therapy at 3 months from randomization, as defined as NIH Stroke Scale score of 0-1 and/or modified Rankin Scale score of 0-1. Design ALIAS Part-1 was configured as two separate, concurrently implemented double-blinded, placebo-controlled, multicenter Phase III clinical trials; separate randomization to ALB or placebo was carried out in a cohort receiving standard-of-care thrombolysis and in a cohort not receiving thrombolytic therapy. By contrast, in the currently ongoing ALIAS Part-2 Trial, these two cohorts are combined, and the primary analysis will adjust for the effect of thrombolysis. Study Population ALIAS Part-2 requires a sample size of approximately 1,100 subjects, randomized 1:1 to ALB or placebo. This sample size ensures 90% power in detecting an absolute treatment effect of 10% with alpha = 0.05, and sufficient (80%) power to detect a thrombolysis x treatment interaction. Inclusion criteria in ALIAS Part-2: age at least 18 and no older than 83 years (new in Part-2); baseline NIHSS score of 6 or greater; initiation of ALB/placebo therapy within 5 h of stroke onset; and informed consent. Major exclusion criteria: congestive heart failure (CHF), cardiac surgery or myocardial infarction in the previous 6 months; myocardial infarction or CHF on admission; acute arrhythmia with hemodynamic instability; evidence of pulmonary edema; and acute or chronic lung disease requiring O2 therapy. In Part-2, a normal serum troponin level is required for inclusion. Intervention Either ALB (25% solution; total dose 2.0 g/kg, not to exceed 750 ml) or saline solution is infused over 2 h. The study drug infusion must start within 60 min of the start of thrombolysis or (in non-thrombolytic subjects) within 60 min of randomization. Other Protocol modifications in Part 2: A mandatory upper limit of 4,200 ml has been imposed on the volume of IV fluids to be administered over the first 48 hours. Administration of a loop diuretic (typically, furosemide 20 mg IV) is now mandatory between 12 and 24 hours after start of study-drug administration. Reporting of IV fluid intake is mandatory during the first 48 h. More frequent cardiac monitoring is required. Careful training and credentialing of all site investigators, sub-investigators, and coordinators is emphasized. Outcome Measures Each subject is followed for one year. The primary efficacy outcome is assessed at 3 months at a clinic visit. Brief (<30 minutes) telephone interviews for clinical and quality-of-life assessments are conducted at 1, 6, 9 and 12 months. Secondary analyses are conducted adjusting for possible confounding factors, using generalized linear regression models. Trial Status ALIAS is being conducted at clinical sites throughout the United States and Canada, including sites participating via the NIH-funded Neurological Emergencies Treatment Trials (NETT) Network. Approximately 75 sites are currently activated. Subject enrollment in ALIAS Part-2 began in February, 2009. Author Disclosure Block: M.D. Ginsberg: Research Grant; Significant; NS40406. M.D. Hill: None. Y.Y. Palesch: Research Grant; Significant; NS054630. R.H. Martin: None. S. Yeatts: None. C.S. Moy: None. D. Tamariz: None. K.J. Ryckborst: None. Presentation Number: CT P29 PI Coordinator Affiliation: National Stroke Research Institute PI Coordinator Name: Julie Bernhardt Trial Abbreviation: AVERT Trial Contact Information: Principal Investigator, Julie Bernhardt, [email protected], nsri.org.au/avert, fax +61394962650 Trial Email: [email protected] Trial Name: A Very Early Rehabilitation Trial Trial Registry Number ID: ACTRNO1260600185561 Trial Sponsor: NHMRC, Stroke Association UK, Chest Heart and Stroke Scotland, Northern Ireland Chest Heart and Stroke, Signapore Health Trial Web Site: www.nsri.org.au/AVERT Publishing Title: A Very Early Rehabilitation Trial (AVERT): Ongoing Phase III Trial of Efficacy and Cost Effectiveness of Early Mobility Training after Stroke Author Block: Julie Bernhardt, Natl Stroke Res Inst, Heidelberg Heights, Australia; on behalf of the AVERT Trialist Collaboration Abstract Body: Introduction: Getting patients out of bed very early after stroke (<24 hours) may be an important component of effective stroke unit care but this requires testing in a randomized controlled trial. We hypothesize that very early and frequent mobilization (VEM) will reduce death and disability and be cost effective. Methods: Study design: Phase III, international, multi-centre, single-blind, randomized controlled trial. Inclusion criteria: Patients over 18 years, admitted within 24 hrs of confirmed cerebral infarct or haemorrhage, whose physiological parameters fall within set limits. Exclusion Criteria: Patients with severe premorbid disability, severe comorbidities or requiring palliative care. Treatment with rtPA is not an exclusion. Randomisation: Web-based, blocked randomisation by site and stroke severity (NIHSS). Intervention: The VEM protocol, delivered by a nurse/physiotherapy team, begins within 24hrs of stroke and continues at least twice daily for up to 14 days. Control patients receive standard care. Primary outcome is modified Rankin Scale at 3 months. Sample size is 2104 patients (n=1052 per group). Analyses will be intention to treat. A cost effectiveness analysis forms part of the study design. Safety outcomes: Deaths and serious adverse events (SAEs), including serious falls, at 3 months are extracted from the medical record by a blinded assessor. Results: Phase III commenced in July 2006 in 7 sites in Australia but the trial has now expanded to include 37 sites from 5 countries (Australia, New Zealand, Malaysia, Singapore and UK), with further UK expansion planned for 2011. At October 2010, 823 patients have been recruited, with a current average recruitment rate of 30 patients per month. The proportion of screened versus recruited patients ranges from 1.4% - 19.0% (mean 6.4%) across sites. Mean age is 70.5 years (SD 13.1), 80.2% with first ever stroke, 86.4% infarct, mean NIHSS score of 9.3 (SD 6.8) at time of randomization 17 (SD 5.9) hours post stroke. Almost half of our patient sample (48.0%) have an NIHSS > 7 (moderate and severe stroke) . To date 140 patients (17.0%) have been treated with rtPA. Sixty one patients (8.3%) have died within 3 months of stroke, and there have been only 7 drop outs (<1% of patients). In conclusion, the trial is progressing well. Recent expansion of trial sites should see recruitment completed by end of 2012. Author Disclosure Block: J. Bernhardt: Research Grant; Modest; National Health and Medical Research Council Grant funds this project. Presentation Number: CT P30 PI Coordinator Affiliation: Klikikum Coburg PI Coordinator Name: Johannes Brachmann Trial Abbreviation: CRYSTAL-AF Trial Contact Information: Frank Beckers Trial Email: [email protected] Trial Name: Cryptogenic Stroke and Underlying Atrial Fibrillation Trial Trial Registry Number ID: NCT00924638 Trial Sponsor: Medtronic, Inc. Trial Web Site: http://clinicaltrials.gov/ct2/show/NCT00924638?term=CRYSTAL-AF&rank=1 Publishing Title: Cryptogenic Stroke And Underlying Af Trial (crystal Af): Design, Status And Clinical Significance To Patients, Physicians, And Hospitals Author Block: Richard A Bernstein, Northwestern Univ, Glenview, IL; Johannes Brachmann, Klinikum Coburg, Coburg, Germany; Hans-Christoph Diener, Univ Hosp Essen, Essen, Germany; Carlos A Morillo MD, McMaster Univ, Hamilton, ON, Canada; Tommaso Sanna MD, Vincenzo DiLazzaro MD, Catholic Univ of the Sacred Heart, Rome, Italy; Rod Passman, Northwestern Univ, Chicago, IL; Marilyn Rymer, St Lukes Hosp, Kansas City, MO Abstract Body: Background: Stroke is the third leading cause of mortality in the US and the leading cause of long-term disability. Stroke of undetermined cause (cryptogenic) accounts for approximately 25-30% of ischemic strokes and it is assumed that asymptomatic paroxysmal atrial fibrillation (AF) may be an important underlying cause. The American and European stroke guidelines recommend patients with cryptogenic stroke to take antiplatelets for secondary stroke prevention (stroke recurrence). However, when a stroke patient is found to have AF, the guidelines recommend anticoagulation due to its superior efficacy over antiplatelets for stroke prevention. Several studies have shown that oral anticoagulation reduced the risk of stroke in AF patients by up to 80%. Stroke in combination with AF is associated with greater disability and mortality than in the absence of AF. It is thus clinically important to detect underlying AF. The technologies currently used to identify episodes of AF appear to be inadequate. The CRYSTAL AF study seeks to provide clinical evidence, demonstrating that long term monitoring by the Reveal XT insertable cardiac monitor in patients with cryptogenic stroke has AF diagnostic superiority compared to usual care and to investigate the true incidence of AF in this population. Study design: CRYSTAL AF is a 1:1 randomized, prospective, multicenter study in which approximately 450 patients will be included in about 60 active sites in Europe, US and Canada. Patients are eligible for inclusion after diagnosis of cryptogenic stroke or Transient Ischemic Attack (TIA). Each patient will be followed until study closure with a minimum of 12 months. Objectives: The primary objective is the time to first documented event of AF by 6 months of continuous rhythm monitoring versus standard arrhythmia diagnostics in subjects with a recent cryptogenic stroke or TIA without previously documented history of AF. The most important secondary objective is the time to first documented AF event by 12 months of continuous rhythm monitoring. Other secondary objectives are: - To compare