(Stroke. 2006;37:e18.)
© 2006 American Heart Association, Inc.
Major Ongoing Stroke Trials |
Major Ongoing Stroke Trials
The following is a list of major ongoing studies about stroke. Information about other multicenter studies that might be included in this list should be submitted to the Stroke Editorial Office by the Principal Investigator. The list will appear online in the February, June and October issues of Stroke.Anticoagulants Versus Aspirin and the Combination of Aspirin and Dipyridamole Versus Aspirin Only in Patients With Transient Ischemic Attacks or Nondisabling Ischemic Stroke: ESPRIT (European/Australian Stroke Prevention in Reversible Ischemia Trial)
The Dutch TIA Trial and a literature review indicate that low-dose aspirin in any daily dose of at least 30 mg up to 325 mg is effective in the prevention of threatened stroke, but 87% of subsequent strokes in patients with TIAs or nondisabling ischemic strokes are not prevented. Anticoagulants have been proven highly efficacious in trials after myocardial infarction and after cerebral ischemia and atrial fibrillation. In patients after cerebral ischemia of presumed atherosclerotic origin, high-intensity anticoagulation (INR 3.0 to 4.5) is not safe. Data from SPIRIT (Stroke Prevention in Reversible Ischemia Trial) indicate that anticoagulant therapy with an intensity of INR 2.0 to 3.0 is safe in stroke prevention. In the 2nd European Stroke Prevention Trial (ESPS-2) a 22% relative risk reduction of the combination of aspirin and dipyridamole above that of aspirin only is reported; the results of this trial, however, are controversial. ESPRIT is designed to randomize 4500 patients between oral anticoagulation (INR 2.0 to 3.0), the combination of dipyridamole (400 mg daily) plus aspirin (in any dose between 30 and 325 mg) and aspirin only (in any dose between 30 and 325 mg). Primary outcome event is the composite event of vascular death, stroke, myocardial infarction, or major bleeding complication; the outcome assessment will be blinded. ESPRIT is an international, multicenter study in (at least) the following countries: Australia, Austria, Belgium, China, Germany, France, India, Israel, Italy, the Netherlands, Portugal, Singapore, Spain, Sweden, Switzerland, United Kingdom and the United States. Recruitment for this trial started in July 1997; as of November 2005, 3366 patients from 88 hospitals had been included. With 12 900 patient-years of follow-up a total of 861 outcome events have been reported, including 43 intracranial bleeds. As the investigators are still blinded, these outcome events are not yet separated per treatment group. However, these data suggest that treatment with oral anticoagulants in the current INR range is safe. At this moment the close-out for the comparison between the combination therapy of aspirin and dipyridamole, and aspirin alone is performed. The first results of ESPRIT are expected to be presented at the European Stroke Conference in Brussels in May 2006. New centers are still invited to participate.
Steering Committee: Australia, G.J. Hankey, MD; Austria, F. Aichner, MD; Belgium, G. Vanhooren, MD; France, D. Leys, MD; Germany, E.B. Ringelstein, MD; Israel, N.M. Bornstein, MD; Italy, S. Ricci, MD; the Netherlands, A. Algra, MD, J. van Gijn, MD, L.I. Hertzberger, MD, P.J. Koudstaal, MD and E.L.L.M. De Schryver, MD; Portugal, J. Ferro, MD; Singapore, C. Chen, MD; Spain, A. Chamorro, MD; Sweden, A. Terent, MD; Switzerland, J. Bogousslavsky, MD; United Kingdom, G.S.Venables, MD; for the ESPRIT group
Location: University Dept of Neurology, PO Box 85500, 3508 GA Utrecht, Netherlands. Phone: 31-30-2508350. Fax: 31-30-2522782. E-mail esprit@neuro.azu.nl.
Number of Centers: 80 to l00
Sponsor: The Netherlands Heart Foundation Association, UK Stroke Association, the French Ministry of Health, the Janivo Foundation, European Commission, University Medical Center Utrecht
Dates of Study: July 1997 through July 2007
Aortic Arch Related Cerebral Hazard (ARCH)
This study is designed to compare the efficacy of warfarin (target INR 2.0 to 3.0) with that of aspirin (75 to 150 mg per day) in combination with clopidogrel (75 mg per day) in the secondary prevention of vascular events in patients with stroke or systemic arterial embolism who are found to have significant atheroma of the aortic arch. Patients will be followed by 4 monthly review from randomization to the end of the study. The primary end point is time to one of a composite of recurrent ischemic stroke, intracranial hemorrhage, myocardial infarction, peripheral embolism or vascular death.
Steering Committee: P. Amarenco, G.A. Donnan, S.M. Davis, B.R. Chambers, A. Cohen, G.J. Hankey, E. Jones, C.R. Levi and P. Ravaud.
Contact: Australia: Prof Geoffrey Donnan, Co-ordination Centre, NSRI, Level 1, Neurosciences Building, Health, 300 Waterdale Road, Heidelberg Heights, Vic 3081, Australia. Phone 61-3-9496-2699. Fax 61-3-9457-2650. E-mail donnan@unimelb.edu.au. Europe: Prof Pierre Amarenco, Department of Neurology and Stroke Centre, Bichat - Claude Bernard University Hospital and Medical School Denis Diderot University - Paris VII 46 rue Henri Huchard, 75018 Paris, France. Phone 33-1-40258726 Fax 33-1-4025-7198. E-mail pierre.amarenco@bch.ap-hop-paris.fr
Location: Australia: Co-ordination Centre, National Stroke Research Centre, Austin Health, Heidelberg Heights Vic 3081, Australia. Europe: Co-ordination Centre, Department of Neurology and Stroke Centre, Bichat - Claude Bernard University Hospital and Medical School Denis Diderot University - Paris VII, 75018 Paris, France.
Number of Centers: Australia: 20; Europe: 40
Sponsors: The National Health and Medical Research Council of Australia; The National Heart Foundation; The Medical Research Council of France; and the Sanofi-Aventis Company.
Dates of Study: Oct 2002 through Dec 2007
*Asymptomatic Carotid Emboli Study (ACES)
Better ways are required to identify high-risk patients with asymptomatic carotid stenosis who may be suitable for endarterectomy. Previous small studies have suggested that the presence of asymptomatic embolic signals detected using transcranial Doppler ultrasound may identify a high-risk group. ACES is a large multicenter international prospective study which will determine whether asymptomatic emboli detected in the middle cerebral artery are an independent predictor of stroke and TIA risk in patients with asymptomatic carotid stenosis (
70%). Carotid stenosis is identified by duplex ultrasound. Unilateral middle cerebral artery transcranial Doppler recordings are made for one hour on each of 2 occasions at study entry. Recordings are made onto digital audiotape and are analysed by the coordinating center, blinded to subject identity. Subjects are then followed for 2 years, at 6 monthly intervals with repeat 1-hour Doppler recordings at 6, 12, and 18 months and repeat carotid duplex at 12 months. There is also an option to perform cerebrovascular reactivity measurements at study entry. Recruitment began in 2000. 375 patients are currently enrolled in the study and we aim to recruit a total of 480 patients. Recruitment is planned to finish in 2006, with follow-up complete in 2008.
