THE SITS MONITORING STUDY (SITS-MOST)

Transcription

1 SITS International Stroke Thrombolysis Collaboration THE SITS MONITORING STUDY (SITS-MOST) Safe Implementation of Thrombolysis in Stroke: A Multinational Multicentre Monitoring Study of Safety and Efficacy of Thrombolysis in Stroke An open, prospective, non-randomised observational study of safety and efficacy of treatment with intravenous rt-pa within 3 hours of onset of acute ischaemic stroke, based on SITS International Stroke Thrombolysis Register. SITS Monitoring Study (SITS-MOST) Final Study Protocol Summary In randomised controlled trials, intravenous rt-pa is a highly effective treatment within 3 hours after onset of neurological symptoms in selected patients with acute ischaemic stroke. There is an increased risk of symptomatic, even fatal, intracranial haemorrhage, but this is offset by a reduction in the proportion of patients being dead or dependent. The overall net benefit of rt-pa given within 3 hours of onset was one fewer dead or dependent patient at follow up per ten treated. Safety and efficacy of a treatment in acute ischaemic stroke may be different in the settings of randomised controlled trials and during implementation into clinical routine. The SITS International Stroke Thrombolysis Register (SITS-ISTR) provides an instrument for continuous monitoring of thrombolysis treatment in stroke. SITS-ISTR provides the technical basis for the SITS Monitoring Study. The Monitoring Study (SITS-MOST) has strictly defined treatment criteria. The study aims to evaluate the proportions of symptomatic intracerebral haemorrhage and death (primary endpoints) as well as independence (secondary endpoint) for stroke patients treated with rt-pa in clinical routine settings within 3 hours from stroke onset, and to compare these results with the corresponding rt-pa treated patients in randomised controlled trials. A further aim of SITS-MOST is to evaluate whether an on-line monitoring system with immediate feed back of a clinical centre s outcome data is associated with improvement of treatment safety and efficacy with time. It is reasonable to hypothesise that immediate feedback encourages a selection of patients who are likely to benefit from thrombolytic treatment and less likely to experience haemorrhagic complications.

2 SITS means Safe Implementation of Thrombolysis in Stroke SITS is an academic-driven, non-profit, international collaboration SITS is a initiative by the medical profession to certify excellence in acute stroke treatment 2

3 CONTENTS I. About SITS and SITS-MOST, an overview 5 SITS-ISTR and SITS-MOST 5 Patient recruitment 6 Overview of primary and major secondary study aims 7 Major analyses planned ins SITS-MOST 8 Overview of SITS organisation 13 SITS responsibilities and representatives 14 II. Abbreviations 16 III. Clinical Trial Protocol Summary 17 IV. Study Flow chart Introduction to the SITS-MOST study protocol Stroke a growing disease Treatment strategies for stroke The rationale for thrombolysis treatment Evidence from randomised controlled trials Experiences from post-trial treatments Consensus at Karolinska Stroke Update Rationale for a monitoring register SITS-ISTR Rationale for a monitoring study SITS-MOST SITS-MOST protocol Aims of the trial Study design Treatment Investigational product Dosage and treatment schedule Concomitant therapy increased blood pressure Concomitant therapy haemorrhage Concomitant therapy overdose Concomitant therapy anaphylactic reactions Restrictions Treatment compliance 2.4 Study population Inclusion criteria Exclusion criteria Consent/assent Level of care 2.5 Outcome measures Primary outcome Secondary outcome Further clinical variables of interest Procedure for evaluation of occurrence of intracerebral symptomatic haemorrhage Procedure for evaluation of mortality Procedure for evaluation of independence/modified Rankin scale 0-2 3

