BASICS Trial Basilar Artery International Cooperation Study Research Protocol
BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 BASICS Trial Basilar Artery International Cooperation Study Research Protocol BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 BASICS Trial protocol Protocol ID NL33550.100.10 / 2010B151 NHS Short title BASICS Trial Version 2.0 Date 14-01-2012 Coordinating investigator/project E.J.R.J. der Hoeven, MD leader St. Antonius Hospital, Nieuwegein Koekoekslaan 1 3435 CM Nieuwegein The Netherlands +31 (0) 88 - 320 30 00 [email protected] Principal investigator(s) (in Dutch: hoofdonderzoeker/uitvoerder) W.J. Schonewille, MD, Neurology PI St. Antonius Hospital, Nieuwegein Koekoekslaan 1 3435CM Nieuwegein The Netherlands +31 (0) 88 - 320 30 00 [email protected] J.A. Vos, MD, PhD, Radiology PI St. Antonius Hospital, Nieuwegein Koekoekslaan 1 3435CM Nieuwegein The Netherlands +31 (0) 88 - 320 30 00 [email protected] BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 Multicenter research: per site St. Antonius Hospital W.J. Schonewille. MD Department of Neurology St. Antonius Hospital, Nieuwegein Koekoekslaan 1 3435CM Nieuwegein The Netherlands [email protected] University Medical Centre Utrecht Prof. L.J. Kappelle, MD, PhD Department of Neurology University Medical Centre Utrecht Heidelberglaan 100 3584CX Utrecht The Netherlands [email protected] Centre Hospitalier Universitaire Vaudois, Lausanne University P. Michel, PD, MER, Médicin adjoint Department of Neurlogy University Medical Centre Vaudois Rue du Bugnon 21 CH-1011 Lausanne Suisse [email protected] Sponsor (in Dutch: verrichter/opdrachtgever) BASICS Study Group BASICS Trial Protocol ID/NL33550.100.10 Independent physician(s) P.J.A.M. Brouwers, MD, PhD Medisch Spectrum Twente Department of Neurology Postbus 50.000 7500KA Enschede The Netherlands +31 (0) 53 - 487 28 50 version 2.0 14-01-2012 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 PROTOCOL SIGNATURE SHEET Name For non-commercial research, Head of Department: H. Koers Coordinating Investigator: E.J.R.J. van der Hoeven, MD St. Antonius Hospital, Nieuwegein University Medical Centre Utrecht Principal Investigator: W. J. Schonewille, MD St. Antonius Hospital, Nieuwegein University Medical Centre Utrecht Signature Date BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 TABLE OF CONTENTS 1. 1. INTRODUCTION AND RATIONALE ..........................................................................10 1.1 Introduction ................................................................................................................10 1.2 Rationale....................................................................................................................11 2. OBJECTIVES ..................................................................................................................13 3. STUDY DESIGN..............................................................................................................14 4. STUDY POPULATION ....................................................................................................15 4.1 Population (base) ......................................................................................................15 4.2 Inclusion criteria .........................................................................................................15 4.3 Exclusion criteria........................................................................................................16 4.4 Sample size calculation .............................................................................................16 5. TREATMENT OF SUBJECTS.........................................................................................16 5.1 Investigational product/treatment...............................................................................17 6. INVESTIGATIONAL MEDICINAL PRODUCT .................................................................17 6.1 Name and description of investigational medicinal product(s)...................................18 6.2 Summary of findings from non-clinical studies...........................................................18 6.3 Summary of findings from clinical studies..................................................................18 6.4 Summary of known and potential risks and benefits..................................................18 6.5 Description and justification of route of administration and dosage...........................18 6.6 Dosages, dosage modifications and method of administration .................................18 6.7 Preparation and labelling of Investigational Medicinal Product .................................18 6.8 Drug accountability ....................................................................................................19 7. METHODS.......................................................................................................................19 7.1 Study parameters/endpoints ......................................................................................19 7.1.1 Main study parameter/endpoint...........................................................................19 7.1.2 Secondary study parameters/endpoints..............................................................19 7.1.3 Other study parameters.......................................................................................19 7.2 Randomisation, blinding and treatment allocation .....................................................19 7.3 Study procedures.......................................................................................................20 7.4 Withdrawal of individual subjects ...............................................................................22 7.5 Replacement of individual subjects after withdrawal. ................................................22 7.6 Follow-up of subjects withdrawn from treatment........................................................22 7.7 Premature termination of the study............................................................................22 8. SAFETY REPORTING ....................................................................................................22 8.1 Section 10 WMO event ..............................................................................................22 8.2 Adverse and serious adverse events.........................................................................23 8.2.1 Suspected unexpected serious adverse reactions (SUSAR) ..............................23 8.2.2 Annual safety report ............................................................................................24 8.3 Follow-up of adverse events ......................................................................................25 8.4 Data Safety Monitoring Board (DSMB) ......................................................................25 9. STATISTICAL ANALYSIS ...............................................................................................25 9.1 Descriptive statistics ..................................................................................................25 9.2 Univariate analysis.....................................................................................................25 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 9.3 Multivariate analysis...................................................................................................25 9.4 Interim analysis ..........................................................................................................26 