Principal Investigator: Hugh Markus, FRCP
Contact: Sheila Reihill, ACES Study Coordinator, Centre for Clinical Neuroscience, St. George’s University London, SW17 ORE, Phone: 020 8725 5374, Fax: 020 8725 2950, E-mail s.reihill@sgul.ac.uk
Location: Croatia, France, Georgia, Germany, Hong-Kong, Ireland, Israel, Italy, Lithuania, Netherlands, Singapore, Slovenia, Spain, United Kingdom, United States
Number of Centers: 27 (still recruiting)
Sponsor: British Heart Foundation
Dates of Study: 2000–2008
Asymptomatic Carotid Surgery Trial (ACST)
This is an international, multicenter trial to assess the place of carotid endarterectomy (CEA) in the management of patients with severe carotid stenosis that are currently asymptomatic. Patients were randomized either to best medical treatment (BMT) alone or to BMT plus CEA. Recruitment is now complete but follow-up continues until 2008.
Principal Investigators: A.W. Halliday, FRCS; A.O. Mansfield, FRCS; D.J. Thomas, MD, FRCP
Contact: Steven Robertson, Trial Manager. Phone +44(0) 20 8725-3746. Fax: +44(0)20 8725-3782. E-mail acst@sghms.ac.uk
Location: The ACST Office, Department of Cardiological Sciences, St. Georges University of London, Cranmer Terrace, London SW17 0RE.
Number of Centers: 120+
Sponsor: Stroke Association and Medical Research Council (UK)
Dates of Study: Commenced April 1993 (ongoing but recruitment closed in 2003)
*Blood Pressure in Acute Stroke Collaboration (BASC)
Hypertension and hypotension in the acute phase of stroke are associated with a poor outcome; paradoxically, lowering blood pressure may also worsen outcome. BASC is performing a systematic review of blood pressure change versus outcome in acute stroke trials that involve vasoactive agents. Both group and individual patient data are being analyzed to assess whether therapeutic alteration of blood pressure is safe and effective in improving outcome, and if so, with which agent. Authors of such trials who are willing to share their trial data are invited to contact the investigators.
Principal Investigator: Philip M.W. Bath, FRCP
Contact: Philip M.W. Bath, FRCP; Division of Stroke Medicine, University of Nottingham, City Hospital Campus, Nottingham NG5 1PB, UK. Phone 44-115-823-1771. Fax 44-115-823-1767. E-mail philip.bath@nottingham.ac.uk
Location: University of Nottingham, Nottingham, UK
Number of Centers: Those centers that have organized a randomized controlled trial in acute stroke involving a vasoactive drug which lowers or raises blood pressure.
Sponsor: South Thames & Trent Regional Health Authority National Health Service Research and Development Executives. The study is being performed under the auspices of the Cochrane Collaboration Stroke Group and is published in the Cochrane Library
Dates of Study: November 1995 (continuing)
Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS)
CAVATAS is a randomized, multicenter trial to determine the benefits and risks of percutaneous transluminal angioplasty of the carotid and/or vertebral arteries in patients with symptomatic and asymptomatic cerebrovascular disease. The study includes a randomized comparison between carotid angioplasty and carotid endarterectomy.
Principal Investigator: Martin M. Brown, MD
Contact: Martin M. Brown, MD, FRCP, Professor of Stroke Medicine, Institute of Neurology, Box 6, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. Phone: 44-20-7829-8753. Fax: 44-20-7833-8613
Location: Europe, North America, and Australia
Number of Centers: 24. Total number of patients recruited=562.
Sponsor: British Heart Foundation, National Health Service Research and Development Programme, The Stroke Association
Dates of Study: April 1992 (continuing). Recruitment stopped on July 31, 1997. Follow-up continues.
Web address: www.cavatas.com
Carotid Occlusion Surgery Study (COSS)
COSS is a randomized, partially blinded, controlled trial to test whether extracranial-intracranial arterial bypass surgery, when added to best medical therapy, can reduce by 40% subsequent ipsilateral ischemic stroke at 2 years in subjects with recently symptomatic internal carotid artery occlusion and ipsilateral increased oxygen extraction fraction measured by PET. PET scans will be performed within 120 days of the qualifying TIA or stroke on 930 clinically eligible subjects to identify 372 with increased oxygen extraction fraction distal to an occluded carotid who will be randomized to receive surgery or no surgery. Study participants will be followed up for a minimum of 2 years. Follow-up includes clinic visits at 1 month, 3 months and every 3 months thereafter. All participants will receive best medical management, which includes management of hypertension and other medical risk factors.
Principal Investigators: William J. Powers, MD (Clinical Coordinating Center), William R. Clarke, PhD (Data Management Center)
Contact: Carol Hess, RN, Carotid Occlusion Surgery Study, Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110 Phone: 314-362-4299. Fax: 314-362-4521. E-mail carol@npg.wustl.edu
Location: Washington University School of Medicine, St. Louis, MO (Clinical Coordinating Center) University of Iowa, Iowa City, IA (Data Management Center)
Number of Centers: 20–40
Sponsor: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Dates of Study: July 2002 through July 2008
Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
CREST is a prospective, randomized, multicenter, clinical trial to assess the relative efficacy of carotid endarterectomy (CEA) versus carotid artery stenting (CAS) using the RX ACCULINKTM Carotid Stent System and RX ACCUNETTM Embolic Protection Device in pre-venting stroke, myocardial infarction and death during the 30-day peri-procedural period and ipsilateral stroke thereafter in subjects with symptomatic and asymptomatic extracranial carotid stenosis. The study includes a lead-in phase for credentialing of interventionalists, beyond their initial training and certification requirements. Approximately 2500 subjects with TIA, amaurosis fugax, or nondisabling stroke within 180 days of randomization and ipsilateral carotid stenosis 50% (defined as 70% by ultrasound or 50% by angiography) for symptomatic patients and >60% (defined as >70% by ultrasound or >60% by angiography) for asymptomatic patients will be followed for up to 4 years. Follow-up includes clinic visits at 1, 6, and 12 months, then every 6 months for study duration with phone contact every 3 months. All patients will receive best medical management, which includes treatment with aspirin, management of hypertension and medical risk factors. Recruitment of patients began in December 2000, but the start-up date will vary across centers depending upon their completion of certification and regulatory requirements. Currently 1370 lead-in participants and 800 randomized subjects have been enrolled.
Principal Investigator: Robert W. Hobson II, MD
Contact: Alice Sheffet, PhD, CREST-Administrative Center, UMDNJ-New Jersey Medical School, 30 Bergen Street, ADMC 617, Newark, New Jersey 07017, USA. Phone 973-972-7718. Fax 973-972-8383. E-mail sheffeaj@umdnj.edu
Location: North America
Number of Centers: 110
Sponsor: National Institute of Neurological Disorders and Stroke, National Institutes of Health.