the incidence of recurrent stroke or TIA in patients with a recent cryptogenic stroke or TIA randomized to long-term rhythm monitoring versus standard of care treatment. - To compare the change, and reasons for change, in use of oral anticoagulation and anti-arrhythmic drugs over time in both arms. - To compare the hazard rate for the amount and duration of cardiovascular related hospitalization in both arms - To describe health outcomes, economic and clinical disease burden and the care pathways of enrolled patients - To evaluate the role of the Patient Assistant device in time to diagnosis in patients implanted with the Reveal XT. The patient follow-up in the Reveal implanted arm will use CareLink remote monitoring system. Current status: As of 26 October 2010, there were 39 centers enrolling 129 patients in the study. Study milestone schedule: Data collection will be closed 12 months after enrollment of the last patient. The study enrolled the first patient on 17 June 2009 and a publication is expected in early 2013. Author Disclosure Block: R.A. Bernstein: Research Grant; Modest; Medtronic. Speakers; Modest; Medtronic. Consultant/Advisory Board; Modest; Medtronic. J. Brachmann: None. H. Diener: None. C.A. Morillo: None. T. Sanna: None. V. DiLazzaro: None. R. Passman: None. M. Rymer: None. Presentation Number: CT P31 PI Coordinator Affiliation: University of Nottingham, United Kingdom PI Coordinator Name: Professor Philip Bath Trial Abbreviation: ENOS Trial Contact Information: Mrs Sally Utton/[email protected] /Tel: +44 (0)115 82 30287/Fax: +44 (0)115 82 31771 Trial Email: [email protected] Trial Name: Efficacy of Nitric Oxide in Stroke Trial Registry Number ID: ISRCTN99414122 Trial Sponsor: University of Nottingham, United Kingdom Trial Web Site: www.enos.ac.uk Publishing Title: Efficacy of Nitric Oxide in Stroke (ENOS) Trial - A Prospective Randomised Controlled Trial in Acute Stroke Author Block: Sandeep Ankolekar, Cheryl Hogg, Sally Utton, Philip M Bath, Univ of Nottingham, Nottingham, United Kingdom Abstract Body: Rationale: Acute hypertension is associated with a poor outcome after stroke. No large trials have assessed the effect of altering BP during the acute phase of stroke on outcome. We are testing whether nitric oxide, a multimodal molecule given as glyceryl trinitrate (GTN), is safe and effective in improving outcome after acute stroke. Furthermore, around half of all patients admitted with acute stroke are taking antihypertensive therapy immediately prior to the stroke. No data exist as to whether it is beneficial or safe to stop or continue this treatment during the acute phase. Design: ENOS is a prospective, international, multicentre, randomised, parallel-group, blinded, controlled trial. 5,000 ischaemic or haemorrhagic stroke patients with systolic BP 140-220 mmHg, and within 48 hours of onset will be included. Subjects will be randomised to 7 days of single-blind treatment with transdermal GTN or control. Those patients taking prior antihypertensive therapy will also be randomised to continue or temporarily stop this for 7 days. ENOS is conducted over a secure internet site. The primary outcome is modified Rankin Scale at 90 days which is carried out by a blinded assessor. The analysis will be by intention to treat. Trial status: As at 28th October, 2010, 2043 patients had been recruited from 116 centres (Australia, Canada, China, Egypt, Hong Kong, India, Italy, Malaysia, New Zealand, Philippines, Poland, Republic of Ireland, Romania, Singapore, Spain, Sri Lanka and UK). More centres welcome to join. Author Disclosure Block: S. Ankolekar: None. C. Hogg: None. S. Utton: None. P.M.W. Bath: None. Presentation Number: CT P32 PI Coordinator Affiliation: UCLA Stroke Center PI Coordinator Name: Jeffrey Saver, MD (not PI- Stroke CDE Working Group Chair) Trial Abbreviation: NINDS CDE Project Trial Contact Information: [email protected] Trial Email: [email protected] Trial Name: National Institute of Neurological Disorders and Stroke Common Data Element Project Trial Registry Number ID: N/A Trial Sponsor: NINDS, NIH Trial Web Site: http://www.commondataelements.ninds.nih.gov/ Publishing Title: Version 1.0 of the Stroke Common Data Elements Available for Public Use from the National Institute of Neurological Disorders and Stroke, National Institutes of Health Common Data Element Project Author Block: Lisa Hunegs, Stacie Grinnon, KAI Res, Inc., Rockville, MD; Joanne Odenkirchen, Natl Inst of Neurological Disorders and Stroke (NINDS), Rockville, MD Abstract Body: Rationale: To assist investigators conducting clinical studies and accelerate data sharing, the NINDS with its contractor, KAI Research, Inc., continues to foster its Common Data Element (CDE) Project. At the past two International Stroke Conferences, the Project convened a Working Group of experts in stroke clinical research to advise the Institute on the development of Stroke CDEs and accompanying resources. Methods: The sixty-three member Stroke CDE Working Group (WG) divided into subgroups who met periodically to identify and define elements for nine specific domains of data (e.g., stroke types and subtypes; outcomes and endpoints; etc.). After each subgroup identified and defined elements for their domain, they vetted their recommendations through the entire WG. The recommendations include the following: • Catalog of approximately 600 Stroke CDEs with detailed specifications for each CDE; • List of approximately 35 standardized instruments with explanations of when each instrument is recommended for use. A beta version of the Stroke CDEs was posted to the CDE Web site (http://www.commondataelements.ninds.nih.gov/) for public review in August 2010. During this one-month review period, select organizations and the larger research community were asked to review the CDEs and provide feedback about their utility. The Working Group is currently addressing the feedback. By the end of November 2010, Version 1.0 of the Stroke CDEs will be published on the Web site for public use. Results: The poster presentation will provide an update about the status of the Stroke CDEs, including: • Report of those researchers who have already begun to use the Stroke CDE; • Examples of how user feedback was used to improve the Stroke CDEs; • Explanation of how the Stroke CDEs can be used by a clinical study; and • Next steps to ensure the Stroke CDEs meet the evolving needs of stroke researchers. Conclusions: The NINDS recognizes that the best way to ensure the Stroke CDEs are useful tools and the CDE Project accomplishes its goals is to continuously revise and add to the CDEs based upon the feedback of researchers. Thus, the Institute strongly encourages investigators conducting clinical research studies to use the CDEs and welcomes users to submit feedback regarding its CDEs through the CDE Web site. Author Disclosure Block: L. Hunegs: None. S. Grinnon: None. J. Odenkirchen: None. Presentation Number: CT P33 PI Coordinator Affiliation: Georgetown University/National Rehabilitation Hospital PI Coordinator Name: Alexander W. Dromerick MD/Chelsea S. Kidwell MD/Deeonna Farr MPH Trial Abbreviation: PROTECT DC Trial Contact Information: Deeonna Farr MPH, [email protected] Trial Email: [email protected] Trial Name: Preventing Recurrence of Thromboembolic Events through Coordinated Treatment in the District of Columbia Trial Registry Number ID: NCT00703274 Trial Sponsor: NINDS U54 057405 Trial Web Site: http://clinicaltrials.gov/ct2/show/NCT00703274?term=protect+dc&rank=1 Publishing Title: A Phase II RCT of Stroke Navigators to Improve Compliance with Secondary Stroke Prevention: PROTECT DC Author Block: Alexander W Dromerick, Natl Rehabilitation Hosp, Washington, DC; M. Christopher Gibbons, Johns Hopkins Sch of Med, Baltimore, MD; Dorothy F Edwards, Univ of Wisconsin, Madison, WI; Deeonna Farr, Natl Rehabilitation Hosp, Washington, DC; Annapurni Jayam-Trouth, Howard Univ Sch of Med, Washington, DC; Nawar M Shara, Georgetown Univ/Medstar Health Res Inst, Washington, DC; Brisa M Sanchez, Univ of Michigan, Ann Arbor, MI; Ali Fokar, Medstar Health Res Inst, Hyattsville, MD; Regina Coles, Georgetown Univ, Washington, DC; Judson D Richardson, Natl Rehabilitation Hosp, Washington, DC; Bruce Ovbiagele, UCLA Sch of Med, Los Angeles, CA; Chelsea S Kidwell, Georgetown Univ, Washington, DC Abstract Body: Trial Abbreviation: PROTECT DC Trial Registry Number: NCT00703274 Background: Despite significant advances in the prevention and treatment of cerebrovascular disease, stroke remains the third leading cause of death and a leading cause of adult disability. The initiation of effective secondary prevention strategies is most effective when implemented early (before disabling stroke occurs), monitored frequently, and maintained long-term after a cerebrovascular event. PROTECT DC facilitates the initiation of secondary prevention behaviors in an attempt to prevent the recurrence of stroke among participants. The program trains a lay person, called a stroke navigator, to provide participants with education on secondary prevention behavior and to navigate the health and human service system, which will assist participants in obtaining the necessary services and programs to engage in secondary prevention behaviors. Population (n=250): 1. Age ≥ 18 years 2. Hospitalized due to ischemic stroke or intercurrent ischemic stroke event within the past 30 days 3. Large vessel, small vessel, or cryptogenic with stroke risk factor etiologies as defined by TOAST criteria 4. Community dwelling prior to stroke 5. Resides within the District of Columbia or closely in its suburbs 6. Expected to reside after hospital discharge within the District of Columbia or closely