10. ETHICAL CONSIDERATIONS ......................................................................................27 10.1 Regulation statement ...............................................................................................27 10.2 Recruitment and consent .........................................................................................27 10.3 Benefits and risks assessment ................................................................................27 10.4 Compensation for injury ...........................................................................................28 11. ADMINISTRATIVE ASPECTS AND PUBLICATION .....................................................28 11.1 Handling and storage of data and documents .........................................................28 11.2 Amendments............................................................................................................29 11.3 Annual progress report ............................................................................................29 11.4 End of study report...................................................................................................29 11.5 Public disclosure and publication policy...................................................................29 12. REFERENCES ..............................................................................................................30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ABR ABR form, General Assessment and Registration form, is the application form that is required for submission to the accredited Ethics Committee (In Dutch, ABR = Algemene Beoordeling en Registratie) AE Adverse Event AR Adverse Reaction CA Competent Authority CCMO Central Committee on Research Involving Human Subjects; in Dutch: Centrale Commissie Mensgebonden Onderzoek CV Curriculum Vitae DSMB Data Safety Monitoring Board EU European Union EudraCT European drug regulatory affairs Clinical Trials GCP Good Clinical Practice IB Investigator’s Brochure IC Informed Consent IMP Investigational Medicinal Product IMPD Investigational Medicinal Product Dossier METC Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing commissie (METC) (S)AE (Serious) Adverse Event SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst) Sponsor The sponsor is the party that commissions the organisation or performance of the research, for example a pharmaceutical company, academic hospital, scientific organisation or investigator. A party that provides funding for a study but does not commission it is not regarded as the sponsor, but referred to as a subsidising party. SUSAR Suspected Unexpected Serious Adverse Reaction Wbp Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medischwetenschappelijk Onderzoek met Mensen 8 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 SUMMARY Rationale: Recently our study group reported the results of the Basilar Artery International Cooperation Study (BASICS), a prospective registry of patients with an acute symptomatic basilar artery occlusion. Our observations in the BASICS registry underscore that we continue to lack a proven treatment modality for patients with an acute BAO and that current clinical practice varies widely. Furthermore, the often-held assumption that intra-arterial therapy (IAT) is superior to intravenous thrombolysis (IVT) in patients with an acute symptomatic BAO is challenged by our data. The BASICS registry was observational and has all the limitations of a non-randomised study. Interpretation of results is hampered by the lack of a standard treatment protocol for all patients who entered the study. Objective: Evaluate the efficacy and safety of additional IA therapy after IV thrombolysis in patients with basilar artery occlusion. Study design: Randomised, multi-centre, open label, controlled phase III, treatment trial. Study population: Patients, aged 18 through 85 years, with CTA or MRA confirmed basilar occlusion treated with IVT. Intervention: Patients will be randomised between additional IAT followed by maximum supportive care versus maximum supportive care alone. IVT has to be initiated within 4.5 hours from estimated time of basilar artery occlusion and IAT within 6 hours. Main study parameters/endpoints: Favourable outcome at day 90 defined as a modified Rankin Score (mRS – functional scale) of 0-3. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Although, to date, no data from a randomised controlled trial support the use of IAT for BAO, IAT was by far the most commonly used treatment type in the BASICS registry. The use of additional IAT after standard IVT is supported by the results of trials performed with patients with occlusions in other vascular territories. Patients randomised into the additional IAT group will undergo intra-arterial catheterization and IAT will be initiated if indicated. Effective amount of radiation during this 1-2 hour procedure will be about 20 mSv. Main risks for catheterization and IAT comprise local and intracranial haemorrhage. In the BASICS registry we reported a risk for symptomatic intracranial haemorrhage of 14% in patients treated with IAT versus 6% in patients treated with IVT. Follow-up telephone surveys at 1 and 12 months and blinded exam at 3 months will take up to 50 minutes in total. 9 of 30 BASICS Trial Protocol ID/NL33550.100.10 1 version 2.0 14-01-2012 INTRODUCTION AND RATIONALE 1.1 Introduction Recently our study group reported the results of the Basilar Artery International Cooperation Study (BASICS), a prospective registry of patients with an acute symptomatic basilar artery occlusion (BAO). The purpose of the registry was to obtain a better understanding of outcomes following acute BAO and to study potential differences in treatment response in anticipation of a definitive randomised controlled acute treatment trial in these patients. We were not able to identify a statistically significant superior treatment strategy. However, by including more than 600 patients in the registry over a 5 years period, we did show that the performance of a randomised trial in patients with basilar artery occlusion is feasible. Our observations in the BASICS registry underscore that we continue to lack a proven treatment modality for patients with an acute BAO and that current clinical practice varies widely. Furthermore, the often-held assumption that IAT is superior to IVT in patients with an acute symptomatic BAO is challenged by our data. Although recanalization rates after IAT are consistently higher after IAT as compared to IVT in observational studies, this was not accompanied by improved outcome. The BASICS registry was observational and has all the limitations of a non-randomised study. Reasons for clinicians to select a specific treatment option are more complex than can be captured in the scope of a prospective registry. Multivariable analyses can never adjust completely for systematic differences between treatment groups – the aim of randomisation in clinical trials. A bias towards a more aggressive treatment approach in patients who were thought to have a worse prognosis may have influenced the outcome in the IAT group and relinquishing both IVT and IAT in patients with a severe deficit may have been an expression of a more palliative approach. Crossover to another treatment group because of clinical worsening or lack of treatment response was not taken into account. There may be variables relevant to outcome that are imbalanced between groups, but that we did not measure. However, the registry collected standard neurological and functional scores and risk factor data across all sites. In the analyses we have adjusted for baseline imbalances between the treatment groups as much as possible. 