Dates of Study: 2000–TBD
*CLOTS Trial (Clots in Legs or TEDS after Stroke): A randomized trial to establish the effectiveness of graduated compression stockings to prevent poststroke deep-vein thrombosis.
The CLOTS Trial is a family of 2 multicenter, international, partially blinded, randomized controlled trials which aim to establish the effectiveness of graduated compression stockings (GCS) to prevent poststroke deep-vein thrombosis (DVT). Trial 1 is comparing full length GCS with no GCS, whilst Trial 2 is comparing full length and below knee GCS. Centers randomize consenting patients into either Trial 1 or 2 depending on their current practice and beliefs with respect to GCS after stroke. Patients who are admitted to hospital within one week of an acute stroke and are immobile can be randomized into CLOTS. The allocated type of GCS is applied to both legs as soon as possible after randomization and worn until the patient is independently mobile around the ward or until they are discharged from hospital or until the patient declines to wear them. Patients undergo a routine Doppler ultrasound of both legs at 7, and wherever possible, 30 days post randomization. The primary outcomes are the presence of DVT in the popliteal vein or more proximal vein detected on either Doppler ultrasound or venography within 7 and 30 days of randomization. Patients are followed up at 6 months to identify late events, survival and functional status.
Chief Investigator: Professor Martin Dennis, Neurosciences Trials Unit, Western General Hospital, Crewe Road, Edinburgh UK. EH4 2XU. Phone 44 (0)131 5371082 Fax 44 (0)131 332 5150, E-mail clots@skull.dcn.ed.ac.uk, Website: www.clotstrial.com
Location: Europe and Australia
Number of Centers: 62 - We estimate we will need to enrol at least 1500 patients in Trial 1 and 2500 in Trial 2, and are actively seeking collaborating centers.
Sponsor: Medical Research Council (UK)
Dates of Study: 2001–2009
The Continue Or Stop postStroke Antihypertensives Collaborative Study (COSSACS)
Summary: Up to 40% of acute stroke patients on hospital admission are already taking antihypertensive therapy, and most will develop elevated blood pressure levels as an acute complication of the stroke. However, no guidelines exist as to whether antihypertensive therapy should be continued or discontinued following acute stroke. The Continue Or Stop postStroke Antihypertensives Collaborative Study (COSSACS) is a multicenter, prospective, randomized, open, blinded-endpoint study to assess whether existing antihypertensive therapy should be continued or discontinued within 48-hours of stroke onset and for the subsequent two weeks. A study population of 2900 patients with both cerebral infarction and haemorrhage on antihypertensive treatment at hospital admission will be recruited giving the study a 90% power at the 5% significance level to detect a relative reduction of 10% (absolute risk reduction of 6%) in death and dependency between continuation and discontinuation groups at 2 weeks. Nondysphagic, hospital-admitted stroke patients will be recruited within 48 hours of stroke onset and also within 24 hours of last dose of pre-existing antihypertensive therapy. Baseline investigations will include: blood pressure measurement using UA-767 monitor, modified Rankin Score, Barthel Index, National Institutes of Health Stroke Score and Oxfordshire Community Stroke Project Classification. Patients will be centrally randomised by secure website to continue or discontinue pre-existing antihypertensive treatment for a 2-week period. Blood pressure, modified Rankin Score, Barthel Index and National Institutes of Health Stroke Score will be repeated at 2 weeks by an observer blinded to the randomized group. Mortality and health-related quality of life outcomes will be centrally recorded at 6 months. The primary outcome will be death or dependency (modified Rankin Score >3) at 2 weeks postrandomization. Early secondary outcomes of neurological deterioration, functional status, blood pressure changes from admission and discharge destination will be recorded at 2 weeks. Late secondary outcome measures of death and dependency, fatal and nonfatal stroke recurrence, functional status, health-related quality of life and discharge destination will be recorded at 6 months.
Principal Investigators: Dr T.G. Robinson and Professor J.F. Potter
Contact Details: Department of Medicine, Division of Medicine for the Elderly, Leicester Warwick Medical School, University Hospitals of Leicester NHS Trust, Groby Road, Leicester LE3 9QP. Telephone +44 (0)116 256 3365. Facsimile +44 (0)116 232 2976. E-mail cossacs@le.ac.uk
Location: United Kingdom
Sponsor: The Health Foundation
Date of Study: December 2002 (ongoing)
Controlling Hypertension and Hypotension Immediately PostStroke (CHHIPS) Trial
Following acute stroke up to 60% of patients will be hypertensive (SBP 160 mm Hg) and nearly 20% hypotensive (SBP <140 mm Hg), both high and low values being associated with adverse prognosis in terms of death and disability. Furthermore, the acute management of these poststroke blood pressure changes is a matter of some debate, as reflected in surveys of clinical practice, and there is a lack of evidence-based clinical guidelines to inform the management of this common problem. The Controlling Hypertension and Hypotension Immediately PostStroke (CHHIPS) Trial is a United Kingdom multicenter, prospective, randomized, double-blind, placebo-controlled, titrated-dose trial to assess whether hypertension and hypotension should be therapeutically manipulated following acute stroke. This trial will assess depressor therapy using lisinopril and labetalol compared to placebo in both dysphagic (sublingual and intravenous administration routes) and non-dysphagic (oral route) hypertensive (SBP 160 mm Hg) ischemic and hemorrhagic stroke patients recruited within 36 hours of stroke onset. Dose titrations will be made at 4 and 8 hours post-randomisation with the aim of achieving target SBP (150 mm Hg (range 145 to 155 mm Hg) or a 15 mm Hg reduction from baseline), and treatment will be continued until 2 weeks following stroke. A population of 1650 hypertensive patients will give the study an 80% power at the 5% significance level to detect a relative reduction of 15% in death and dependency between either of the 2 treatment groups and placebo. Also, hypotensive (SBP <140 mm Hg) patients will be recruited within 12 hours of neuroradiologically-confirmed non-hemorrhagic stroke, and receive intravenous phenylephrine or placebo infusion to achieve target SBP (150 mm Hg (range 145 to 155 mm Hg) or a 15 mm Hg rise from baseline). Pressor treatment will be continued for a 24-hour period only. A population of 400 hypotensive patients will give the study an 80% power at the 5% significance level to detect a relative reduction of 25% in death and dependency between active treatment and placebo groups. The primary outcome measure will be death and dependency at 2 weeks post-stroke, and secondary neurological, disability and health-related quality of life outcomes will be collected at 2 weeks and 3 months.
Principal Investigators: Professor J. F. Potter and Dr T. G. Robinson
Contact: Department of Cardiovascular Science, Ageing and Stroke Research Group, Leicester Warwick Medical School, University Hospitals of Leicester NHS Trust, Groby Road, Leicester LE3 9QP. Telephone +44 (0)116 256 3365, Fax +44 (0)116 232 2976, E-mail chhips@le.ac.uk
Location: United Kingdom
Sponsor: National Health Service Research and Development Health Technology Assessment Programme
Dates of Study: January 2004 (ongoing)
DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral artery)
To compare the efficacy of decompressive surgery in addition to conservative treatment to reduce mortality and to improve functional outcome after malignant hemispheric ischemic cerebral infarction with space-occupying edema with conservative treatment alone. Primary endpoints: Mortality after 30 days, functional outcome (mRS, dichotomized at 
3) after 6 months. Secondary endpoints: Mortality after 30 days and 6 months, functional outcome after 12 months, complications related to surgery, infarct size. Prospective, randomized, open, controlled, multicenter study.