in its suburbs 7. Caregiver or interested party available, if moderately or severely disabled (not required to actually reside with participant) 8. Sufficient number of collateral contacts to assure follow-up. 9. NIHSS <20 Objective: To determine whether stroke navigators can improve compliance with secondary stroke prevention measures in an urban underserved population with atherogenic ischemic stroke. Design: Phase II, single-blind, randomized controlled trial Interventions: Experimental: Stroke navigation for a one year period. Control: Usual and customary care for one year Outcome Measures: Primary: Composite score of compliance with objective measures of risk factor control (e.g. systolic blood pressure, HbA1c, LDL, INR, antithrombotic pill count) at one year after stroke onset. Secondary: Stroke knowledge, exercise, dietary modification, smoking cessation at one year. Analysis: Intention to treat Trial status: Actively enrolling since July 1, 2008; As of October 15, 2010, 150 of the target 250 participants have been enrolled, with 75 randomized to the experimental condition and 75 randomized to the control condition. Thus far, 73 participants have completed the primary 1-year time point. Mean age of the enrolled participants is 61 years (SD=12, range 33 - 90), 91% are African-American, 44% are male and the median NIHSS score is 3 (range 0 - 16). PI/Coordinator Name: Alexander W. Dromerick MD/Chelsea S. Kidwell MD/Deeonna E. Farr MPH PI/Coordinator Affiliation: Georgetown University/National Rehabilitation Hospital Trial Sponsor: National Institute of Neurological Disorders and Stroke Contact Information: [email protected]; Voice: 202-877-1931 Author Disclosure Block: A.W. Dromerick: None. M.C. Gibbons: None. D.F. Edwards: None. D. Farr: None. A. Jayam-Trouth: None. N.M. Shara: None. B.M. Sanchez: None. A. Fokar: None. R. Coles: None. J.D. Richardson: None. B. Ovbiagele: None. C.S. Kidwell: None. Presentation Number: CT P34 PI Coordinator Affiliation: University of Cincinnati PI Coordinator Name: Arthur M. Pancioli, MD Trial Abbreviation: The CLEAR-ER Stroke Trial Trial Contact Information: Pamela A. Schmit RN BSN [email protected] 513-558-6142 Trial Email: [email protected] Trial Name: The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke Enhanced Regimen Trial Registry Number ID: P50-NS044283 Trial Sponsor: NINDS Trial Web Site: www.clear-er.org Publishing Title: The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke Enhanced Regimen (The CLEAR-ER Stroke Trial): An Ongoing Phase IIb Trial Author Block: Arthur M. Pancioli, U CINCINNATI MEDICAL CTR, Cincinnati, OH; for the CLEAR-ER Investigators Abstract Body: INTRODUCTION AND HYPOTHESIS: The CLEAR-ER trial is a NIH-funded, Phase IIb, randomized, multi-center, double-blind, controlled trial of the combination of medium dose rt-PA plus eptifibatide versus standard dose rt-PA in acute ischemic stroke patients that can have rt-PA treatment begun within 3 hours of symptom onset. METHODS: A total of 126 subjects with a NIHSSS> 5 will be enrolled over the next 3 years at 10 centers in the United States. Patients are randomized to a combined intravenous medium-dose rt-PA (0.6mg/kg, 60 mg max) and eptifibatide (135 mcg/kg IV bolus and a 2 hour infusion of 0.75 mcg/kg/min) or standard dose (0.9 mg/kg, 90 mg max, 10% as bolus) rt-PA in a 5 to 1 ratio. This will result in a total of 105 patients treated with the combined regimen, and 21 patients treated with standard dose IV rt-PA alone. The primary safety outcome measure is symptomatic ICH within 36 hours of initiation of therapy. The study will determine if there is a signal of efficacy such that a Phase III Trial of this combination is warranted. The primary measure of clinical outcome is the percentage of patients meeting a modified Rankin Scale score of 0 or 1 or return to their baseline at 90 days post treatment. CONCLUSIONS: The CLEAR-ER Trial will obtain reliable estimates of the safety of an enhanced dosing regimen of eptifibatide in combination with medium-dose rt-PA in acute stroke patients in whom treatment is begun within three hours of onset. As of November 1, 2010, 39 subjects have been randomized into the trial. Author Disclosure Block: A.M. Pancioli: Research Grant; Significant; NINDS, EKR Therapeutics. Other Research Support; Significant; Genentech, Schering Plough. Consultant/Advisory Board; Modest; NTI. Presentation Number: CT P35 PI Coordinator Affiliation: University of Edinburgh PI Coordinator Name: JM Wardlaw, PAG Sandercock, RI Lindley Trial Abbreviation: IST3 Perfusion+Angiography Study Trial Contact Information: Joanna Wardlaw, Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. Fax ++ 44 (0)131 332 5150 email: [email protected] Trial Email: [email protected] Trial Name: Third International Stroke Trial Perfusion and Angiography Study Trial Registry Number ID: ISRCTN25765518 Trial Sponsor: University of Edinburgh and NHS Lothian, co-sponsors Trial Web Site: www.ist3.com Publishing Title: The Third International Stroke Trial (IST-3) A Large Randomised Controlled Trial of rt-PA in Acute Ischemic Stroke: Perfusion and Angiography Study: Current Progress and Recruitment Author Block: Joanna Wardlaw Sr., Peter Sandercock Sr, Trevor Carpenter Jr, Univ of Edinburgh, Edinburgh, United Kingdom; Rudiger von Kummer Sr, Univ of Dresden, Dresden, Germany; Anders von Heijn, Veronica Murray, Karolinska Inst, Stockholm, Sweden; Andre Peeters, St Luc Hosp, Louvain, Belgium; Mark Parsons, John Hunter and Calvary Mater Hosp, Newcastle, Australia; Adam Kobayashi, Univ of Warsaw, Warsaw, Poland; Max Wintermark, Univ of Virginia, Charlottesville, VA; Richard Lindley, Univ of Sydney, Sydney, Australia; IST3 Perfusion and Angiography Study Group Abstract Body: Background: MR and CT Perfusion (MRP, CTP) and Angiography (MRA, CTA) are used increasingly in clinical practice but their role in stroke diagnosis and to guide thrombolytic therapy remains unclear. Opinion on which perfusion parameter to use and whether only patients with an occluded artery or perfusion deficit should receive rt-PA varies widely. Objective: To determine the effect of rt-PA 0.9mg/kg on lesion growth and functional outcome in the presence/absence of a perfusion deficit or occluded artery and which perfusion parameter best predicts lesion growth and functional outcome. Study Design: IST-3 is a randomised controlled trial of rt-PA given up to six hours after acute ischemic stroke with blinded prospective outcome assessment. CTP/MRP and/or CTA/MRA are acquired at randomisation and/or 24 hours after trial treatment. Eligibility: Patients with acute ischemic stroke (CT or MR imaging having excluded hemorrhage) who can start treatment within 6 hours of stroke. No definite indication for rt-PA, perfusion or angiography imaging. No contraindication to rt-PA, contrast agents or MR imaging. Trial procedures: In addition to those of IST3 core trial, patients have CTP/MRP and/or CTA/MRA pre and/or 24 hours post rt-PA treatment. Data are analysed centrally using dedicated software. Trial outcome measures: Infarct growth from pre-randomisation to 24 hours; functional outcome on the modified Rankin Scale at 6 months; hemorrhagic transformation. Sample size: At 80% power (alpha of 0.05) 100 patients would detect a 27% difference and 400 a 15% difference in infarct growth between patients allocated rt-PA and control according to perfusion defect or arterial occlusion. We aim to recruit a total of 300 patients. Analysis: 12 quantitative and qualitative perfusion parameters and thresholds are being assessed with bespoke and commercial software. Arterial patency is quantified using TIMI and MORI scores. Analysis will adjust for patient, image, and stroke variables. Trial Status: 45 centres in 10 countries are participating. The IST3 Perfusion and Angiography study has perfusion data on 104 patients from 21 centres (mostly CTP) and angiography data from 29 centres on 221 patients (mostly CTA). Recruitment continues until 30th June 2011. The results will be reported in 2012. Author Disclosure Block: J. Wardlaw: Research Grant; Significant; EME study funding, MRC trial funding. P. Sandercock: ; EME study funding, MRC trial funding. T. Carpenter: ; EME study funding. R. von Kummer: None. A. von Heijn: None. V. Murray: None. A. Peeters: None. M. Parsons: None. A. Kobayashi: None. M. Wintermark: None. R. Lindley: None. Presentation Number: CT P36 PI Coordinator Affiliation: Massachusetts General Hospital PI Coordinator Name: Albert Yoo, MD Trial Abbreviation: PICS Trial Contact Information: Siu Po Sit, PhD, [email protected], 510-748-3221 Trial Email: [email protected] Trial Name: Penumbra Imaging Collaborative Study Trial Registry Number ID: NCT00785161 Trial Sponsor: Penumbra, Inc. Trial Web Site: www.penumbrainc.com Publishing Title: Final (post-treatment) ASPECTS Score Is An Independent Predictor Of Clinical Outcome Following Endovascular Treatment Of Acute Anterior Circulation Ischemic Stroke: Analysis Of The PICS Database Author Block: Albert Yoo, Massachusetts General Hosp, Boston, MA; Michael Brant-Zawadzki, Hoag Hosp, Newport Beach, CA; Donald Frei, Swedish Medical Ctr, Englewood, CO; Donald Heck, Forsyth Medical Ctr, Winsten-Salem, NC; Tim Malisch, Alexian Brothers Medical Ctr, Elk Grove Village, IL; Sean Meagher, OSF Saint Francis Medical Ctr, Peoria, IL; Darryn Shaff, Lehigh Valley Health Network, Allentown, PA; Benjamin Crandall, Abbott Northwestern Hosp, Minneapolis, MN; Osama Zaidat, Medical Coll of Wisconsin, Milwaukee, WI; Michael Alexander, Cedars-Sinai Medical Ctr, Los Angeles, CA; Laszlo Miskolczi, Holy Cross Hosp, Fort Lauderdale, FL; Brian Chong, Mayo Clinic, Phoenix, AZ; Robert Tarr, Univ Hosp of