10 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 As the IA treatment approach becomes increasingly available and utilized throughout the world, we believe that a large randomised controlled phase III trial investigating the added value of this therapy in patients with an acute symptomatic BAO is a high priority. 1.2 Rationale Study population: basilar artery occlusion There are several factors that distinguish patients with BAO from those with middle cerebral artery (MCA) occlusion and which may warrant a different treatment approach: • Severity of deficit: previous studies have suggested a greater benefit of IA therapy in patients with a severe deficit. • High poor outcome rate: because of a higher poor outcome rate, patients with basilar artery occlusion have more to gain. • Collateral flow: the basilar artery not only receives collateral flow through cortical cerebellar branches, comparable to the cortical hemispheric branches of the MCA, but also by retrograde filling by the anterior circulation through the posterior communicating arteries as part of the circle of Willis. IVT may be more effective in the presence of good collateral flow, by attacking the thrombus from both sides. • Time window for treatment: the BASICS registry data suggests the presence of a longer time window from symptom onset to time of treatment. The PROACT studies used a limit of time from symptom onset to time of treatment of 6 hours. The current IMS III study uses a 5 hours time window from symptom onset to initiation of IAT. The BASICS trial uses a 6 hours time window from estimated time of basilar artery occlusion to initiation of IA treatment. The BASICS registry used the estimated time of symptom onset consistent with the clinical diagnosis of BAO to treatment rather than the more commonly used time of onset of any symptoms to treatment in our analyses. Previous studies have shown that BAO is preceded by prodromal symptoms in over 60% of patients. Most of these patients would be excluded from a potential trial using the time of onset of any symptom to treatment as an inclusion criterion. We believe that our results support the use of the estimated time of BAO rather than using the time of onset of any symptom to treatment as an inclusion criterion for the BASICS trial. IVT versus IVT&IAT comparison 11 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 IV thrombolysis is the current standard of care in patients presenting with acute ischemic stroke with a proven safety and efficacy and therefore should be regarded as the current “Golden Standard” with which potential new treatment strategies should be compared. The use of an IVT only arm in a trial of patients with acute symptomatic basilar artery occlusion is supported by the results of the BASICS registry in which no significant difference was found between IVT or IAT treated patients with a severe deficit. The performance of a trial comparing IVT alone vs. IAT alone in patients with BAO does not seem feasible. Referral of a patient to an intervention center in order to being randomised between IVT vs. IAT alone would mean delaying the initiation of a treatment, which is of proven benefit – while there is convincing evidence for the principle of “time is brain”. The number of patients with BAO presenting directly to an intervention centre will be too limited. Patients with basilar artery occlusion only represent an approximate 5% of all IVT eligible patients, while only 40% of patients in the BASICS registry where admitted directly (without referral) to an intervention center. In order to include a sufficient number of patients the BASICS trial will therefore mainly depend on the inclusion of patients referred from non-intervention community hospitals. The non-intervention hospitals are encouraged to start IVT without delay before sending the patient with the clinical diagnosis of BAO to the intervention center, where the patient will be randomised if eligible. A combined IV and IA approach to acute ischemic stroke therapy was designed to offer rapid initiation of IV rt-PA, followed by additional titrated local IA therapy, to patients with moderate-to-severe strokes (NIHSS≥10). The goal was to achieve higher rates of early, successful reperfusion in a widely accessible manner. This approach has been tested in clinical trials of over 200 patients, starting with the Emergency Management of Stroke (EMS) pilot trial from 1994 to 1995, followed by the Interventional Management of Stroke (IMS) I trial in 2001, the IMS II trial from 2003 to 2006, and several additional cohorts. The data from EMS and IMS show that the combined approach to recanalization may be more effective than standard IV rt-PA alone for moderate-to-severe (NIHSS ≥10) strokes, while maintaining a similar safety profile. IVT arm • 4.5 hours time window: based on the results of the ECASS III study a time window of 0 to 4.5 hours from symptom onset to treatment in patients with acute ischemic stroke is widely accepted. The BASICS registry results show the safety of using a 0 to 4.5 hours time window from estimated time of occlusion to treatment in patients with acute BAO. 12 of 30 BASICS Trial Protocol ID/NL33550.100.10 • version 2.0 14-01-2012 Full dose IVT: in a case series of 69 patients treated with IA thrombolysis (urokinase or alteplase) following full dose IVT symptomatic haemorrhage occurred in 4 out of 69 (5.8%) patients. The MERCI trials have shown the safety of mechanical thrombectomy after full dose IVT. IAT arm • Time to treatment: based on the results of the PROACT studies the 6 hours time window for IA thrombolysis in patients with MCA occlusion is widely accepted. The MERCI studies have shown the safety of mechanical thrombectomy up to 8 hours from symptom onset. The BASICS study shows that a time window of 0 to 6 hours from estimated time of occlusion to IA treatment is safe in patients with a severe deficit while little can be gained in both IVT and IAT treated patients beyond the 6 hours time window. • Full option IA therapy arm: the main theoretical advantage of an IA approach is the variety of treatment options, which can be tailored to the individual patient. Because of the great variety in IA treatment options and the limited number of patients, the experience with specific devices or thrombolytics varies considerably among stroke centers both within and between countries. Limiting the use of treatment options would exclude centers from participation because of lack of experience with the selected device or thrombolytic despite ample experience in the use of alternative devices or thrombolytics. New devices or thrombolytics that become available during the duration of the study may be used in the IAT arm depending on local approval and experience. Prior approval by the steering committee needs to be obtained. 