Posttreatment observation phase: 1 year. Patients with space-occupying infarction of the middle cerebral artery aged 18 to 60 years with an onset of symptoms before 12 and less than 36 hours previous to randomization.
Sequential statistical analysis. The study will be interrupted when mortality at 30 days has reached statistically significant difference. After blinded analysis of primary outcome recalculation of sample size. Patients will be randomized to either conversation full scale ICU-treatment or decompressive surgery plus ICU treatment. After randomization treatment is started immediately.
Principal Investigators: Prof Dr Werner Hacke, Prof Dr Peter Schmiedek, Prof Dr Stefan Schwab, University of Heidelberg
Location: Coordinating center Department of Neurology, University of Heidelberg. Phone +49 6221 568210. Fax +49 6221 565348. E-mail neurology@med.uni-heidelberg.de
Number of Centers: German multicenter study. Ten centers are active.
Sponsor: investigator
Dates of Study: Patient recruitment has started in January 2004. More than 20 patients have been randomized and treated. Concerning the total number of patients fulfilling the inclusion criteria for the study in all participating centers the estimated duration of the study will be 3 years
*Efficacy of Nitric Oxide in Stroke (ENOS) trial
Nitric oxide is a multimodal molecule which is a candidate treatment for acute ischemic and hemorrhagic stroke, as based on preclinical and clinical data from 3 phase II trials. Potential mechanisms of action include lowering blood pressure, improving cerebral perfusion, and neuroprotection. ENOS is a large collaborative international academic randomized controlled trial designed to test the safety and efficacy of transdermal glyceryl trinitrate (a nitric oxide donor) in 5000 patients when given within 48 hours of stroke onset. Patients who are taking antihypertensive therapy at the time of their stroke will also be randomized to continue or temporarily stop this. The primary end point is combined death or dependency (modified Rankin Scale 3 to 6) at 3 months, to be assessed centrally by telephone. Subgroup analyses will include efficacy in patients with: ischemic stroke, high blood pressure (systolic BP >160 mm Hg), and treatment <12 hours. Randomization and data registration are performed over the internet. Centers are invited to join the collaborative group.
Principal Investigator: Philip M.W. Bath, MD FRCP
Contact: Philip M.W. Bath, ENOS Trial Centre, Division of Stroke Medicine, University of Nottingham, City Hospital Campus, Nottingham NG5 1PB, UK. Phone 44-115-823-1768. Fax 44-115-823-1771. E-mail enos@nottingham.ac.uk. Internet: http://www.enos.ac.uk/
Location: Global
Number of Centers: 28, looking for 200
Sponsor: BUPA Foundation, The Hypertension Trust, University of Nottingham
Dates of Study: July 2001 (continuing)
Evaluation of the STARflex® Septal Closure System in Patients with a Stroke or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a PFO (CLOSURE)
CLOSURE is a prospective, multicenter, randomized controlled trial to evaluate the safety and efficacy of the STARflex® Septal Closure System versus aspirin and/or warfarin therapy for the prevention of stroke, TIA and mortality in patients with an initial stroke or TIA due to a presumed paradoxical embolism through a patent foramen ovale (PFO). The goal is to determine if device closure of a PFO is superior to best medical therapy for preventing recurrent stroke or TIA in patients with an initial cryptogenic stroke/TIA and a PFO. Sixteen hundred patients (800 in each group) at up to 100 sites nationally will be randomized within 180 days of the entry event. Study patients will be followed for 2 years. All strokes and TIAs will be adjudicated by a blinded Clinical Events Committee using pre-specified clinical and MR imaging definitions. The primary endpoint of incidence of 24-month stroke or TIA, all cause mortality for the first 30 days of follow up or hospital discharge, whichever is longer, and neurological mortality from 31 days of follow-up will be analyzed on an intent-to-treat basis using the chi-square test and logistic regression adjusting for study center and demographic characteristics deemed related to the primary endpoint. Safety analyses will focus on the incidence of severe adverse events related to either device insertion or major bleeding complications on medical therapy.
Principal Investigator: Anthony J. Furlan MD
Co-Principal Investigator: Marc Reisman MD
Executive Committee: A.J. Furlan, M. Reisman, H. Adams, L. Wechsler, Gregory Albers, Robert Felberg C. Thomas, M. Landzberg, H. Hermann, Al Raizner, Saibal Kar
Data Safety Monitoring Board: J. P. Mohr, Chairman
Clinical Events Committee: Marc Fisher, Chairman
Data Management: Harvard Clinical Research Institute
Contact: A.J. Furlan, Cleveland Clinic Department of Neurology, S91, 9500 Euclid Avenue, Cleveland, Ohio 44195. Fax 216 444 0232. Phone 216 444 5535. E-mail furlana@ccf.org.
Sponsor: NMT Medical, 27 Wormwood St., Boston MA 02210-1625
Dates of Study: July 2003 through July 2006
*The Field Administration of Stroke Therapy - Magnesium (FAST-MAG) Phase 3 Trial
Magnesium is neuroprotective in preclinical models of stroke and has been safe and shown signals of potential efficacy when administered early after onset in initial human stroke clinical trials. Delayed initiation of neuroprotective agents has hindered past phase 3 neuroprotective agent trials. The purpose of the FAST-MAG phase 3 trial is to demonstrate that paramedic initiation of intravenous magnesium sulfate within 2 hours of symptom onset improves the longterm functional outcome of hyperacute stroke patients.
FAST-MAG is a multicenter, randomized, double-blind, placebo-controlled phase 3 trial that will enroll 1298 patients (649 in each arm). The study population consists of prehospital patients 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 greater than or equal to 15 minutes. Study agent will be started within 1 hr of onset in 1/2 of enrolled patients and between 1 to 2 hrs after onset in the remainder. Study sites are up to 80 ambulance-receiving hospitals in Los Angeles County, serviced by the LA County EMS Agency. In the study 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. Explicit informed consent is obtained in the field by phone physician contact, either from competent patients or on scene legally authorized representatives, employing an in-vehicle FAST-MAG cellular phone.
The primary endpoint is the distribution of scores across all 7 strata of 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).
Principal Investigator: Jeffrey L. Saver, MD
Co-Principal Investigators: Sidney Starkman, MD; Sam Stratton, MD; Chelsea Kidwell, MD; Marc Eckstein, MD
Contact: Jeffrey L. Saver, MD, Professor of Neurology, UCLA Stroke Center, 710 Westwood Plaza, Los Angeles, CA 90095. Phone 310-794-6379. Fax 310-267-2063. E-mail jsaver@ucla.edu.