Cleveland, Cleveland, OH; Aaron Daniel Sasson, Maimonides Medical Ctr, Brooklyn, NY; Avi Setton, North Shore Univ Hosp, Manhasset, NY; Aquilla Turk III, MUSC, Charleston, SC; Christopher Zylak, Sacred Heart Medical Ctr, Spokane, WA; R. Gilberto Gonzalez, Zeshan A. Chaudhry, Massachusetts General Hosp, Boston, MA; Elan Mualem, Penumbra, Inc, Alameda, CA; Arani Bose, Siu Po Sit, Penumbra, Inc., Alameda, CA; For the PICS Investigators Abstract Body: Purpose: Preliminary data suggests that pre-treatment ASPECTS score predicts the clinical response to reperfusion in patients with anterior circulation proximal artery occlusions (PAO) treated with endovascular therapy. We sought to validate the clinical importance of ASPECTS-determined infarct size in this patient population by analyzing final infarct extent using post-treatment imaging. Methods: PICS is a prospective multicenter registry of clinical and imaging data in PAO patients treated with the Penumbra Stroke System. Anterior circulation stroke patients were identified for inclusion into this analysis. ASPECTS scores were determined by a central core imaging laboratory on available pre-treatment (pre-) CT scans and post-treatment (post-) CT and MRI studies. Imaging analysis was performed blinded to all clinical data, except stroke side. Statistical analysis was performed to determine the clinical and imaging predictors of functional outcome. Variables with a univariate p-value <0.2 were included in a multivariate model. Statistical significance was considered at p<0.05. Results: A total of 102 anterior circulation PAO patients were identified, which included 55 (53.9%) left-sided strokes and 56/101 (55.4%) females. The mean age was 66.0 ± 15.8 years; the median NIHSSS was 16.0 (IQR 12-22). The mean time from stroke onset to presentation was 3.0 ± 3.5 hours. The mean time from groin puncture to termination of thromboaspiration was 91.4 ± 54.3 minutes. The rate of TIMI 2/3 revascularization was 83.3%. Thirty-nine (38.2%) patients achieved 90-day mRS 0-2, and 22 (21.6%) patients died. The median pre-ASPECTS score (n=92) was 8.0 (IQR 7-10), and median post-ASPECTS score (n=67) was 6.0 (IQR 5-8). Patients with good clinical outcome (mRS 0-2) had a higher median post-ASPECTS score than those with mRS 3-6 (7 [IQR 6-8] versus 5 [IQR 4-7]; p=0.01). In Receiving Operating Characteristic (ROC) analysis, a post-ASPECTS threshold of >5 optimized sensitivity and specificity for good outcome. Among patients with post-ASPECTS >5, 53.7% (22/41) had a good outcome, compared with 20.0% (5/25) of patients with post-ASPECTS ≤5 (p=0.01). In multivariate analysis, only post-ASPECTS >5 (OR 5.77, p=0.005) and age <80 (OR 4.65, p=0.02) were independent predictors of good outcome (Table). Reperfusion status was the best predictor of the change in ASPECTS between pre-and post-treatment scans (multivariate p=0.049). Patients with TIMI 2-3 revascularization had a smaller median decrease in ASPECTS (less infarct growth; 2 [IQR 0-3] vs. 3 [IQR 1.5-6], p=0.08) and higher post-ASPECTS scores (6 [IQR 5-8] vs. 4 [IQR 3-7], p= 0.04) compared to those without reperfusion, despite similar pre-ASPECTS scores (median of 8 for both). Conclusions: Final infarct size quantified using ASPECTS is an important determinant of clinical outcome following endovascular stroke therapy. Reperfusion limits infarct growth between the pre- and post-treatment ASPECTS. Author Disclosure Block: A. Yoo: Research Grant; Significant; Penumbra, Inc. M. Brant-Zawadzki: Honoraria; Modest; Penumbra, Inc. D. Frei: ; Penumbra, Inc. D. Heck: ; Penumbra, Inc. T. Malisch: ; Penumbra, Inc.. S. Meagher: None. D. Shaff: None. B. Crandall: None. O. Zaidat: ; Penumbra, Inc.. M. Alexander: None. L. Miskolczi: None. B. Chong: None. R. Tarr: None. A.D. Sasson: None. A. Setton: None. A. Turk: ; Penumbra, Inc.. C. Zylak: None. R. Gonzalez: None. Z.A. Chaudhry: None. E. Mualem: Employment; Significant; Penumbra, Inc. A. Bose: ; Penumbra, Inc. S. Sit: ; Penumbra, Inc.. Presentation Number: CT P37 PI Coordinator Affiliation: TBD PI Coordinator Name: TBD Trial Abbreviation: None Trial Contact Information: Pfizer CT.gov Call Center 1-800-718-1021 Trial Email: TBD Trial Name: A Phase 2 Multicenter, Randomized, Double-blind, Placebo Controlled Study of the Safety and Efficacy of PF-03049423 in Subjects with Ischemic Stroke Trial Registry Number ID: NCT01208233 Trial Sponsor: Pfizer Inc Trial Web Site: www.clinicaltrials.gov ID # NCT01208233 Publishing Title: A Phase 2 Multicenter, Randomized, Double-blind, Placebo Controlled Study of the Safety and Efficacy of PF-03049423 in Subjects with Ischemic Stroke Author Block: Martin M Bednar, Pfizer Inc, Groton, CT; Steven C Cramer, U. California, Irvine, CA; Seth P Finklestein, Biotrofix Inc, Waltham, MA; Joseph Park, Lucio Ferreira, Pfizer Inc, Groton, CT; Ruth McKernan, Pfizer Inc, Cambridge, United Kingdom; Larry D Altstiel, James W Kupiec, Pfizer Inc, Groton, CT; Natalie Mount, Pfizer Inc, Cambridge, United Kingdom; Paul Maruff, CogState Inc, Melbourne, Australia Abstract Body: BACKGROUND: There are no approved therapies for reducing disability from stroke that are initiated beyond the first few hours. Furthermore, in most studies where patients do receive an approved hyperacute stroke therapy, most patients are left with significant disability despite overall efficacy. Therapies based on brain repair have the potential to improve outcomes with a relatively wide time window. Preclinical studies of PF03049423 suggest efficacy for this approach with improvement in motor outcome when therapy is initiated up to 3 days post stroke. Moreover, clinical stroke trial designs have been criticized for their lack of concordance on key translational endpoints demonstrated in animal stroke models. Thus, the design of the current clinical trial seeks to specifically emulate the translational aspects of motor function consistently demonstrated in preclinical neurorecovery stroke models. OBJECTIVE: The objectives of this study are to evaluate the safety and tolerability of PF-03049423 following multiple dose administration to subjects with ischemic stroke, including the relationship between PF-03049423 concentration and blood pressure. The study will also evaluate the efficacy of PF-03049423, relative to placebo, in subjects with ischemic stroke following 90 days of therapy. DESIGN: This is a multicenter, double-blind, placebo controlled, randomized, international study. POPULATION STUDIED: A total of 240 stroke patients will be enrolled with dosing initiated 24-72 hours after stroke onset. Inclusion criteria NIHSS 6-20; the stroke must be radiologically confirmed by MRI to be ischemic and in the territory of either the MCA, ACA, or PCA; age 18-85 years. Exclusion criteria include severe acute or chronic medical or psychiatric condition apart from the index stroke, women of child bearing potential, and uncontrolled hypertension. Gender, introduction of thrombolytic therapy, and choice of antiplatelet therapy do not influence study eligibility. INTERVENTION: Each patient will be randomized to receive placebo or PF-03049423 (1, 3, or 6 mg), p.o. daily, for 90 days. OUTCOME MEASURES: The primary outcome measure for Part 1 of the trial is safety and tolerability, as determined from data, adverse events, vital signs, brain MRI, ECG, physical/neurological exam, NIHSS scores, and laboratory tests over 14 days. In Part 2, the primary endpoint is the proportion of subjects with modified Rankin Scale (mRS) score ≤2; over 90 days. Secondary outcome measures include plasma concentrations of PF-03049423; Additionally, specific assessment of motor scores will provide a translational comparison from the preclinical animal models to clinical, using Box & Blocks Test, Hand Grip Strength Test and gait velocity. Additional endpoints include the proportion of subjects with day 90 mRS score ≤1, NIH Stroke Scale score ≤1, Barthel Index (BI) ≥95 and BI=100. This trial will also assess scores on individual cognitive domains of interest including RBANS Coding Sub Test, RBANS Naming Sub Test, Line Cancellation Test, and Recognition Memory Test. ANALYSIS: Adverse events and safety findings will be tabulated and examined. Estimates of the effect of PF03049423 at each dose relative to placebo will be calculated for behavioral/outcome measures. The proportion of subjects with mRS ≤ 2 on Day 90 will be analyzed with a logistic regression including treatment, t-PA usage for current stroke, geographical region as fixed effects and baseline NIHSS total score as a continuous covariate. TRIAL STATUS: Worldwide trial in 6 countries (~ 35 sites) with first enrollment expected in November, 2010. Author Disclosure Block: M.M. Bednar: Employment; Modest; Significant. Employment; Significant; Employee of Pfizer Inc. S.C. Cramer: Consultant/Advisory Board; Significant; Pfizer Inc. S.P. Finklestein: ; Pfizer Inc. J. Park: Employment; Significant; Pfizer Inc. L. Ferreira: ; Pfizer Inc. R. McKernan: ; Pfizer Inc. L.D. Altstiel: ; Pfizer Inc. J.W. Kupiec: ; Pfizer Inc. N. Mount: ; Pfizer Inc. P. Maruff: Other; Significant; Contracted Organization. Presentation Number: CT P38 PI Coordinator Affiliation: University of Nottingham, UK PI Coordinator Name: Professor Philip Bath Trial Abbreviation: PODCAST Trial Contact Information: Mrs Lynn Stokes / [email protected] / Tel: +44 (0)115 8231671 / Fax: +44 (0)115 8230273 Trial Email: [email protected] Trial Name: Prevention Of Decline in Cognition After Stroke Trial Trial Registry Number ID: ISRCTN85562386 Trial Sponsor: University of Nottingham, UK Trial Web Site: www.podcast-trial.org/ Publishing Title: Podcast: Prevention Of Decline In Cognition After Stroke Trial: A Factorial Randomised