2. OBJECTIVES Primary Objective: • To evaluate the efficacy of additional IA therapy after IVT in terms of favourable outcome at 90 days, defined as a modified Rankin score of 0-3, in patients with an acute ischemic stroke caused by basilar artery occlusion. • Secondary analysis will compare outcome in the following pre-defined subgroups: patients with a baseline NIHSS of 10 -19, and those with a baseline NIHSS of ≥ 20. - Patients treated with IVT within 4.5 hours of symptom onset, and those treated beyond 4.5 hours of symptom onset within 4.5 hours of estimated time of basilar artery occlusion. Secondary Objectives: 13 of 30 BASICS Trial Protocol ID/NL33550.100.10 • version 2.0 14-01-2012 To evaluate the safety of a combined IV/IA approach compared to IV rt-PA alone. The primary measures of safety will be symptomatic intracranial haemorrhage or intracranial haemorrhage contributing to patients’ death as determined by the study safety committee confirmed on neuroimaging within 3 days of treatment initiation (CT or MRI), or overall mortality at 90 days. • To evaluate the efficacy of a combined IV/IA approach compared to IV rt-PA alone in terms of a favourable outcome at day 90 on other clinical and radiological measures: 1) Excellent outcome defined as a mRS of 0-2, 2) mRS - not dichotomized and 3) EQ-5D. 4) An improved early response to treatment as determined by a reduction in NIHSS by 5 points or more at 24 hours. 5) A CT or MR angiography assessment of basilar artery patency at 24 hours. 6) The volume of cerebral infarction as measured by a NCCT + CTA-SI at 24 hours. • To evaluate the safety and efficacy of mechanical devices as part of a combined IV/IA approach as the BASICS trial progresses. 3. STUDY DESIGN • Multinational, multi-centre, randomised, open-label, controlled. • Study duration per subject will be 12 months from the time of randomisation • Two-arm study (1:1 randomisation) comparing a combined IV/IA approach versus IV rt-PA alone. • The trial is designed to test the hypothesis that there is an overall absolute difference of 10% in favorable outcome (moderate or no disability as measured by a modified Rankin Score of 0-3) for subjects treated with the combined IV/IA approach as compared to those treated with standard IV rt-PA. • All subjects are treated with IV rt-PA as soon as possible. Consideration for trial participation or actual randomisation in the trial may not cause any delay in the initiation of IV rt-PA. • A diagnostic neuroimaging screening with CT/CTA or MRI/MRA confirming the presence of basilar artery occlusion and the absence of imaging exclusion criteria, and an NIHSS of 10 or more at time of randomisation will be used to identify patients eligible for the trial. • After eligibility is confirmed and informed consent obtained from the subject or his proxy, the subject will be randomised to additional IAT as soon as possible. • IV rt-PA has to be initiated within 4.5 hours of estimated time of occlusion. If randomised to the combined IV/IA approach, IA therapy should be initiated within 6 hours of estimated time of basilar artery occlusion. 14 of 30 BASICS Trial Protocol ID/NL33550.100.10 • version 2.0 14-01-2012 Bolus injection in case of IV rt-PA and needle-to-groin time for IAT are considered as initiation of therapy. • Treatment options allowed in the IA arm include; Urokinase (max. dose 1.500.000 Units), rt-PA (max. dose 22mg), MERCI, Penumbra, EKOS, Solitaire, angioplasty and stenting, or any other thrombolytic or device depending on local approval, after approval by the steering committee. • Follow-up of patients will subsequently be performed at 24 hours ± 6 hours, 7 days or discharge, 1 month (telephone survey), 3 months (blinded examiner) and at 12 months (telephone survey). • All patients will have a follow-up CT/CTA or MRI/MRA within 24 hours, ± 6 hours, of initiation of treatment to monitor vessel patency, presence of intracranial haemorrhage and extend of ischemic changes. • The study will have a steering committee, an independent data and safety monitoring committee. 4. STUDY POPULATION 4.1 Population (base) Patients with basilar artery occlusion represent an approximate 5% of all IVT eligible patients. By including more than 600 patients in the BASICS registry over a 5 years period, we showed that the performance of a randomised trial comprehending 750 patients with a basilar artery occlusion is feasible. Patients aged 18 through 85 years, treated with IVT and a documented basilar artery occlusion will be included in the trial. 4.2 • Inclusion criteria Symptoms and signs compatible with ischemia in the basilar artery territory and an NIHSS ≥ 10 at time of randomization. • Basilar artery occlusion confirmed by CTA or MRA. • Age18 through 85 years (i.e., candidates must have had their 18th birthday, but not had their 86th birthday). • Initiation of IV rt-PA within 4.5 hours of estimated time of basilar artery occlusion. (Estimated time of basilar artery occlusion is defined as time of onset of acute symptoms leading to clinical diagnosis of basilar artery occlusion or if not known last time patient was seen normal prior to onset of these symptoms). • Initiation of IA therapy should be feasible within 6 hours of estimated time of basilar artery occlusion. 15 of 30 BASICS Trial Protocol ID/NL33550.100.10 4.3 version 2.0 14-01-2012 Exclusion criteria • Pre-existing dependency with mRankin ≥3. • Females of childbearing potential who are known to be pregnant and/or lactating or who have positive pregnancy tests on admission. • Patients who require hemodialysis or peritoneal dialysis. • Other serious, advanced, or terminal illness. • Any other condition that the investigator feels would pose a significant hazard to the patient if IA therapy is initiated. • Current participation in another research drug treatment protocol (patient cannot start another experimental agent until after 90 days). • Informed consent is not or cannot be obtained. Imaging Exclusion Criteria • Lesion consistent with hemorrhage of any degree. • Significant cerebellar mass effect or acute hydrocephalus. • Bilateral extended brainstem ischemia. 4.4 Sample size calculation Assuming an absolute risk increase of 10% of favourable outcome at 90 days by additional IA therapy by comparison with maximum supportive care alone, we calculated that 712 patients would be needed. This calculation was based on a type 1 error of 5%, a type 2 error of 20%, and a presumed incidence of the primary outcome event of 30% in the maximum supportive care group. This latter incidence was based on data of the BASICS registry study. [ref 2 section K4] Based on these assumptions the trial would yield a risk ratio of 1.33 with a 95% confidence interval of 1.09 to 1.63, i.e. a relative risk increase of 33% more patients with a favorable outcome with additional IA therapy. The sample size formula used originated from the standard work on clinical trials “Clinical Trials: A Practical Approach” by S.J. Pocock (p 125). To account for potential dropout a target of 750 patients is set. 5. TREATMENT OF SUBJECTS One of the guiding principles of the BASICS trial is rapid initiation of thrombolytic therapy to an eligible subject to provide maximal benefit. To minimize any delay in the administration of a proven effective therapy (i.e., IV rt-PA), the standard dose of openlabel IV rt-PA (0.9 mg/kg; 90 mg maximum) is initiated prior to enrollment and randomization in the trial if standard eligibility criteria are met. 16 of 30 BASICS Trial Protocol ID/NL33550.100.10 5.1 version 2.0 14-01-2012 Investigational product/treatment IV rt-PA All patients are treated with a standard full dose of open-label IV rt-PA (0.9mg/kg; 90mg maximum) if standard eligibility criteria are met. Patients treated with IVT within 4.5 hours of symptom onset, and those who are treated beyond 4.5 hours of symptom onset but within 4.5 hours of estimated time of basilar artery occlusion will be regarded as two prespecified subgroups for secondary analysis. In patients treated beyond 4.5 hours of symptom onset, informed consent needs to be obtained