Location: Los Angeles County
Number of Centers: Up to 80
Sponsor: National Institute of Neurologic Disorders and Stroke - National Institutes of Health
Dates of Study: 2003–2008
*Global Carotid Artery Stent Registry
This registry is an expanding multicenter, retrospective study to determine the benefits and risks of percutaneous transluminal angioplasty with stent placement of the cervical carotid arteries in patients with cerebrovascular disease. The basic intent of the survey is to evaluate the growth of carotid stent placement and obtain an early review of its results, including stent procedures, technical success, and types of stems placed. In addition, complications such as TIAs, minor and major strokes, and deaths for symptomatic and asymptomatic patients will be studied. Long-term follow-up involving restenosis rates and neurological events will be monitored.
Principal Investigator: Michael H. Wholey, MD, MBA
Contact: Michael H. Wholey, MD, MBA, Department of Radiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284. Phone: 210-567-6433. Fax: 210-567-5541. E-mail wholey@uthscsa.edu
Location: Global
Number of Centers: Currently 30, looking for l00+ . Recruitment criteria is a minimum of 15 carotid stent procedures performed to date. Open to all interventional specialists.
Sponsor: None
Dates of Study: June 1997 (continuing)
International Carotid Stenting Study (ICSS)
ICSS is a randomized, multicenter trial to compare the risks of treatment and benefits in the prevention of stroke of primary carotid stenting in comparison with conventional carotid endarterectomy.
Principal Investigator: Martin M. Brown, MD
Contact: Martin M. Brown, MD, FRCP, Professor of Stroke Medicine, Institute of Neurology, Box 6, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. Phone: 44-20-7829-8753. Fax: 44-20-7833-8613
Location: Europe, North America, Australia and New Zealand
Number of Centers: 33. New centers welcome
Sponsor: The UK Stroke Association.
Dates of Study: Recruitment started in 2001.
Web Address: www.cavatas.com
Magnesium in Aneurysmal Subarachnoid Hemorrhage (MASH-II)
The MASH-II study is a prospective randomized, placebo-controlled, international multicenter trial to determine whether magnesium reduces the frequency of poor outcome (death or dependence) in patients admitted within 4 days after aneurysmal subarachnoid hemorrhage. Magnesium sulfate 64 mmol/d (or placebo) is started intravenously as soon as possible after informed consent and continued until 20 days after the hemorrhage. We plan to include 1200 patients in 5 years.
Steering Committee: W.M. van den Bergh, MD; A. Algra, MD; C. Dirven, MD; K.N. Fountas, MD; J. van Gijn, MD; G.J.E. Rinkel, MD; M. Vermeulen, MD (New members may be added if more (international) centers join the study)
Contact: Sanne M. Dorhout Mees, MD, Department of Neurology G03.224, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Phone +31-30-2508350. Fax +31-30-2522782. E-mail s.m.dorhoutmees@umcutrecht.nl
Number of Centers: 5
Sponsor: The Netherlands Heart Foundation (grant number: 2005B016)
Dates of Study: Randomization will be started in January 2006
Optimizing the Analysis of Stroke Trials (OAST)
Most trials in acute stroke have been neutral (or even negative). One possible explanation is that they may have been analyzed suboptimally. Functional outcome is usually scored using ordinal scales (eg, modified Rankin Scale, Barthel Index) and yet analyses are often based on dichotomization of the data (eg, mRS 0 to 2 vs 3 to 6), a process that would be expected to reduce statistical power. We are comparing a variety of ordinal and nominal statistical approaches using individual patient data from interventions which modify outcome (either positively or negatively) in acute stroke or stroke rehabilitation; neutral trial data from neutral interventions will not be included. The aim is to identify one (or more) optimal approach(es) for use in future stroke trials. Authors of relevant trials who are willing to share their trial data are invited to contact the investigators.
Contact: Philip M.W. Bath, FRCP; Division of Stroke Medicine, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK. Phone: 44-115-823-1023. Fax: 44-115-823-1023. E-mail Philip.bath@nottingham.ac.uk
Location: University of Nottingham, Nottingham, UK
Number of Centers: Those centers that have organized a positive or negative randomized controlled trial in acute stroke or stroke rehabilitation
Sponsor: The Stroke Association (UK)
Dates of Study: October 2004 (continuing)
PAIS: Paracetamol (Acetaminophen) In Stroke
A randomized, placebo-controlled, double-blind clinical trial.
Subfebrile temperature and fever are strong predictors of poor functional outcome in acute stroke. Two pilot studies showed that high-dose paracetamol induces a decrease in body temperature of 0.3°C to 0.4°C in patients with acute ischemic stroke, even if they are normothermic. This effect was noted within 4 hours after the start of treatment. The purpose of PAIS is to assess whether this decrease in body temperature translates into better clinical outcomes.
The study is designed as a multicenter, randomized, double-blind, placebo controlled trial. In total, 2500 patients with an acute ischemic or hemorrhagic stroke will be included. Treatment with high dose paracetamol (6 g/day) or placebo will be started within 12 hours after the onset of symptoms, and continued for 3 days. Exclusion criteria are a body temperature <36°C or >39°C, a history of liver disease, alcohol abuse, liver enzymes increased above twice the upper limit of normal, allergy to paracetamol and significant pre-stroke impairment (a score of 3 or more on the modified Rankin Scale (mRS)). Follow-up at 3 months is done by telephone, by the central study office. The primary outcome measure is dichotomized score on the mRS (0 to 2: good outcome, 3 to 6: poor outcome) at 3 months. Secondary endpoints are the score on the Barthel index after two weeks, the EuroQol at 3 months, and body temperature after 24 hours of treatment.
Steering Committee: M.H. den Hertog (study-coordinator), D.W.J. Dippel (principal investigator), H.B. van der Worp (co-principal investigator), H.M.A. van Gemert, A. Algra, J. van Gijn, L.J. Kappelle, P.J. Koudstaal.
Contact: M.H. den Hertog, Erasmus Medical Center Rotterdam, Dr Molewaterplein 40, Suite 22-40, PO Box 1738, 3000 DR, Rotterdam, The Netherlands, Phone 31-10-4088206, Fax 31-10-4089446, E-mail m.denhertog@erasmusmc.nl, Website: www.pais-study.org
Number of Centers: Currently 20, other centers are invited to participate.
Sponsor: Netherlands Heart Foundation NHF grand 2002 B148
Dates of Study: Randomization and follow-up May 30, 2003 through the end of 2008, 735 patients have been randomized until December, 2005.