Trial Of Blood Pressure And Lipid Lowering Author Block: Sandeep Ankolekar, Lynn Stokes, Philip M Bath, Univ of Nottingham, UK, Nottingham, United Kingdom Abstract Body: Rationale: Stroke and dementia are common, economically costly to society, and devastating to patients and their family. Elevated BP and cholesterol are common after stroke and may be associated with increasing cognitive decline. Although BP-lowering post-stroke may reduce cognitive decline, there is little evidence to date that lipid lowering is effective in preventing cognitive decline. Critically, it is unknown whether BP and cholesterol should be lowered intensively, or moderately as per current guidelines. The aim of the proposed trial is to determine if intensive BP and/or lipid lowering therapy after stroke is better in preventing cognitive decline, compared to current guideline treatment. Design: PODCAST is a prospective, randomised, open-label, blinded end-point, controlled, partial factorial, phase IV trial. The start up phase will assess feasibility of the study over 3 years in 600 patients. The main phase will then assess the efficacy of intensive treatment in a further 2,800 patients over 8 years in total. The target SBP is <125 mm Hg for the intensive BP lowering group and <140 mm Hg for the guideline group. For the intensive lipid lowering group the target LDL-C is <2 mmol/L and <3 mmol/L for the guideline group. The primary outcome is Addenbrooke’s Cognitive Examination. Secondary outcomes include quality of life, vascular events, functional outcome, depression and death. Trial Status: The trial has Ethics and NHS R&D approvals and commenced recruitment in September 2010. Author Disclosure Block: S. Ankolekar: None. L. Stokes: None. P.M.W. Bath: None. Presentation Number: CT P39 PI Coordinator Affiliation: Stanford University Stroke Center PI Coordinator Name: Gregory Albers Trial Abbreviation: DIAS-4 Trial Contact Information: H. Lundbeck A/S Trial Email: [email protected] Trial Name: Desmoteplase In Acute Ischemic Stroke Trial Registry Number ID: NCT00856661 Trial Sponsor: H. Lundbeck A/S, Copenhagen, Denmark Trial Web Site: www.lundbeck-dias.com Publishing Title: Desmoteplase in Acute Ischemic Stroke (DIAS) Clinical Trial Program: Regional Hub-Spoke Recruitment in DIAS-4 in the United States Author Block: Philip B Gorelick, Dept of Neurology, Univ of Illinois Coll of Med, Chicago, IL; Gregory W Albers, Stanford Univ Stroke Ctr, Palo Alto, CA; Rüdiger von Kummer, Univ of Technology, Dresden, Germany Abstract Body: Introduction The Desmoteplase in Acute Ischemic Stroke (DIAS) clinical trial program is designed to assess the safety and efficacy of desmoteplase, a novel, highly fibrin-specific thrombolytic agent in Phase III of clinical development. Currently, three studies are active: DIAS-3, DIAS-4, and DIAS-Japan. DIAS-3 and DIAS-4 were initiated in 2009 to evaluate the efficacy and safety of a single intravenous bolus of 90 µg/kg desmoteplase given 3-9 hours after onset of ischemic stroke (NIHSS Score 4-24, age 18-85 y). Patients (n=800) are selected with occlusion or high-grade stenosis (TIMI scores 0-1) in proximal cerebral arteries as assessed by magnetic resonance or computed tomography (CT) angiography. Recruitment in DIAS-3 is mainly focused on Asia and Europe; while in DIAS-4 most sites are located in the United States. DIAS-4 Hub-Spoke Model The hub-spoke model is a well-known system that is successfully used in telemedicine-delivered stroke care. In the DIAS-4 trial, it is implemented to support the recruitment and retention of acute ischemic stroke (AIS) patients. Overall, the coordination of the system is done by the Central Coordinating Center (CCC) based at the Center for Stroke Research at the University of Illinois College of Medicine, led by the first author of this abstract. The CCC oversees six hubs in the United States: Midwest, Northeast, South/Southeast, Mid-Atlantic, Southwest, and West. Each hub has a designated director, who is responsible for selection of and coordinating their network of hospitals, patient recruitment and retention, and peer support for principal investigators. Each of the six hubs will have 15-20 local sites, anticipating to recruit one to four patients per year per site. Sites are selected based on willingness to commit to DIAS-4; competition for patients from current ongoing or anticipated trials and from local interventionalists; availability of technology (e.g., CT angiography) and personnel to begin study enrollment in a timely manner; adequate number of AIS patients; and track record of success in the field. It is estimated that recruitment of 200 patients can be completed at US sites in 1.5-2 years. Recruitment is heightened by careful CCC surveillance and frequent communications via teleconference or face-to-face meetings. Moreover, the CCC strives to maintain consistent messages to monitors, hub directors, and local site staff. In addition, the CCC will review and discuss trial recruitment, patient/site retention, and any other issues weekly with hub directors and H. Lundbeck, the sponsor of the DIAS program. The hub-spoke model in the DIAS-4 trial will facilitate the progress of the DIAS program, which is important because desmoteplase is the only thrombolytic agent in late-stage development despite the high unmet treatment need in AIS. Many patients are not eligible for treatment because they fall outside the approved therapeutic window (0-3 h): 50%-80% of patients arrive after 6 hours in many tertiary care centers. In addition, US trials have largely excluded small- to medium-sized hospitals, where patients often arrive for initial assessment. Conclusion The DIAS-4 trial initiative represents an academic-industrial collaboration of the type that is needed to move the field of AIS treatment forward and to provide the US Food and Drug Administration, European Medicines Agency, other regulatory agencies, and physicians with confidence in desmoteplase treatment outcomes. It provides a network of both tertiary and community-based acute stroke centers representing standard clinical practice for a majority of potential stroke patients. The initiative will provide an opportunity to extend medical treatment to patients who would ordinarily not have access to thrombolytic therapy, and the results will be important for physicians and patients in need of a safer, effective treatment for AIS. Author Disclosure Block: P.B. Gorelick: Speakers; Modest; Boehringer Ingelheim. Honoraria; Modest; Bayer, Takeda, Abbott, Roche/Parexel, Savient, H. Lundbeck A/S. Consultant/Advisory Board; Modest; Boehringer Ingelheim. G.W. Albers: Honoraria; Modest; H. Lundbeck A/S, Boerhinger Ingelheim. R. von Kummer: ; H. Lundbeck A/S. Presentation Number: CT P40 PI Coordinator Affiliation: Reza Jahan PI Coordinator Name: Jeffrey Saver Trial Abbreviation: SWIFT Study Trial Contact Information: ev3 Trial Email: None Trial Name: Solitaire™ FR With The Intention For Thrombectomy (SWIFT) Study Trial Registry Number ID: NCT01054560 Trial Sponsor: ev3 Trial Web Site: None Publishing Title: Solitaire™ FR With The Intention For Thrombectomy (SWIFT) Study Author Block: Jeffrey Saver, Reza Jahan, UCLA, Los Angeles, CA; Wayne Clark, Oregon Health & Science Inst, Portland, OR; Elad Levy, Millard Fillmore Gates Circle Hosp, Buffalo, NY; Ronald Budzik, Riverside Methodist Hosp, Columbus, OH; Tudor Jovin, Univ of Pittsburgh Medical Ctr, Pittsburgh, PA; Raul Nogueria, Emory Univ, Atlanta, GA; Blaise Baxter, Erlanger Hosp, Chattanooga, TN; for the SWIFT Investigators Abstract Body: Background and Objective: The SOLITAIRE™ Revascularization Device is a retrievable stent designed to restore blood flow in patients experiencing ischemic stroke due to large intracranial vessel occlusion. This trial is intended to demonstrate substantial equivalence by obtaining prospective clinical data on the safety and efficacy of the SOLITAIRE TM Device compared to MERCI® Device for patients diagnosed with acute ischemic stroke. Design: The SWIFT Study is a multi-center IDE, randomized, prospectively controlled study in clot retrieval for patients diagnosed with an acute ischemic stroke. 200 patients will be enrolled in the study Intervention: Patients who are ineligible for or who have failed IV t-PA are randomized to embolectomy employing the Concentric Retriever or Solitaire FR within 8 hours of system onset. Outcome Measures: The primary outcome is arterial recanalization of occluded target vessel measured by TIMI score of 2 or 3 following the use of the SOLITAIRE™ or MERCI® Device without any symptomatic intracranial hemorrhage. Secondary outcomes include time to initial recanalization, measurement of patient’s neurological condition including NIHSS, Barthel Index and mRS at 30 and 90 days post procedure, rates of morbidity and mortality, and incidence of intracranial hemorrhage Analysis: The primary hypothesis is that the proportion of patients with TIMI flow of 2 or 3 will be non-inferior in the SOLITAIRETM Device treated group compared to the control group, the MERCI® Device Study population, using a clinically relevant non-inferiority margin Δ which is defined a priori to be 10%. Trial Status: Actively recruiting. As of October 2010, 84 patients have been enrolled and 21 total sites are participating. Author Disclosure Block: J. Saver: Research Grant; Modest; ev3. Consultant/Advisory Board; Modest; ev3, Concentric. R. Jahan: Consultant/Advisory Board; Significant; ev3. W. Clark: Research Grant; Significant; ev3. E. Levy: ; ev3. Consultant/Advisory Board; Modest; ev3, Concentric. R. Budzik: Research Grant; Significant; ev3. Consultant/Advisory Board; Modest; Concentric. T. Jovin: Research