prior to initiation of IVT. IA therapy IA therapy has to be initiated within 6 hours of estimated time of basilar artery occlusion. If an appropriate thrombus or residual stenosis is identified, the choice of IA strategy will be made by the treating neurointerventionalist. IA treatment options available will be any of the following devices or thrombolytics, depending on local approval and experience; the Concentric Merci® thrombus-removal device, Penumbra, Solitaire, infusion of rt-PA combined with an application of low-intensity ultrasound at the site of the occlusion via the EKOS® Micro-Infusion Catheter, infusion of alteplase or urokinase via a standard micro-catheter. If IA thrombolysis is the chosen strategy, a maximum of 22 mg of IA rt-PA or 1.500.000 Units of Urokinase may be given. Stenting is allowed in the presence of a high-grade vertebral artery stenosis or occlusion hampering adequate endovascular access to the basilar artery and in case of a residual high-grade basilar artery stenosis. The use of any other treatment strategy depends on local approval and experience, and is only allowed after prior approval of the steering committee. The IA approach is aimed at recanalization of the basilar artery. In order to ensure optimal perfusion one posterior cerebral artery should be patent. In the presence of residual occlusions of branches of the basilar artery after complete recanalization of the basilar artery the use of additional thrombolytic therapy should be kept to a minimum due to the limited potential gain. Clinical improvement could be a reason not to initiate IA therapy despite the presence of persistent basilar artery occlusion on conventional angiography. The initiation of IA therapy after identification of an appropriate thrombus in the basilar artery or high grade residual stenosis considered to have been the cause of occlusion on conventional angiography will be left to the judgment of the treating physician. 6. INVESTIGATIONAL MEDICINAL PRODUCT IV thrombolysis is the current standard of care in patients presenting with acute ischemic stroke with a proven safety and efficacy and therefore should be regarded as the current 17 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 for the principle of “time is brain”. All patients are treated with a standard full dose of openlabel IV rt-PA (0.9mg/kg; 90mg maximum) if standard eligibility criteria are met. 6.1 • Name and description of investigational medicinal product(s) Registration name: Medacinase, active substance: Urokinase, RVG 11731, powder for solution for injection and infusion. • Registration name: Actilyse, active substance: Alteplase, RVG 15228, powder for solution for injection and infusion. 6.2 Summary of findings from non-clinical studies • Ad I. SPC section 5 page 6. • Ad II. SPC section 5 page 11-13. 6.3 Summary of findings from clinical studies • Ad I. SPC section 5 page 6, chapter 12 ref. 2, 3, 7, 11, 12, 13, 14, 15, 17, 19 • Ad II. SPC section 5 page 11-13, chapter 12 ref. 2, 3, 7, 11, 12, 13, 14, 15, 17, 19 6.4 Summary of known and potential risks and benefits • Ad I. SPC section 4 page 1-6, chapter 12 ref. 2, 3, 7, 11, 12, 13, 14, 15, 17, 19 • Ad II. SPC section 4 page 3-11, chapter 12 ref. 2, 3, 7, 11, 12, 13, 14, 15, 17, 19 6.5 Description and justification of route of administration and dosage A combined IV and IA approach to acute ischemic stroke therapy was designed to offer rapid initiation of IV rt-PA, followed by additional titrated local IA therapy, to patients with moderate-to-severe strokes (NIHSS≥10). The goal was to achieve higher rates of early, successful reperfusion in a widely accessible manner. This approach has been tested in clinical trials of over 200 patients, starting with the Emergency Management of Stroke (EMS) pilot trial from 1994 to 1995, followed by the Interventional Management of Stroke (IMS) I trial in 2001, the IMS II trial from 2003 to 2006, and several additional cohorts. The data from EMS and IMS show that the combined approach to recanalization may be more effective than standard IV rt-PA alone for moderate-to-severe (NIHSS ≥10) strokes, while maintaining a similar safety profile. The MERCI trials have shown the safety of mechanical thrombectomy after full dose IVT. 6.6 Dosages, dosage modifications and method of administration • Ad I. Maximum of 1.500.000 Units intra-arterial. • Ad II. Maximum of 22 mg intra-arterial. 6.7 Preparation and labelling of Investigational Medicinal Product Medacinase and Actilyse are commercially available products. 18 of 30 BASICS Trial Protocol ID/NL33550.100.10 6.8 version 2.0 14-01-2012 Drug accountability Medacinase and Actilyse are commercially available products. 7. METHODS 7.1 Study parameters/endpoints 7.1.1 Main study parameter/endpoint Favourable outcome at day 90 defined as a modified Rankin Score (mRS – functional scale) of 0-3. 7.1.2 Secondary study parameters/endpoints Excellent outcome at day 90 defined as a modified Rankin Score (mRS – functional scale) of 0-2. Modified Rankin Score – not dichotomized. National Institutes of Health Stroke Scale (NIHSS – acute assessment scale) at time of IVT, at time randomization, at 48 hours post treatment. EQ-5D (quality of life) at day 90 and at 12 months 7.1.3 Other study parameters Radiologic outcomes Recanalization at 24 hours, ± 6 hours, by CT angiography. Volume of cerebral infarction on NCCT and CTA source images. Safety outcomes Symptomatic intracranial hemorrhage at 24 hours CT imaging, ± 6 hours. Mortality at 90 days. Quality of life outcomes EuroQol EQ-5D 7.2 Randomisation, blinding and treatment allocation Study enrollment Only subjects treated with IVT within 4.5 hours of estimated time of basilar artery occlusion can be considered for enrollment in the study. Randomization follows the confirmation of basilar artery occlusion as soon as possible. Patients are randomised by a secure link to a central randomization database. 19 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 The randomization and study enrollment process may not interfere in any way with the timely initiation of standard IVT. Subjects treated with standard IVT who did not fulfill all inclusion/exclusion criteria at the time of IVT may not be considered for randomization. Based on the experience in the BASICS registry an estimated 40 to 50% of patients will present in community hospitals with subsequent referral to an intervention center. Community hospitals should be encouraged to initiate IVT prior to transfer according to the “drip and ship” principle. Intubation prior to transfer should be strongly encouraged in any subject deemed unstable or at high risk of aspiration. If sedation is needed, short acting drugs, like propofol (di-isopropylfenol) should be given to avoid interference with the neurological examination upon arrival at the intervention center. In case of an increase in NIHSS by ≥ 5 points during transfer and in any comatose subject a repeat CT scan of the brain should be performed prior to randomization. Utmost care is taken to avoid unnecessary delay between IVT and the initiation of IAT. Registry of patients with basilar artery occlusion who are not randomised To evaluate a possible selection bias of patients included in the trial, participating centers are obliged to enter all trial eligible patients with acute symptomatic basilar artery occlusion presenting at their center which are not randomised, in a registry. Data are collected on baseline characteristics, reason for non-inclusion and type of treatment. 