4 2.6 Investigational procedures National Institute of Health Stroke Scale, NIHSS Modified Rankin Scale, mrs Global Evaluation Scale, GES Brain CT scan Brain MRT scanning (optional) Criteria for stopping treatment 2.7 Planned analyses Primary outcome analyses Further evaluations of interest 2.8 Schedule of study procedures Patient identification and monitoring of source data Patient identification Source data monitoring 2.10 Centre eligibility General requirements for SITS-MOST centres Previous ECASS centres with current rt-pa protocols Other centres Investigators and study nurses 2.11 Administrative and ethical matters Institutional Review Board or Independent Ethics Committee Informed consent and subject information Safety evaluation Drug accountability Data entry Database Ownership and Data Transfer Financing Insurance 2.12 Study termination, confidentiality and publication policy Study termination Statement of confidentiality Publication policy 3. References Signature page Attachments Karolinska Stroke Update Consensus Statement on Thrombolysis October Patient information and Informed Consent Form NIHSS Rankin scale Global evaluation scale Statistical considerations Data entry form Educational programme outline SAE form to be used in reporting serious drug reaction 63 4

5 I. SITS AND SITS-MOST POINT BY POINT: This is a presentation of SITS and a study protocol for the SITS Monitoring study SITS-MOST SITS means Safe Implementation of Thrombolysis in Stroke. It started as an initiative by participants in the European-Australian randomised stroke thrombolysis studies (ECASS) and then spread to many centres in several countries SITS is an academy driven, non-profit organisation The scientific leadership of SITS is in the hands of the Scientific Committee, an international group of leading experts in the field SITS initiated an internet-based interactive thrombolysis register, to serve as an instrument for clinical centres to follow their own treatment results and compare with other centres in their countries and in the collaborating countries The SITS register is now the technical basis for the SITS Monitoring Study (SITS- MOST), which aims at exploring whether implementation of thrombolysis into clinical routine treatment of stroke will be as safe and as beneficial as the results achieved in the strict format of randomised controlled trials Centres with experience from thrombolysis in stroke, e.g., ECASS centres, and qualified stroke centres without such experience will be invited to participate in SITS- MOST SITS-MOST includes patients who can be treated within 3 hours after stroke onset and who do not meet treatment exclusion criteria The study will continue recruitment for at least three years Data entry into SITS-MOST will be through SITS thrombolysis register over secure internet and follow up will be done by the treating centre after three months An alternative paper data entry form will be available for centres without internet connection until this has been established The SITS Executive Committee will form the SITS-MOST steering committee and the SITS National Coordinators will be Study National Coordinators. 5

6 PATIENT RECRUITMENT TO SITS MONITORING STUDY (SITS-MOST) Patients and reports in SITS-MOST Selected patients treated < 3h after stroke onset in qualified stroke centres (n>1000) SITS-MOST CENTRE STATISTICAL REPORT Immediate on-line plus annual statistical report Comparison centre data-national data-international data SCIENTIFIC REPORT Is routine thrombolysis at least as safe and beneficial as reported from randomised controlled trials? 6

7 OVERVIEW OF PRIMARY AND SECONDARY STUDY AIMS: The study aim for SITS-MOST is to evaluate whether routine use of intravenous rt-pa within three hours after onset of stroke symptoms is at least as safe(primary aim) and as beneficial(secondary aim) as the results reported from randomised controlled trials. SITS-MOST will use the following primary safety outcome variables: Symptomatic intracerebral haemorrhage Mortality Intracerebral haemorrhage (parenchymatous haemorrhage type 2*), at post-treatment scan combined with neurological deterioration leading to an increase of 4 points on the NIH Stroke Scale Death (mrs = 6) within three months SITS-MOST will use the following major secondary efficacy outcome variable: Independence Independence for the activities of daily living at three months In SITS-MOST defined as a modified Rankin score (mrs) of 0-2 * defined in