Grant; Significant; ev3. Consultant/Advisory Board; Modest; ev3, Concentric. R. Nogueria: Research Grant; Modest; ev3. Consultant/Advisory Board; Modest; ev3, Concentric. B. Baxter: Research Grant; Modest; ev3. Honoraria; Significant; Concentric. Consultant/Advisory Board; Modest; ev3, Concentric. Presentation Number: CT P41 PI Coordinator Affiliation: University of Southern California PI Coordinator Name: Gene Sung Trial Abbreviation: Advancing Telestroke Care Trial Contact Information: Gene Sung, [email protected], 323.409.8686 Trial Email: [email protected] Trial Name: Western States Stroke Consortium Telemedicne Project Trial Registry Number ID: NCT012268862 Trial Sponsor: National Stroke Association Trial Web Site: N/A Publishing Title: Western States Stroke Consortium Telemedicine for Stroke Project Author Block: Gene Y Sung, Univ of Southern California, Los Angeles, CA; Bart Demaerschalk, Mayo ClinicScottsdale, Phoenix, AZ; Chris Fanale, Swedish Medical Ctr, Denver, CO; Paul Katz, Renown Regional Medical Ctr, Reno, NV; Jennifer Majersik, Univ of Utah, Salt Lake City, UT; David Tong, California Pacific Medical Ctr, San Francisco, CA Abstract Body: On-Going Clinical Trial ABSTRACT WSSC Teletroke Study Western States Stroke Consortium Telemedicine for Stroke Study NCT01226862 BACKGROUND The use of telemedicine is rapidly expanding in the United States. It has been proven to be a useful tool in the delivery of health care to rural and underserved areas. Although researchers estimate that up to 30% of stroke patients could have improved outcomes based on use of iv-thrombolysis, actual rates of use remain disappointingly low. This is especially true for stroke patients who live in more rural settings, where distances to hospitals can be significant, and where there is typically no neurological presence to guide diagnosis and treatment. Similar problems are encountered in some suburban “community” hospitals where bed-size (e.g. < 200 beds) is associated with the absence of 24/7 neurology support, a key requirement for guidelines-based stroke care. Studies have reported accurate stroke diagnosis and increased use of tPA based on the use of a variety of telemedicine solutions. This study of telestroke across networks and systems boundaries is unique, previously published telestroke studies have tended to focus on the results of a single network with common technological underpinnings. The Advancing Telestroke Care study will establish treatment and outcomes in three distinct study cohorts: hub telemedicine hospital, spoke telemedicine hospital and non-telemedicine control hospital. OBJECTIVES The objectives of the study are to: · Determine if the use of telemedicine consultations for stroke patients will improve their care per guidelines compared to stroke patients treated by control hospitals · Determine if the care per guidelines provided via telemedicine consultations for stroke patients will be similar or equivalent to care per guidelines provided to stroke patients treated at hub hospitals DESIGN This is a prospective observational study. 600 subjects meeting inclusion and exclusion criteria will be enrolled consecutively over approximately 12 months and followed for 90 days post-stroke. The sites will be divided into the following three cohorts: · Hub hospital cohort: JCAHO-certified Primary Stroke Centers where patients are treated using hospital-based stroke teams and pathways; these hospital personnel also provide telemedicine consultation to satellite hospitals · Spoke hospital cohort: non-stroke center certified sites, where patients are treated at an in-network telestroke community hospital using telemedicine technology with consultation provided by physicians from a hub hospital · Control hospital cohort: non-stroke center certified sites with no telemedicine services · The hub hospitals are five member hospitals of the Western States Stroke Consortium (WSSC): California Pacific Medical Center, Mayo Clinic-Scottsdale, Renown Medical Center-Reno, Swedish Medical CenterDenver and the University of Utah. Each of the hub hospitals has affiliated spoke hospitals and has recruited participating community hospitals as controls. The study will avoid selection bias by having many study sites, which will include urban, suburban and rural hospitals. To maintain patient demographic balance, enrollment of subjects will occur in blocks of 20 for each group at each network. For instance, after 20 subjects are enrolled at a hub hospital, no more subjects can be enrolled until there have also been 20 subjects enrolled at the affiliated spoke hospitals and 20 subjects enrolled at the affiliated community hospitals. Inclusion criteria: Subjects will be eligible if the following criteria are met: · Age ≥18 years old · Acute stroke within 12 hours of symptom onset Exclusion criteria: Subjects who meet any of the following criteria will be excluded from this study: · Life expectancy less than 90 days · Patient unwilling to participate in study The sample size provides sufficient power to detect differences in the primary endpoint across cohorts. The statistical power and sample size were based on consecutive AIS patients in the 0 to 12 hour window resulting in a high correct tPA decision rate at control hospitals since many patients were excluded from tPA due to timing. Assuming correct tPA decision rates (as per tPA eligibility according to the ASA/AHA guidelines) of 88% in community hospitals with telestroke and 77% in community hospitals without telestroke, a sample size was calculated to be 187 subjects per group (80% power) to detect an 11% telestroke effect size with 0.05 twosided significance level. In anticipation of a 6.5% attrition rate, a total of 600 subjects (200 in each group) will be recruited to achieve a sample size goal of 187 subjects per group. ASSESSMENTS AND OUTCOMES • Demographic data (age, race, gender) • Comorbidity data (heart disease, diabetes, cancer, concurrent medications) • Clinical evaluation (NIHSS, mRS, vital signs, radiologic and laboratory data) Additional Assessment Study investigators recognize the importance of being able to compare the costs of care across all study cohorts. Each telestroke site will provide detailed descriptions of equipment and associated costs (including operating and setup costs) of their respective telestroke networks. All sites will 1) describe the care provided: what happens, how it happens, where it happens and 2) itemize cost elements such as tPA utilization (and coding accuracy), hospital length of stay (LOS), and EMS road and air-ambulance transfer. ANALYSIS Data analysis will focus on the primary outcome measure, accurate decision making for IV tPA administration in acute stroke as defined by ASA/AHA/ guidelines compared across cohorts. Patient data will be analyzed within the study cohort their care originated. For example, if a patient entered treatment through a spoke hospital and subsequently was transported to a hub hospital for further treatment, patient data will be analyzed as part of the spoke hospital data. Investigators may conduct a secondary analysis to examine the impact of assigning transported patients to receiving hospitals (and therefore, a different study arm). This type of secondary analysis would only be considered for patients that were transported in less than 24 hours after care was initiated. Patient data will also be analyzed between study cohorts. Detailed descriptions of equipment used in telestroke will be summarized and associated costs will be tabulated. Such details will enable a directional view of the cost differences between stroke care provided via hub/spoke hospitals and stroke care in control hospitals. Further, cost element detail will enable additional health economic analyses in the future, should a formal cost effectiveness analysis be undertaken. Again, formal health economic analysis of telestroke and telestroke networks of care is outside the scope of this study. Statistical analysis for the primary outcome will be performed using a random-effects logistic regression model (PROC GLIMIXED in SAS). The accurate decision making of IV tPA administration will be modeled as a function of the hospital cohort (spoke, control vs. hub hospital). The hospital cohort will be modeled as a fixed effect, and the clinical site will be modeled as a random effect with an exchangeable correlation structure. Potential confounding factors (e.g. time of symptom onset to treatment, NIHSS) will be included as covariates. As we mentioned above in Section 4.4.4, patient data will be analyzed within the study cohort their care originated. For example, if a patient entered treatment through a spoke hospital and subsequently was transported to a hub hospital for further treatment, patient data will be analyzed as part of the spoke hospital data. Patient data will also be analyzed between study cohorts. All analyses will be conducted using Statistical Analysis System version 9.2 software (SAS Institute, Cary, NC). Statistical significance will be accepted at twosided p < 0.05. Trial Status: Recruiting Patients Author Disclosure Block: G.Y. Sung: None. B. Demaerschalk: None. C. Fanale: None. P. Katz: None. J. Majersik: None. D. Tong: None. Presentation Number: CT P42 PI Coordinator Affiliation: National University of Singapore, Singapore PI Coordinator Name: Dr. Christopher Chen Trial Abbreviation: CHIMES Trial Contact Information: Chen, [email protected], +65 6516 5885 Trial Email: [email protected] Trial Name: Double-Blind, Placebo Controlled, Randomized, Multicenter Study to Investigate CHInese medicine NeuroAid Efficacy on Stroke Recovery Trial Registry Number ID: NCT00554723 Trial Sponsor: National Medical Research