7.3 Study procedures To minimize any delay in the administration of a proven effective therapy (i.e., IV rt-PA), the standard dose of open-label IV rt-PA (0.9 mg/kg; 90 mg maximum) is initiated prior to enrollment and randomization in the trial if standard eligibility criteria are met. A diagnostic neuroimaging screening with CT/CTA or ,MRI/MRA confirming the presence of basilar artery occlusion and the absence of imaging exclusion criteria, and an NIHSS of 10 or more will be used to identify patients eligible for the trial. After obtained informed consent patients will be randomised in one of two treatment arms. Imaging CT is the preferred imaging modality. MRI may be used if part of the local standard imaging protocol. Prior to IVT 20 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 Patients will need a NCCT or MRI scan of the brain prior to initiation of IVT to exclude hemorrhage or extensive brainstem ischemia. Prior to randomization All patients should have a CTA or MRA before, during or at the end of IVT and prior to randomization, for confirmation of BAO. Confirmation of BAO should not delay the initiation of IVT. IVT should preferably be started immediately following NCCT/MRI, prior to CTA/MRA. Repeat CTA or MRA before randomization is not mandatory, but recommended in case of significant neurological improvement or worsening, and in case of a more than 2 hours time delay after initial confirmation of BAO. 24 hours follow-up All patients will have a follow-up CT/CTA or MRI/MRA within 24hours ± 6 hours of initiation of treatment to monitor vessel patency, presence of intracranial haemorrhage and extend of ischemic changes. Treatment arms IV rt-PA All patients are treated with a standard full dose of open-label IV rt-PA (0.9mg/kg; 90mg maximum) if standard eligibility criteria are met. Patients treated with IVT within 4.5 hours of symptom onset, and those who are treated beyond 4.5 hours of symptom onset but within 4.5 hours of estimated time of basilar artery occlusion will be regarded as two prespecified subgroups for secondary analysis. In patients treated beyond 4.5 hours of symptom onset, informed consent needs to be obtained prior to initiation of IVT. IA therapy IA therapy has to be initiated within 6 hours of estimated time of basilar artery occlusion. If an appropriate thrombus or residual stenosis is identified, the choice of IA strategy will be made by the treating neurointerventionalist. IA treatment options available will be any of the following devices or thrombolytics, depending on local approval and experience; the Concentric Merci® thrombus-removal device, Penumbra, Solitaire, infusion of rt-PA combined with an application of low-intensity ultrasound at the site of the occlusion via the EKOS® Micro-Infusion Catheter, infusion of alteplase or urokinase via a standard micro-catheter. If IA thrombolysis is the chosen strategy, a maximum of 22 mg of IA rt-PA 21 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 or 1.500.000 Units of Urokinase may be given. Stenting is allowed in the presence of a high-grade vertebral artery stenosis or occlusion hampering adequate endovascular access to the basilar artery and in case of a residual high grade basilar artery stenosis. The use of any other treatment strategy depends on local approval and experience, and is only allowed after prior approval of the steering committee. The IA approach is aimed at recanalization of the basilar artery. In order to ensure optimal perfusion at least one posterior cerebral artery should be patent. In the presence of residual occlusions of branches of the basilar artery after complete recanalization of the basilar artery the use of additional thrombolytic therapy should be kept to a minimum due to the limited potential gain. Clinical improvement could be a reason not to initiate IA therapy despite the presence of persistent basilar artery occlusion on conventional angiography. The initiation of IA therapy after identification of an appropriate thrombus in the basilar artery or high grade residual stenosis considered to have been the cause of occlusion on conventional angiography will be left to the judgment of the treating physician. Follow-up Follow-up of patients will subsequently be performed at 24 hours ± 6 hours, 7 days or discharge, 1 month (telephone survey: mRS) 3 months (blinded examiner mRS, EQ-5D) and at 12 months (telephone survey: EQ-5D, mRS). 7.4 Withdrawal of individual subjects Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons. 7.5 Replacement of individual subjects after withdrawal. After withdrawal from the study individuals will not be replaced. 7.6 Follow-up of subjects withdrawn from treatment Subjects withdrawn from treatment will be followed-up if informed consent is maintained. 7.7 Premature termination of the study For procedures concerning premature termination of the study we refer to chapter 9.4. 8. SAFETY REPORTING 8.1 Section 10 WMO event In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and the reviewing accredited METC if anything occurs, on the basis of which it 22 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the accredited METC, except insofar as suspension would jeopardise the subjects’ health. The investigator will take care that all subjects are kept informed. 8.2 Adverse and serious adverse events Adverse events are defined as any undesirable experience occurring to a subject during the study, whether or not considered related to the investigational product or the experimental treatment. All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded. A serious adverse event is any untoward medical occurrence or effect that at any dose: - results in death; - is life threatening (at the time of the event); - requires prolongation of existing inpatients’ hospitalisation; - results in persistent or significant disability or incapacity; - is a new event of the trial likely to affect the safety of the subjects, such as an unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the treatment of a life threatening disease, major safety finding from a newly completed animal study, etc. Acute basilar artery occlusion has a high morbidity and mortality. All deaths and adverse events will be collected and analysed by an independent AE-committee. An independent medical monitor will direct this committee. When they conclude that the event is attributable to the treatment and is not a result of the disease, the event will be reported as a SAE. All SAEs will be reported through the web portal ToetsingOnline to the accredited METC that approved the protocol, within 15 days after the sponsor has first knowledge of the serious adverse reactions. SAEs that result in death or are life threatening should be reported expedited. The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction. This is for a preliminary report with another 8 days for completion of the report. 8.2.1 Suspected unexpected serious adverse reactions (SUSAR) Adverse reactions are all untoward and unintended responses to the investigational product related to any dose administered. Unexpected adverse reactions are adverse reactions, of which the nature, or 23 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 severity, is not consistent with the applicable product information (Summary of Product Characteristics (SPC)). The sponsor will report expedited the following SUSARs through the web portal ToetsingOnline to the METC: − SUSARs that have arisen in the clinical trial that was assessed by the METC; − SUSARs that have arisen in other clinical trials of the same sponsor and with the same medicinal product, and that could have consequences for the safety of the subjects involved in the clinical trial that was assessed by the METC. The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every half year to the METC. This line-listing provides an overview of all SUSARs from the study medicine, accompanied by a brief report highlighting the main points of concern. The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as notification to the competent authority. The sponsor will report expedited all SUSARs to the competent authorities in other Member States, according to the requirements of the Member States. The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report. 