Prevention of Poststroke Depression after Acute Ischemic Stroke Using the Selective Serotonine Reuptake-Inhibitor Sertraline (PreDIS-Study)
The development of persistent depressive symptoms is a severe and frequent complication of ischemic stroke (ie, poststroke depression, PSD). The reported prevalences of depressive symptoms in stroke patients varied from 20% to 50% and from 12% to 26% for major depressive symptoms in previous studies. Several follow-up studies revealed a higher overall mortality and a less beneficial functional outcome in stroke patients with major depression. Data from interventional studies treating or preventing PSD are rare. In most trials tri- or tetracyclic antidepressive agents were used, which are often accompanied by therapy limiting adverse events, especially in elderly patients with cardiovascular disease. The PreDIS-Study was designed to limit such adverse events by the use of a selective serotonine reuptake inhibitor for which safety, tolerability, and efficacy has been shown in depressive patients with stroke or myocardial infarction. The primary endpoint of the study is to demonstrate a preventive effect of sertraline on the incidence of PSD. Secondary endpoints are improvement of functional outcome and quality of life. The PreDIS-Study is a double-blind, randomized, placebo-controlled trial that will enroll 300 patients from 10 neurological stroke units in Germany. Interim analysis will be performed after 180 patients will have completed their follow-up. Inclusion criterion is a unilateral ischemic cerebral infarction within 3 days prior to hospital admission. Major exclusion criteria are early and complete recovery of neurological symptoms, mechanical ventilation for more than 2 days, severe aphasia, dementia, preexisting antidepressive medication, or dpressive symptoms at study entry. Patients will be randomized to 50 mg/d sertraline or placebo within the first 6 days after hospital admission. Depressive symptoms will be assessed using the Hospital Anxiety and Depression Scale, the Montgomery-Asberg-Depression-Scale, and the International Diagnosis Checklist for ICD-10 at baseline, 4, 12, and 24 weeks. Functional outcome will be determined by the European Stroke Scale, the modified Rankin Scale, and the Barthel Index. Cognitive performance will be assessed by the Mini-Mental-State Examination and the Digit-Span-Test. Quality of life will be determined at 12 and 24 weeks using the SF36. Treatment and follow-up is scheduled to continue for 6 months with follow-up visits after 4 weeks, 3 and 6 months.
Principal Investigators: Dr W. Huff, PD Dr M. Sitzer, Prof Dr H. Steinmetz
Contact: PD Dr M. Sitzer, Zentrum der Neurologie und Neurochirurgie, J.W. Goethe-Universitat Frankfurt/Main, Schleusenweg 2-16, D-60528 Frankfurt/Main, Germany. Phone:49-6301-5942. Fax 49-6301-4498. E-mail sitzer@em.uni-frankfurt.de
Location: Germany
Number of Centers: 10
Sponsor: Pfizer Inc.
Dates of Study: Randomization and follow-ups August 2001 through January 2005
Safety of Tirofiban in Acute Ischemic Stroke (SaTIS)
The administration of highly selective glycoprotein IIb/IIIa-receptor-antagonists has been shown to improve the treatment of acute coronary and experimental cerebral ischemia. Results of pilot studies in the setting of acute ischemic stroke with tirofiban, a nonpeptide substance with fast acting and deactivating properties, led to the initiation of a multicenter, prospective, randomized and placebo-controlled trial, targeting the frequency of cerebral hemorrhages as primary endpoint. 240 stroke patients with a symptom onset <22 hours and NIHSS Score of 4 to18, admitted outside the 3- to 6-hour time window, will receive either tirofiban or placebo, in addition to the centers’ respective standard therapy. Study drug administration of tirofiban will be performed according to the concentration described in the PRISM-Plus study. A preliminary interim analysis will be due after inclusion of 30 patients per group. Patients’ CCT-scans at the time of admission and 4 to 6 days after symptom onset will be subject to central, blinded evaluation. Secondary endpoint is the neurological outcome within 3 to 5 months after enrollment as judged by clinical disability scales: Barthel Index and modified Rankin Scale. The results of this study could be a rationale for a subsequent phase III-study to examine the efficacy of tirofiban in acute ischemic stroke.
Principal Investigators: M. Siebler MD
Steering Committee: G. F. Hamann MD, M. Hennerici MD, Fiebach MD; U. Junghans MD, G.-M. van Reutern MD, J. Röther MD, R.J. Seitz MB, A. Villringer MD, O.W. Witte MD
Safety Committee: M. Bähr MD, Chr. Hamm, R. von Kummer MD,
Contact: Verica Jovanovic, Clinical Trial Coordinator, Department of Neurology, University of Duesseldorf, Moorenstrasse 5, D-40225 Duesseldorf. Phone 49-211-8119148. Fax 49-211-8116635. E-mail jovanovv@uni-duesseldorf.de
Location: Germany
Number of Centers: 9
Sponsor: Investigator driven, supported by BMBF/Competence network stroke
Dates of Study: August 2002 through August 2005
Siblings With Ischemic Stroke Study (SWISS)
Cohort and twins studies suggest that there is an important genetic component to the overall risk of acquiring ischemic stroke. SWISS is a prospective, multicentered clinical investigation to search for chromosomal regions of interest that harbor stroke susceptibility genes. A microsatellite genome-wide screen will be carried out using DNA collected in this study from sibships consisting of a proband with ischemic stroke and one or more concordant sibling with or without discordant siblings. Three hundred concordant sibling pairs and 200 discordant siblings (800 total study subjects) will be enrolled. A genotype-blinded central committee adjudicates concordance and discordance for ischemic stroke in siblings. Probands are enrolled at participating clinical centers. Probands are potentially eligible for SWISS if they are diagnosed by a study neurologist as having had a CT- or MRI-confirmed ischemic stroke, have at least 1 living sibling with a history of stroke, and are at least 18 years old. Probands are excluded if the index stroke occurred within 48 hours after an invasive cerebrovascular or cardiovascular procedure or within 60 days after a nontraumatic subarachnoid hemorrhage. Also excluded are subjects with brain biopsy-proven CNS vasculitis, mechanical aortic valve, mechanical mitral valve, bacterial endocarditis, CADASIL, Fabry disease, homocystinuria, MELAS, or sickle cell disease. As of July 2005, 195 stroke-affected sibling pairs had been enrolled.
Principal Investigator: James F. Meschia, MD
Contact: Tammy Olson, Clinical Trial Assistant, Mayo ACT, Stabile 5, 150 Third Street SW, Rochester, MN, 55902. Phone: 800-541-5815. Fax: 866-222-8029. E-mail olson.tammy@mayo.edu
Location: Stroke Verification Committee: Department of Neurology, Mayo Clinic, Jacksonville, Fla. Statistical Coordinating Center: Department of Biostatistics, Wake Forest University School of Medicine, Winston-Salem, NC. DNA Banking: Coriell Cell Repository, Camden, NJ. Core Genetics Laboratory: National Institute on Aging (Bethesda, MD). Data Management: Mayo Alliance for Clinical Trials (Mayo ACT), Mayo Clinic, Rochester, MN.
Number of Centers: 50
Sponsor: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Dates of Study: Ongoing.