Council of Singapore Trial Web Site: http://chimes-society.org/ Publishing Title: The CHInese Medicine (MLC 601, NeuroAid®) Efficacy on Stroke recovery (CHIMES) Trial : Progress and Safety Update. Author Block: Christopher Chen, Chimes Society, Singapore, Singapore Abstract Body: Background and Aims : Stroke is a leading cause of death and disability worldwide. Despite improvements in acute stroke treatment, many patients only make a partial or poor recovery. During the early days to weeks following stroke, repair spontaneously occurs and the neurobiology of these events suggests a number of therapeutic targets to further promote recovery. Traditional Chinese Medicine (TCM) is commonly used to enhance the recovery process after stroke in China but lacks a reliable evidence base. Methods : MLC 601, a TCM widely used in China to improve recovery after stroke, has recently been shown to restore neurological and cellular function in animal models of stroke by processes involved in repair. Previous clinical trials have shown that MLC601 shows good tolerability and superiority over another TCM in terms of neurological disability and functional outcome. A large double blind randomized placebo controlled clinical trial is underway to further assess the safety and efficacy of MLC 601. Results : 665 patients (out of a planned total of 1100) have been randomised as of October 2010 from 16 sites in 5 Asian countries. We assessed the safety of MLC 601 in a substudy of CHIMES. Longer term laboratory safety data shows no differences between MLC601 and placebo, confirming MLC601’s safety in acute stroke patients receiving a 3-month treatment. Conclusions : Because TCM may be potentially beneficial with an encouraging safety profile, large randomised, double blind, placebo controlled clinical trials using TCM focused on stroke rehabilitation and repair, such as CHIMES are important. Author Disclosure Block: C. Chen: Research Grant; Modest; funding support from the National Medical Research Council of Singapore for CHIMES. Speakers; Modest; sponsorship from Moleac for travel to attend the European Stroke Congress. Presentation Number: CT P43 PI Coordinator Affiliation: University of Nottingham, United Kingdom PI Coordinator Name: Professor Philip Bath Trial Abbreviation: TARDIS Trial Contact Information: Mrs Margaret Adrian/[email protected] /Tel: +44 (0)115 82 30210/Fax: +44 (0)115 82 30273 Trial Email: [email protected] Trial Name: Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke Trial Registry Number ID: ISRCTN47823388 Trial Sponsor: University of Nottingham, United Kingdom Trial Web Site: www.tardistrial.org Publishing Title: Triple Antiplatelets For Reducing Dependency After Ischaemic Stroke (tardis). Safety And Tolerability Of Clopidogrel When Added To Aspirin And Dipyridamole In High Risk Patients With Recent Ischaemic Stroke: A Randomised Controlled Trial Author Block: Sandeep Ankolekar, Margaret J Adrian, Philip M Bath, Univ of Nottingham, Nottingham, United Kingdom Abstract Body: Rationale: The risk of recurrence is greatest immediately after stroke or TIA. Existing prevention strategies (antithrombotic, lipid/blood pressure lowering, endarterectomy) reduce, not abolish, further events. Dual antiplatelet therapy - aspirin & clopidogrel (AC) for IHD, aspirin & dipyridamole (AD) for stroke, is superior to aspirin monotherapy. We hypothesise that triple antiplatelet therapy (ACD) will be superior to AD in patients at high-risk of recurrence, providing bleeding does not become excessive. Design: TARDIS is a multicentre, parallel-group, prospective, randomised, open-label, blinded-endpoint, controlled trial. In the start-up phase, we will assess over 3 years the safety, tolerability and feasibility of triple therapy (ACD) versus dual therapy (AD) given for 1 month in 350 patients with acute stroke/TIA. The main phase will then assess the safety and efficacy of ACD in up to 5000 patients. The primary outcome is ordinal stroke (fatal/severe non-fatal/mild/TIA/none) at 90 days. Secondary outcomes include death, MI, vascular events, function, bleeding, serious adverse events; sub-studies will assess cerebral emboli and platelet function. Trial Status: The trial started in April 2009. As of 02 November 2010, 249 patients have been recruited from 34 centres within the UK Stroke Research Network. Author Disclosure Block: S. Ankolekar: None. M.J. Adrian: None. P.M.W. Bath: None. Presentation Number: CT P44 PI Coordinator Affiliation: Univ of Wisconsin PI Coordinator Name: Jon Matsumura Trial Abbreviation: ACT I Trial Contact Information: Sandy Lee, [email protected] Trial Email: [email protected] Trial Name: Asymptomatic Carotid Trial I Trial Registry Number ID: NCT00106938 Trial Sponsor: Abbott Vascular Trial Web Site: www.act1trial.com Publishing Title: Asymptomatic Carotid Trial I Author Block: Seemant Chaturvedi, WAYNE STATE UNIVERSITY, Detroit, MI; Lawrence Wechsler, Univ of Pittsburgh, Pittsburgh, PA; Jon Matsumura, Univ of Wisconsin, Madison, WI; Kenneth Rosenfield, Massachusetts General Hosp, Boston, MA; Gary Ansel, Riverside Hosp, Columbus, OH; Thomas Riles, NYU, New York, NY Asymptomatic Carotid Trial 1 (ACT 1) NCT00106938 Objective: To demonstrate non-inferiority of carotid artery stenting (CAS) using the Emboshield® Embolic Protection System with the Xact® RX Carotid Stent System, when compared with carotid endarterectomy (CEA) for the treatment of asymptomatic extra-cranial carotid stenotic disease. Study Design • Prospective, randomized, parallel, 2-arm, multi-center trial • 3:1 randomization ratio of CAS to CEA • Lead-in enrollment of up to 400 subjects • Maximum of 1658 pivotal subjects • Up to 100 sites in North America • Subjects followed at 1, 6, and 12 months post-procedure and annually for 5 years Eligible Patients • Asymptomatic • Standard risk for CEA • Single de novo lesion within the ICA, with or without involvement of the common carotid artery • Stenosis ≥70% and ≤99% by angiography or duplex ultrasound Key Inclusion Criteria • Subject ≥18 and <80 years of age • Subject asymptomatic No stroke or TIA (hemispheric or ocular) within the 180 days prior to the procedure Neurologist must confirm status Key Exclusion Criteria • Symptomatic_stroke or TIA within 180 days • Bilateral carotid stenosis (contralateral stenosis >60% by ultrasound or angiography) • High-risk surgical candidate • Known cardiac sources of emboli, including paroxysmal or sustained atrial fibrillation (treated or untreated) • Aortic arch anatomy unacceptable for carotid stent placement • Presence of carotid artery dissection, aneurysm, pseudo- aneurysm, arteritis, or fibromuscular dysplasia (FMD) in target vessel • Occlusion (TIMI 0 flow) or string sign of ipsilateral common or internal carotid artery • Excessive calcification at lesion • Tortuosity* and/or occlusive disease that might preclude the safe introduction of a guiding catheter/sheath, cerebral protection device, or stent Primary Endpoint • Composite of Death, Stroke, MI at 30 days post procedure PLUS • Ipsilateral Stroke from 31 to 365 days post procedure Follow-up for endpoints • An independent CEC reviews and adjudicates the following events: Cause of Death through 30 days (Attempt to determine if neurological, cardiac, other) Suspected Stroke (All through 30 days, Ipsilateral between 31 days and 365 days (post-procedure) Suspected MI (All suspected Q wave and non-Q wave through 30 days of procedure) Study Progress As of Sept 1, 2010: Total Randomized Subjects: 1138 - Total number of lead-ins to date: 189 Total number of sites initiated: 57 Lead in patient characteristics (n=180) as of 6/30/10: Mean age 68.2 years % male: 59% Diabetes: 35.0% HTN: 81.1% Hyperlipidemia: 84.4% CAD: 53.3% Previous MI: 20.0% Current smoker: 28.9% Current contralateral disease: 50.6% Previous coronary stent or angioplasty: 29.4% Previous CABG: 23.3% History of PAD: 28.9% Lead in patient Outcomes (n=160) as of 6/30/10: Death/stroke/MI 1.7% All stroke 1.7% Major stroke 0% Minor stroke 1.7% MI 0% Conclusions • Level I evidence defines standards of clinical care • ACT I is a randomized trial comparing patients at standard risk for CEA and CAS Only includes asymptomatic non-octogenarians patients High levels of operator and interventional skills/experience Routine embolic protection and dual antiplatelet therapy • All patients have modern medical therapy • Lead-in data suggests CAS event rates comparable to CEA Author Disclosure Block: S. Chaturvedi: Consultant/Advisory Board; Significant; Abbott Vascular. L. Wechsler: Consultant/Advisory Board; Significant; Abbott Vascular. J. Matsumura: Consultant/Advisory Board; Significant; Abbott Vascular. K. Rosenfield: Consultant/Advisory Board; Significant; Abbott Vascular. G. Ansel: Consultant/Advisory Board; Significant; Abbott Vascular. T. Riles: Consultant/Advisory Board; Significant; Abbott Vascular. Presentation Number: CT P45 PI Coordinator Affiliation: University of Massachusette Medical School PI Coordinator Name: Susanne Muehlschlegel, M.D., M.P.H. Trial Abbreviation: Safety Study of Dantrolene in Subarachnoid Hemorrhage Trial Contact Information: Susanne Muehlschlegel, M.D., M.P.H., [email protected] Trial Email: [email protected] Trial Name: Dantrolene for the Prevention and Treatment of Cerebral Vasospasm after Subarachnoid Hemorrhage – a Phase II Trial Trial Registry Number ID: NCT01024972 Trial Sponsor: American Heart Association Trial Web Site: n/a Publishing Title: Dantrolene for the Prevention and Treatment of Cerebral Vasospasm after Subarachnoid Hemorrhage - a Phase II Trial Author Block: Susanne Muehlschlegel, Bridget Garland, Raphael Carandang, Wiley Hall, Univ of Massachusetts Medical Sch, Worcester, MA; John