8.2.2 Annual safety report In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout the clinical trial, a safety report to the accredited METC, competent authority, Medicine Evaluation Board and competent authorities of the concerned Member States. This safety report consists of: − a list of all suspected (unexpected or expected) serious adverse reactions, along with an aggregated summary table of all reported serious adverse reactions, ordered by organ system, per study; − a report concerning the safety of the subjects, consisting of a complete safety analysis and an evaluation of the balance between the efficacy and the harmfulness of the medicine under investigation. 24 of 30 BASICS Trial Protocol ID/NL33550.100.10 8.3 version 2.0 14-01-2012 Follow-up of adverse events All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist. 8.4 Data Safety Monitoring Board (DSMB) An independent Data Safety and Monitoring Board, consisting of clinicians familiar with the treatment of stroke, a biostatistician and a neuro-interventionalist, will be established to monitor the progress of the trial. Additionally, two stroke neurologists will be appointed as internal and external safety monitors. The Internal Safety Monitor will review safety data on an ongoing basis, including monitoring the trend in serious adverse outcome events and submitting reports to regulatory agencies. The External Safety Monitor, an independent and experienced neurologist, will review all serious life-threatening bleeding events during this study and be the final adjudicator of intracranial hemorrhage endpoints (symptomatic or asymptomatic and the relationship to study intervention) when there is disagreement between the local site and the Internal Medical Monitor. This is the same methodology used by the NINDS rt-PA Stroke Trial and IMS Studies. Details on the advice(s) of the DSMB will be notified upon receipt by the sponsor to the METC that approved the protocol. With this notification a statement will be included indicating whether the advice will be followed. 9. STATISTICAL ANALYSIS 9.1 Descriptive statistics Continuous data will be summarised with means and standard deviations. For count data percentages will be given. 9.2 Univariate analysis The primary aim of the analysis is to compare the proportion of patients with a favourable outcome at 90 days between the two treatment groups. For this purpose a risk ratio with corresponding 95% CI will be calculated. The analyses will be based on the intention-totreat principle. 9.3 Multivariate analysis Multivariable analyses will only be carried out if important incomparability is detected between the two treatment groups. In that case risk ratios will be calculated that are adjusted for the variables that show baseline imbalance. To this end Poisson regression will be used, similar to that used in the BASICS registry study [ref 2 chapter 12]. 25 of 30 BASICS Trial Protocol ID/NL33550.100.10 9.4 version 2.0 14-01-2012 Interim analysis An independent data safety monitoring board will monitor the trial. For efficacy a symmetrical two-sided stopping rule will be used. The size of the trial is based on the assumption of a 10% absolute increase of the proportion of patients with a favorable outcome treated with additional IA therapy as compared with maximum supportive care alone. If the observed benefit is ‘clearly’ larger or if maximum supportive treatment appears to be better than additional IA therapy early termination of the trial may be recommended. A restricted procedure (Whitehead1997; PEST 4) will be used with alpha equal to 0.05 and a power of 0.80. Safety will be monitored as follows. The BASICS registry observed that the risk of symptomatic intracranial hemorrhage in patients treated with IA therapy was 14% (95% CI 10-18%) and 7% (95%CI 3-11%) in those treated with IVT only. [ref Lancet Neurology 2009] A more than two-fold excess of symptomatic intracranial hemorrhage in the group treated with additional IA therapy as compared with maximum supportive treatment may therefore be considered as problematic. However, symptomatic intracranial hemorrhage is a contributing component of the primary outcome and hence is weighed during monitoring of this outcome. Nevertheless the Steering Committee of the BASICS trial will develop a criterion in close collaboration with the DSMB of the trial when an excess of symptomatic intracranial hemorrhage would warrant at least reconsideration of continuation of the trial. The BASICS Trial Office will put an active follow-up system into effect, such that for each patient 90-day follow-up data and those on the occurrence of symptomatic intracranial hemorrhage are obtained without delay. After the collection of the follow-up data on ten patients and after each safety outcome these data will be sent to the DSMB that will perform an interim analysis. Every four months the DSMB will advise the steering committee about the continuation of the trial. The recommendation on the continuation will be based on 1) stopping rules as described above and 2) the most recent information from medical literature or congresses in the field of cerebrovascular disease. References Whitehead J. The design and analysis of sequential clinical trials. rev. 2nd ed. 1997, John Wiley & Sons, Chichester. PEST 4: Operating Manual. MPS Research Unit (2000). The University of Reading. 26 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 10. ETHICAL CONSIDERATIONS 10.1 Regulation statement The study will be conducted according to the principles of the Declaration of Helsinki (www.wma.net 21-10-2008) and in accordance with the Medical Research Involving Human Subjects Act (WMO). 10.2 Recruitment and consent See also chapter 7.2. The responsible neurologist or neurology resident obtains informed consent. In acute situations or if the patient is incapable to give written informed consent oral informed consent may be obtained. In case of oral informed consent a witness (e.g. family or nurse) should be present when the information is presented to the patient or patient representative. A written summary that describes the essential information will be presented to the patient or patient representative. The witness, and responsible neurologist or neurology resident will sign this short document. In case of a comatose subject informed consent can be obtained from the patient’s proxy in person or by telephone as long as the identity of the proxy can be confirmed. Community hospitals are encouraged to obtain informed preliminary consent for trial participation of the subject or his proxy prior to transfer. In patients who are not eligible for standard IVT because IVT cannot be initiated within 4.5 hours of symptom onset, who can be treated within 4.5 hours of estimated time of BAO informed consent has to be obtained prior to IVT. In those centers where CTA or MRA is not part of the standard