Stent-protected Percutanous Angioplasty of the Carotid versus Endarterectomy (SPACE)
SPACE is a multicenter, prospective, randomized trial to determine whether carotid endarterectomy (CEA) and percutaneous angioplasty (PTA) are equivalent with respect to ipsilateral stroke, a restenosis degree of 70% ECST criteria or 50% NASCET criteria, respectively, and technical success in patients with transient cerebral ischemia (TIA) or nondisabling stroke because of severe carotid stenosis. This study will include 950 patients per group. Interim analysis is planned after 450 patients per group have been treated or 3 years. Inclusion criterion is symptomatic, high-grade carotid stenosis (70% ECST or 50% NASCET) within 180 days before randomization (TIA or nondisabling stroke). Primary endpoint is ipsilateral stroke or death within 30 days after intervention. Secondary endpoints are: Ipsilateral stroke or death within 24 months after randomization; restenosis 70% of treated carotid artery within 6, 12, and 24 months after randomization; technical complications (ME, vascular occlusion, residual stenosis 70%) within 6 and 30 days after intervention; stroke of any localization within 30 days and 24 months after intervention. Each study center consists of three departments (Neurology, Vascular Surgery, and Interventional Radiology). Certification for each of the three specialities has to be given by a quality standards committee, with documentation of 25 CEA per vascular surgeon, 25 PTA per interventional radiologist, and ultrasound expertise for neurologists. An external data monitoring strategy is in place.
Steering Committee: Neurology: Werner Hacke; Heidelberg, Germany (Chair), Michael Hennerici; Mannheim, Germany; Vascular Surgery: Jens R. Allenberg; Heidelberg, Germany; Henning Eckstein, Munich, Germany; Interventional Radiology: Hermann Zeumer; Hamburg, Germany; Olav Jansen; Kiel, Germany
Contact: Alexandra K. Kunze, MD; Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400; D-69 120 Heidelberg; Phone: +49/622 l/568211; Fax: +49/622 I/565348; E-mail alexandra_kunze@med.uni-heidelberg.de. Website: www.space.stroke-trial.com
Location: Europe
Number of Centers: 37
Sponsors: BMBF (German Ministry of Science), DFG (German Research Council), Guidant, Boston Scientific
Dates of Study: 2000–2005
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
A number of large randomized trials have shown that statin treatment of patients with coronary heart disease (CHD) not only reduces the incidence of myocardial infarction (MI) and death, but also the occurrence of stroke. However, data on the effect of statins in the secondary prevention of stroke in patients with previous stroke or TIA are lacking. The SPARCL trial will evaluate the benefits of aggressive lipid lowering in this patient population by comparing the effects of atorvastatin versus placebo on specified cerebrovascular end-points. The SPARCL study is a double-blind, randomized, placebo-controlled trial that enrolled over 4200 patients from more than 200 centers worldwide. Inclusion criteria are previous stroke or TIA and low-density lipoprotein cholesterol >100 mg/dL (2.6 mmol/L) and <l90 mg/dL (4.9 mmol/L). Patients with evidence of CHD will be excluded. Patients were randomized to 80 mg/day atorvastatin or placebo. The primary efficacy parameter is the time from randomization to the first occurrence of a primary end point, defined as a fatal or nonfatal stroke. Secondary efficacy parameters will include the occurrence of at least one primary end point, the time from randomization to the first occurrence of a secondary end point (cardiac death, nonfatal MI, resuscitated cardiac arrest, unstable angina) and the occurrence of at least one secondary end point. Treatment and follow-up is planned until 540 primary end points have occurred.
Steering Committee: K.M.A. Welch, USA (Chairman); P. Amarenco, France; J. Bogousslavsky, Switzerland; A. Callahan, USA; L. Goldstein, USA; M. Hennerici, Germany; H. Sillesen, Denmark; J. Zivin, USA.
Contact: Henirk Sillesen, MD, DMSc, Department of Vascular Surgery, Gentofte University Hospital, DK-2900 Hellerup (Denmark) Ph: 45 3977 3402 fax: 45 3977 7674 E-mail hens@gentoftehosp.kbhamt.dk
Location: Worldwide
Number of Centers: >200
Sponsor: Pfizer Inc.
Study Dates: Recruitment started November 1998. Enrollment of 4732 patients was completed in March 2001. Patient follow-up is for an average of 5 years. The study is expected to complete in 2005.
Study of Efficacy of Tirofiban in Acute Ischemic Stroke (SETIS)
Study design: double-blind randomized trial of IV tirofiban versus IV ASA. Patients with acute ischaemic stroke presented within 6 hours will be randomized to treatment with tirofiban (0.6 µg/kg/min for 30 minutes followed by 0.15 µg/kg/ min infusion for 72 hours) or acetylsalicilic acid (ASA, 300 mg IV daily bolus for 3 days), following a 1-way, matched pair, randomization list. Matching will be performed according to gender, age 
70 or >70 years, NIHSS score 14 or >14. Treatment will be administered on a double-blind basis, using undistinguishable vials both for bolus infusion and continuous infusion. Serious adverse events will be reported to an unassociated physician of the safety committee. The choice of ASA and not placebo for the nontreatment group, is due to the evidence that early treatment with ASA has some beneficial effect, though limited, in short term mortality.
Study objectives: Assess the efficacy of tirofiban in terms of short term neurological improvement (NIHSS score reduction of at least 4 points), and absence or minimal long term disability (NIHSS score and mRS score at three months decreased to 0 or 1).
Sample size: Sample size was based on an expected percentage of favourable outcomes on primary variables (short term neurological improvement and absence of long term disability) at least 15% greater in patients treated with tirofiban than those treated with ASA, and considering in the latter treatment group a favourable outcome in at least 40% of the patients. Considering the short term primary variable, the total number of patients, increased by estimating a 10% total drop-out rate, is 150 for each treatment group. Sample size computed on long term primary variables, under the same conditions, would require 120 patients for each treatment group, so that a series of 300 patients would be adequate for analysis of the protocol-specified primary variables. Variables will be analyzed on the basis of either the ‘intention-to-treat‘ or the ‘per-protocol‘ criteria. Pre-specified causes of treatment withdrawal are intracranial haemorrhage, severe uncontrolled hypertension, allergic reactions, extracranial haemorrhage, severe thrombocytopenia.
Patients: main inclusion criteria are the following: onset of symptoms within 6 hours, absence of haemorrhage at CT scan, absence of severe anemia, thrombocytopenia, major trauma or recent surgery, prolonged PT.
Principal Investigators: G. Torgano, C. Mandelli, B. Zecca
Contact: Dr Giuseppe Torgano, Dipartimento di Medicina d’Urgenza, Ospedale Policlinico, Via F. Sforza, 20122 Milano, Italy. Phone 0039-02-55033620, Fax 0039-02-55033600, E-mail setis@policlinico.mi.it.
Location: Northern Italy
Number of Centers: 3 centers currently authorized; investigators from other centers are invited to participate.
Sponsor: spontaneous study.
Dates of Study: randomization started by the end of 2003; recruitment up to obtaining computed sample size; interim analysis for sample size correct estimation has been scheduled; expected length of recruitment two years.