R. Sims, Massachusetts General Hosp, Harvard Medical Sch, Boston, MA Abstract Body: Rationale: Subarachnoid hemorrhage (SAH) is one of the most devastating forms of stroke affecting primarily young patients before the age of 65, and has a fatality of 50% in the first 30 days. For survivors of the initial insult, cerebral vasospasm (CVSP) is the leading cause of disability and death, and therefore points to an inviting therapeutic target. CVSP occurs in 70% of patients with SAH, and one third develops neurologic deficits. Available treatments for CVSP are limited, and new treatments are needed. Although CVSP is a multi-factorial disease process, the common pathway of vasoconstriction is the continuous elevation of intracellular Ca2+-levels due to a combination of influx from extracellular Ca2+, and release from the largest intracellular Ca2+ store, the endo/sarcoplasmatic reticulum mediated by the ryanodine receptor (RyR). Nimodipine and nicardipine, both L-type specific Ca2+-channel blockers, have been used for CVSP, but are only partially effective, possibly because they affect only the influx of extracellular Ca2+, and have no effect on RyR-mediated intracellular Ca2+-release. Dantrolene is an F.D.A. approved RyR inhibitor. It is neuroprotective, has been shown to inhibit cerebral vasoconstriction alone as well as in combination with nimodipine in an exvivo rat model, and two small human studies have suggested that dantrolene may attenuate CVSP after SAH. Important potential side-effects that require study in a clinical trial in SAH patients include hyponatremia (its chemical structure requires solution in free water and 5% mannitol), and liver toxicity (black box warning for chronic dantrolene use). Design: Double-blind, placebo-controlled Phase II trial comparing intravenous dantrolene 1.25 mg IV every 6 hours x 7 days to placebo. Eligibility: Inclusion criteria are age ≥ 18 years, no upper age limit; documented aneurysmal SAH by CT/CT angiography or cerebral angiography ≤ 5 days after aneurysmal SAH; this time window was chosen because it is highly unlikely to have developed cerebral vasospasm before then; the aneurysm must have been secured either by clipping or coiling; baseline serum sodium before enrollment ≥ 135 mmol/L. Exclusion criteria are patients with severe clinical grade SAH (Hunt & Hess Grade 5 or World Federation of Neurological Surgeons Grade 5) due to the high risk of developing brain edema and/or dying early from severity of SAH; radiological grade of modified Fisher Scale of 1 or 0 due to the extremely low risk of developing cerebral vasospasm; patients receiving mannitol, hypertonic saline or florinef prior to enrollment (both alter serum sodium); pregnant patients (unknown risk of dantrolene to the unborn fetus). No restrictions to race will be made. Recruitment Update: A total n=30 (n=15 per group) will be recruited at a single center over a three year period. Currently, 15 patients have been enrolled (Sept 2009 - Oct 2010). Three patients did not complete the study: two patients dropped out of the study by their own will (reasons: anxiety and nausea), one patient was given a dose of 23.4% saline by the clinical team for headache for suspicion of brain edema. One patient died several days after the completion of the infusion period due to vessel rupture during cerebral angioplasty for vasospasm. An interim analysis is in preparation (after half of all subjects have been recruited) and will be presented to the data safety monitoring board. Author Disclosure Block: S. Muehlschlegel: Research Grant; Significant; American Heart Association Scientist Development Grant 09SDG2030022, Worcester Research Foundation Grant 2010. Other Research Support; Significant; J.H.P. Pharmaceuticals (Parsippany, NJ) provides the study drug, but has no influence on study design, execution or analysis.. B. Garland: None. R. Carandang: None. W. Hall: None. J.R. Sims: None. Presentation Number: CT P46 PI Coordinator Affiliation: Hospital das Clínicas/São Paulo University PI Coordinator Name: Adriana B. Conforto Trial Abbreviation: rTMS-Stroke Trial Contact Information: Adriana Conforto, [email protected] Trial Email: [email protected] Trial Name: Low-frequency Transcranial Magnetic Stimulation To Enhance Motor Recovery In The Subacute Phase After Stroke Trial Registry Number ID: 2006/55504-0 Trial Sponsor: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Trial Web Site: None Publishing Title: Low-frequency Transcranial Magnetic Stimulation To Enhance Motor Recovery In The Subacute Phase After Stroke Author Block: Adriana Conforto, Eduardo Mello, Erina Nagaya, Waldyr Santos Jr., Eduardo Melo, Milberto Scaff, Hosp das Clinicas/Sao Paulo Univ, Sao Paulo, Brazil; Leonardo Cohen, Human Cortical Physiology Section, NINDS, NIH, Bethesda, MD Abstract Body: Rationale: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the unaffected hemisphere (UH) transiently improves motor function in patients in the chronic phase after stroke. The goal of this study is to investigate effects on motor recovery of low-frequency rTMS of the UH, administered in the subacute phase after stroke. Design: Randomized, double-blind clinical trial. Intervention: Patients are randomized to either active or sham low-frequency rTMS of the UH followed by physical therapy, five days a week, for two weeks. Outcome measures: Primary outcome: Motor function of the paretic hand evaluated with the Jebsen-Taylor test. Secondary outcomes: Force of the paretic hand, Fugl-Meyer evaluation of motor performance (upper limb), modified Rankin scale, Functional Independence Measure, NIH Stroke Scale, measures of corticomotor excitability evaluated with transcranial magnetic stimulation. Outcomes are evaluated at baseline, at end of treatment and one, three and six months after end of treatment. Eligibility criteria: Inclusion Criteria: First-ever ischemic stroke in the internal carotid artery territory confirmed by CT or MRI, 5-45 days before, leading to contralateral hand weakness; age, 18-80 years. Exclusion criteria: cardiac pacemaker; pregnancy; implantable medication pump; intracranial hypertension; history of seizures; metal in the head; decompressive surgery; other neurological diseases; shoulder pain; joint deformity in the paretic upper limb; severe chronic disease such as end-stage cancer or end-stage renal failure; inability to provide informed consent due to severe language or cognitive impairment. Analysis: Intent to treat. Status: Actively recruiting since February, 2008. As of October 25th, 2010, 27 patients have been enrolled. Author Disclosure Block: A. Conforto: None. E. Mello: None. E. Nagaya: None. W. Santos: None. E. Melo: None. M. Scaff: None. L. Cohen: None. Presentation Number: CT P47 PI Coordinator Affiliation: Peking Union Medical College Hospital PI Coordinator Name: LY Cui Trial Abbreviation: Trial Contact Information: [email protected] Trial Email: [email protected] TrialName: Trial Registry Number ID: NCT00664846 TrialSponsor: Trial Web Site: www.sps-pumch.com Publishing Title: Interim Analysis of a Multi-center Trial in Secondary Ischemic Stroke Prevention in China Author Block: Bin Peng, Yicheng Zhu, Jun Ni, Weihai Xu, Lixin Zhou, Ming Yao, Jianming Wang, Peking Union Medical Coll Hospit, Beijing, China; Jiang Wu, Jilin Univ, Changchun, China; Chuanqiang Pu, 301 Hosp, Beijing, China; Yongjun Wang, Beijing Tiantan Hosp, Beijing, China; Liying Cui, Peking Union Medical Coll Hospit, Beijing, China; SMART Study Group Abstract Body: Background: Few information are available about the status of secondary ischemic stroke prevention in China. We conducted a multicentre, paralleled, randomized, open label, controlled trial (SMART trial) to evaluate the efficacy and safety of the standard medical management in secondary stroke prevention. Methods: Patients were randomized to two groups: standard medical management group and usual care group. In the interim analysis,we reviewed the baseline data of the two groups to evaluate the current status of secondary ischemic stroke, no difference in intervention between two groups. Results: At the time submission, 3904 patients were enrolled into the trial. Baseline characteristics of 3154 patients were available, 1504 patients in standard medical treatment group, 1631 patients in usual care group. Among the 3154 patients, 68.26% were male, 26.07% have history of ischemic stroke, 7.18% of TIA, 2.26% of intracerebral hemorrhage, 63.99% of hypertension, 22.55% of diabetes mellitus, 15.69% of dyslipidemia, 4.4% of atrial fibrillation and 14.55% of coronary heart disease. Percentage of medicine usage for risk factor control 3 months before stroke onset were as following: 46.06% of antihypertension agents, 17.83% of antiplatelet, 16.67% of anticoagulant, 28.86% of lipid lowering agent, and 60.39% of antihyperglycemic agents. Discussion: In China, hypertension is the first risk factor of ischemic stroke. Low use of medications for control of risk factors indicates that patients are at high risk of ischemic stroke. Strategies of standard medical intervention in secondary ischemic stroke are warranted. Funding Supported by Key projects in the National Science & Technology Pillar Program in the Eleventh Fiveyear Plan Period Contact Information: PI (Corresponding author): LY Cui Department of Neurology Peking Union Medical College Hospital Beijing, China PR 100730 Email: [email protected] Website: www.sps-pumch.com ClinicalTrial.gov Indentifier: NCT00664846 We have no conflict of interest. Author Disclosure Block: B. Peng: None. Y. Zhu: None. J. Ni: None. W. Xu: None. L. Zhou: None. M. Yao: None. J. Wang: None. J. Wu: None. C. Pu: None. Y. Wang: None. L. Cui: None.