8 MAJOR ANALYSES PLANNED IN SITS-MOST Table I: This is an observational study which will assess the proportions of symptomatic intracerebral haemorrhage (SICH) and death (primary endpoints) as well as independence (secondary endpoint) in patients treated in clinical routine with rt- PA within three hours after onset of stroke. Table I shows the corresponding proportions, and their 95% confidence intervals (CI), observed in a systematic review of all randomised controlled trial (RCT) data on rt-pa within 3 hours after onset of acute stroke. Proportions of SICH, death and independence per 100 patients treated and 95% confidence intervals (CI) in randomised controlled trials (Ref 17, 26, 36) SICH* (N=465) Death (N=479) Independence (N=465) Proportion 95% CI Proportion 95% CI Proportion 95% CI * SICH has been defined differently in various trials. For reasons of consistency we refer to symptomatic parenchymatous haemorrhage type 2 only. A. Is routine rt-pa treatment for stroke as safe and efficacious as in RCT? The aim of the study is to evaluate safety (primary aim) and efficacy (secondary aim) of rt-pa in clinical routine, compared to randomised controlled trials (RCT). Figure 1a and 2a show the number of patients required to ascertain that the upper confidence limit of the point estimate of SICH and death is below the corresponding upper confidence limit in the systematic review. Figure 3a shows the corresponding figure for independence with regard to lower confidence limits. Figure 1b, 2b and 3b show the number of patients required to exclude worsening of safety and efficacy, i.e., to exclude that an observed difference in events between SITS-MOST and RCT, and its 95% CI is greater than 0 (for SICH and death) or lower than 0 (for independence). It should be noted that such statistical bounds are not necessarily identical with the clinical thresholds around which the benefit/risk ratio is expected to fall one side or the other. Hence, these statistical bounds cannot be the only basis of the decision rules, 8

9 especially given the nature of the historical comparison. Therefore also all relevant descriptive statistics for the safety and efficacy measures, along with their respective 95% confidence intervals will be taken into account. Furthermore it should be noted that conclusions about outcomes are difficult to draw unless at least 1000 patients have been included in the study. 9

10 Fig 1a: Fig 1b: Number of patients required to verify that the proportion of SICH is equal or better in SITS- MOST compared to RCT Number of patients required to exclude that the proportion of SICH is worse in SITS- MOST compared to RCT Number of patients Number of patients ,6 9,6 10, Observed proportion of SICH in SITS-MOST (hypothetical) Vertical line represents upper confidence limit of RCT 5,5 4,5 % worsening to be excluded, compared to RCT 3,5 Fig 2a: Fig 2b: Number of patients required in SITS-MOST to verify that the observed mortality is w ithin 95% CI of RCT Number of patients required to exclude that the mortality is worse in SITS-MOST compared to RCT Number of patients ,3 18,3 19,3 20,3 21,3 Number of patients Observed mortality in SITS-MOST (hypothetical). Vertical line represents upper confidence limit of RCT 5,5 4,5 % w orsening to be excluded, compared to RCT 3,5 10

11 Fig 3a: Fig 3b: Number of patients required to verify that the proportion of independence is equal or better in SITS-MOST compared to RCT Number of patients required to exclude that the proportion of independence is worse in SITS-MOST compared to RCT Number of patients ,1 46,1 47,1 48,1 49,1 50,1 Observed proportion of SICH in SITS-MOST (hypothetical). Vertical line represents upper confidence limit of RCT Number of patients ,5 6 5,5 5 % worsening to be excluded, compared to RCT 4,5 4 3,5 B. Can safety and efficacy in SITS-MOST even be improved compared to RCT? Additionally SITS-MOST will evaluate whether rt-pa treatment in clinical routine can suggest a better outcome compared to RCT. Figure 4, 5 and 6 show the number of patients required to show that patients in SITS-MOST have a higher proportion of independence, and lower proportion of deaths and SICH compared to RCT. Again it should be noted that such statistical bounds are not necessarily identical with the clinical thresholds around which the benefit/risk ratio is expected to fall one side or the other, especially given the nature of the historical comparison. 11

12 Fig 4: Fig 5: Number of patients required to verify that the proportion of independence is better in SITS-MOST compared to RCT Number of patients required to verify that the mortality is better in SITS-MOST compared to RCT Number of patients Number of patients ,5 5 5,5 6 6, ,5 3 3,5 4 4,5 5 5,5 6 % improvement to be verified, compared to RCT % imporvement to be verified, compared to RCT Fig 6: Number of patients required to verify that the proportion of SICH is better in SITS- MOST compared to RCT Number of patients ,5 3 3,5 4 4,5 5 5,5 6 %improvement to be verified, compared to RCT 12