Third International Stroke Trial (IST-3)
Background: for every 1000 patients with acute stroke treated with intravenous recombinant tissue-plasminogen activator (IV rt-PA) within 6 hours of stroke onset, 55 avoid death or dependence, yet few patients are being treated worldwide. The third International Stroke Trial (IST-3) aims to provide more reliable evidence on which categories of patients benefit most from IV rt-PA and how it could be more widely used. Study design: IST-3 is an international, multicenter, randomized, controlled, postlicensing trial of IV rt-PA (0.9 mg/kg) for acute ischemic stroke, with a PROBE (Prospective, Randomized, Open, Blinded Endpoint) design. Patient eligibility: eligible patients must be assessed and able to start treatment within 6 hours of onset, and a CT (or MR) scan must have excluded intracranial hemorrhage. Details of inclusion/exclusion criteria are given in the trial protocol. Center eligibility: to join the study, centers must have an established acute stroke service which meets predefined criteria. Trial procedures are very efficient and aim to ensure trial treatment is started with minimal delay. Patient inclusion is by telephone call to a rapid centralized randomization system which balances on key prognostic factors. Trial treatment is only allocated by the system after the baseline data have been successfully recorded and cross-checked. Brain imaging (CT or MR) must be repeated after treatment (at 24 to 48 hrs). An international expert panel reviews ’blinded’ all baseline and follow-up CT/MR images by means of an innovative centralized web-based image-reading system (see ACCESS study for details). In all centers, follow-up is conducted by centralized (blinded) postal or telephone questionnaire, conducted independently of the clinician treating the patient. Trial outcome measures: the primary measure of outcome is death or dependence at six months (poor functional outcome). A number of secondary outcomes are specified in the protocol. Planned subgroup analyses will include an assessment of the effect of: age, stroke severity, time to randomization, CT appearances, blood pressure and other factors on the risks and benefits of treatment. Study progress: the randomized start-up study began cautiously in 2001 and was completed successfully on 31st December 2002. Following a review of the safety and efficacy data by the independent Data Monitoring Committee (Chair Professor Rory Collins), recruitment continued without interruption into the expansion phase (2003–2005), and again, after review, into the main Medical Research Council funded phase which began in May 2005 and will continue until 2008, with trial reporting in 2009. The trial will involve 6000 patients recruited from 250 to 400 centers in up to 40 countries world-wide. A total of 438 patients had been recruited by 25th November 2005 and the recruitment rate is accelerating.
Trial Co-principal Investigators: Richard Lindley and Peter Sandercock.
Imaging Principal Investigator: Joanna Wardlaw
Contact: Professor Peter Sandercock, Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. Fax ++ 44 (0)131 332 5150 E-mail IST3@skull.dcn.ed.ac.uk
Location: UK, Italy, Norway, Belgium, Sweden, Australia, New Zealand, Canada, Poland, Austria with additional countries due to join.
Number of Centers: currently 55, but up to 400 may join the main phase
Sponsor: The study is an investigator led trial. The University of Edinburgh and the Lothian Health Board are co-sponsors. The start-up phase was supported by a grant from the Stroke Association, UK. The expansion phase was funded by The Health Foundation UK. The main phase of the trial is supported by: UK MRC, Norwegian Research Council, AFA Insurances (Sweden); the Swedish Heart Lung Fund, the Government of Poland, the Australian Heart Foundation, the Dalhousie University Internal Medicine Research Fund. Drug and placebo for the 300 patients in the double-blind component of the start-up phase were supplied by Boehringer-Ingelheim. The study is being designed, conducted, analyzed and reported independently of all of the sponsors and funding agencies.
ISRCTN: ISRCTN25765518
Dates of Study: 2001–2009.
The United Kingdom Glucose Insulin in Stroke Trial (GIST - UK)
There is an increasing evidence from both animal and clinical studies that diabetes and/or hyperglycaemia following stroke is associated with an adverse prognosis although this association has never been confirmed in any clinical trial. In addition, although treatment of hyperglycaemia with insulin is increasingly undertaken as part of acute stroke care, the risks/benefits have never been formally explored in a randomized controlled trial. The safety and practicability of Glucose/Potassium/Insulin GKI infusions to maintain euglycemia following stroke has previously been demonstrated in the GIST study. GIST UK seeks to determine by means of a multicenter randomized trial whether outcome from acute stroke can be favorably influenced by GKI induced and maintained euglycemia. Patients presenting with CT proven acute stroke within 24 hours of onset and admission plasma glucose >6.0 mmol/l and <17 mmol/l are eligible. The primary end points are: all cause mortality and the proportion of patients with a poor outcome (modified Rankin Score 4 to 6) at 90 days.
Principal Investigator: Professor C.S. Gray, Newcastle University, Department of Geriatrics, Sunderland Royal Hospital, Kayll Road, Sunderland, UK SR4 7T9. Phone: 44-191-565-6256 ext 41245. Fax: 44-191-569-9767.
Location: United Kingdom
Number of Centers: Currently 20 UK centers, recruitment ceases March 2006.
Sponsors: NHS R&D (Northern & Yorkshire), PPP Foundation
Dates of Study: Close down - August 2006
VITAmins TO Prevent Stroke (VITATOPS)
The VITATOPS study is a multicenter, randomized, double blind, placebo-controlled secondary stroke prevention trial to determine whether the addition of vitamin supplements (B12 500 µg, B6 25 mg, Folate 2 mg) to best medical/surgical management (including modification of risk factors) will reduce the combined incidence of recurrent vascular events (stroke, myocardial infarction) and vascular death in patients with recent stroke or transient ischemic attack (TIA). All patients presenting to one of the participating neurologists or general physicians within seven months of stroke (ischemic or hemorrhagic) or TIA (eye or brain) are eligible for this trial. Eligible patients will be randomized in a double-blind fashion to receive multivitamins or placebo, 1 tablet daily. The primary outcome event is the composite event "stroke, myocardial infarction, or death from any vascular cause", whichever occurs first. Our target is to recruit a total of 8000 patients over the next 2 years with a median follow-up of 2.5 years. Recruitment to the trial began in November 1998 and is planned to continue until mid 2007. We aim to complete final follow-up by mid 2008. However, the Steering Committee will be flexible in dictating the need for ongoing recruitment and continuing follow-up, depending on the overall rate of the primary outcome event in the entire cohort at each interim analysis.
Steering Committee (alphabetically): Dr Ross Baker, Dr John Eikelboom, Ms Anna Gelavis, Clin Prof Graeme Hankey (chairman), Mrs Siobhan Hickling, Prof Konrad Jamrozik, A/Prof Francesco van Bockxmeer
Contact: VITATOPS Trial Office, Stroke Unit, Royal Perth Hospital, Wellington St Perth 6001, Australia. Phone: +61 8 9224 7004. Fax +61 8 9224 8424. E-mail VITATOPS@health.wa.gov.au Website: http://vitatops.highway1.com.au
Centers: Australia (15), Austria (1), Belgium (1), Brazil (1), Hong Kong (2), India (14), Italy (7), Malaysia (2), Moldova (1), Netherlands (3), New Zealand (5), Pakistan (1), Philippines (8), Portugal (4), Republic of Georgia (1), Serbia & Monte Negro (2), Singapore (1), Sri Lanka (1), United Kingdom (16) and United States (5) and actively seeking centers worldwide.
Dates of study: 1998–2008.
Footnotes
*Indicates centers that are currently recruiting 
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