acute stroke work-up informed consent has to be obtained prior to CTA or MRA. 10.3 Benefits and risks assessment A combined IV and IA approach to acute ischemic stroke therapy was designed to offer rapid initiation of IV rt-PA, followed by additional titrated local IA therapy, to patients with moderate-to-severe strokes (NIHSS≥10). The goal was to achieve higher rates of early, successful reperfusion in a widely accessible manner. This approach has been tested in clinical trials of over 200 patients, starting with the Emergency Management of Stroke (EMS) pilot trial from 1994 to 1995, followed by the Interventional Management of Stroke (IMS) I trial in 2001, the IMS II trial from 2003 to 2006, and several additional cohorts. The data from EMS and IMS show that the combined approach to recanalization may be more effective than standard IV rt-PA alone for moderate-to-severe (NIHSS ≥10) strokes, while maintaining a similar safety profile. The MERCI trials have shown the safety of mechanical thrombectomy after full dose IVT. 27 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 10.4 Compensation for injury The sponsor/investigator has a liability insurance which is in accordance with article 7, subsection 6 of the WMO. The sponsor (also) has an insurance which is in accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research in Humans of 23th June 2003). This insurance provides cover for damage to research subjects through injury or death caused by the study. 1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each subject who participates in the Research; 2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for all subjects who participate in the Research; 3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the organisation for all damage disclosed by scientific research for the Sponsor as ‘verrichter’ in the meaning of said Act in each year of insurance coverage. The insurance applies to the damage that becomes apparent during the study or within 4 years after the end of the study. 11. ADMINISTRATIVE ASPECTS AND PUBLICATION 11.1 Handling and storage of data and documents After randomization all patient data (including digital case record forms) will be kept in a Data management system. The principal investigator safeguards the key to the code. All de-identified imaging data will be sent to the Clinical Coordinating Center at the St. Antonius Hospital, Nieuwegein for standardized CD archiving and data blinding (if needed). CT and CTA imaging will then be transferred to the Imaging Analysis Center at the University of Dresden for central interpretation by a blinded three-member consensus panel. To expedite safety reporting, all acute CT data received from a clinical center will initially be reviewed by a blinded central reader at the St. Antonius Hospital, Nieuwegein. All angiographic data will be reviewed by two independent readers at the Angiographic Imaging Center at the University of Bern, and a third reader will provide final adjudication as needed. The handling of all personal data will comply with the Dutch Personal Data Protection Act. 28 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 11.2 Amendments A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree: - the safety or physical or mental integrity of the subjects of the trial; - the scientific value of the trial; - the conduct or management of the trial; or - the quality or safety of any intervention used in the trial. All substantial amendments will be notified to the METC and to the competent authority. Non-substantial amendments will not be notified to the accredited METC and the competent authority, but will be recorded and filed by the sponsor. 11.3 Annual progress report The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events/ serious adverse reactions, other problems, and amendments. 11.4 End of study report The sponsor will notify the accredited METC and the competent authority of the end of the study within a period of 90 days. The end of the study is defined as the last patient’s last visit. In case the study is ended prematurely, the sponsor will notify the accredited METC and the competent authority within 15 days, including the reasons for the premature termination. Within one year after the end of the study, the investigator/sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC and the Competent Authority. 11.5 Public disclosure and publication policy Publication policy is in accordance with the CCMO’s statement containing the basic principles of the CCMO’s position on the disclosure/publication of research results obtained from studies involving human subjects. Results will be disclosed unreservedly. The BASICS trial will be registered in a public trial registry. 29 of 30 BASICS Trial Protocol ID/NL33550.100.10 version 2.0 14-01-2012 REFERENCES 1. Leys, D. Atherothrombosis: a major health burden. Cerebrovasc. Dis. 2001;11 suppl 2:1-4. 2. Schonewille, WJ et al. Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry. Lancet Neurol. 2009 Aug;8(8):724-30. 3. Furlan, A et al. Intra-arterial prourokinase for acute ischemic stroke: the PROACT II study: a randomised controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999 Dec 1;282(21):2003-11. 4. Tissue plasminogen activator for acute ischemic stroke: The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Eng J Med. 1995 Dec 14;333(24):1581-7. 5. Hacke, W et al. Randomised double-blind placebo-controlled trial of thromblolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998 Oct 17;252(9136):1245-51. 6. Hacke, W et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS and NINDS rt-PA stroke trials. Lancet. 2004 Mar 6;363(9411):768-74. 7. Ogawa, A et al. Randomised trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke. 2007 Oct;38(10):2633-9. 8. Hacke, W et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13)1317-29. 9. Weimar, C et al. Distribution and outcome of symptomatic stenoses and occlusions in patients with acute cerebral ischemia. Arch Neurol. 2006 Sep;63(9):1287-91. 10. Lindsberg, PJ et al. Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment. Neurology. 2006 Jul 25;67(2):334-6. 11. Macleod, MR et al. Results of a multicentre, randomised controlled trial of intraarterial urokinase in the treatment of acute posterior circulation ischaemic stroke. Cerebrovasc Dis. 2005;20(1):12-7. 12. Lindsberg, PJ et al. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke. 2006 Mar;37(3):922-8. 13. Lewandowski, CA et al. Combined intravenous and intra-arterial r-TPA versus intraarterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999 Dec;30(12):2598-605. 14. IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke. 2004 Apr;35(4):904-1. 15. IMS II Trial investigators. The interventional Management of Stroke (IMS) II study. Stroke 2007 Jul;38(7):2127-35. 16. Lindsberg, PJ et al. Long-term outcome after intravenous thrombolysis of basilar artery occlusion. JAMA. 2004 Oct 20;292(15):1862-6. 17. Pfefferkorn, T et al. Drip, ship, and retrieve: cooperative recanalization therapy in acute basilar artery occlusion. Stroke. 2010 Apr;41(4):722-6. 18. Puetz, V et al. CT angiography source images predict final infarct extent in patients with basilar artery occlusion. Am J Neuroradiol. 2009 Nov;30(10):1877-83. 19. Nagel, S et al. Therapy of acute basilar artery occlusion: intraarterial thrombolysis alone vs bridging therapy. Stroke. 2009 Jan;40(1):140-6. 20. Smith, WS et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008 Apr;39(4):1205-12. 30 of 30
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