13 OVERVIEW OF SITS ORGANISATION SITS has National Coordinators in 16 countries. In four countries nominations of National Coordinators are in progress. NCO Austria SITS International NCO Belgium NCO Czech Rep. NCO Denmark NCO Finland NCO France NCO Germany Clinical centre Clinical centre Clinical centre Clinical centre Clinical centre Clinical centre Steering Board Scientific Committee NCO Greece Clinical centre Brain Imaging Committee National Representatives NCO Hungary Clinical centre Board of Directors International Coordinating NCO Ireland Clinical centre Office ICO NCO Israel Clinical centre NCO Italy NCO Luxembourg Clinical centre Clinical centre NCO Netherlands NCO Norway NCO Portugal NCO Spain NCO Sweden NCO Switzerland NCO UK 13

14 SITS ORGANISATION - RESPONSIBILITIES SITS Institution: Responsibility: Representatives: Steering Board Administrative Nils Gunnar Wahlgren Niaz Ahmed Hans-Göran Hårdemark Scientific Committee (and Steering Committee of SITS- MOST) National Coordinators Scientific responsibility Data evaluation Reports and publications Data entry formatting Monitoring safety/efficacy Represent SITS to national authorities, centres and the public Authorising language version of SITS homepage and register Coordinating information to centres in the country Coordinating monitoring of centre data in the country Central follow up (e.g. SITS-MOST) Nils Gunnar Wahlgren Antoni Davalos Cesare Fieschi Martin Grond Werner Hacke Markku Kaste Vincent Larrue Kennedy Lees Deputies: Hans-Göran Hårdemark Danilo Toni Risto Roine Gary Ford N.N. Austria Franz Aichner Belgium Geert Vanhooren Czech Republic (Not yet determined) Denmark Gudrun Boysen Finland Markku Kaste France Vincent Larue Germany Martin Grond Greece (Not yet determined) Hungary Lászlo Csiba Ireland (Not yet determined) Israel Natan Bornstein Italy Danilo Toni Luxembourg (Not yet determined) Netherlands Cees Franke/ Jan Lodder Norway Lars Thomassen Portugal Maria Antonia Ferro Spain José Castillo Sweden Nils Gunnar Wahlgren Switzerland Marc Reichhart UK Kennedy Lees 14

15 National Representatives Advisory Board Represent national perspectives to international collaborative group Represent SITS in the country Austria Franz Aichner Belgium Geert Vanhooren Chech Republic Not yet determined Denmark Gudrun Boysen Denmark Karsten Overgaard Finland Markku Kaste Finland Risto Roine France Vincent Larue France Didier Leys Germany Werner Hacke Germany Martin Grond Greece Not yet determined Hungary Lászlo Csiba Hungary Zoltan Nagy Ireland Not yet determined Israel Natan Bornstein Italy Danilo Toni Luxembourg Not yet determined Netherlands Cees Franke Netherlands Jan Lodder Norway Lars Thomassen Norway David Russell Portugal Maria Antonia Ferro Spain José Castillo Spain Antonio Davalos Sweden Hans-Göran Hårdemark Sweden Nils Gunnar Wahlgren Switzerland Marc Reichhart UK Kennedy Lees UK Gary Ford International Coordinating Office Board of Directors Brain Imaging Committee Statistical Consultant Day-to-day management of SITS Service to centres (access codes, data control, registration of new centres and collaborators) Preparation of periodic reports Review CT scans Review MR scans Define criteria for classification of brain imaging Statistical advice SITS Directors (prel) Nils Gunnar Wahlgren (Chair) H-G Hårdemark (Imaging) Lena Lundqvist (SITS ICO) Geert Vanhooren (IT) Staff ICO Sandra Backlund Anita Tyrén-Hansson Rüdiger von Kummer Joanna Wardlaw Coordinator HG Hårdemark : N.N. Erich Bluhmki 15

16 II. Abbreviations ADL ADR AE ASA AICH BRIC COED CT CTEP EC ECG EUSI GES GCP HI ICH ICO IEC IRB ISTR (-SITS) i.v. MCA MOST MRI mrs n.a. NCO NIHSS NINDS PH PHr rt-pa SAE SAR SDM SICH SITS SITS-BRIC SITS-EC SITS-ISTR SITS-MOST SPC Activities of Daily Living Adverse Drug Reaction Adverse Event Acetyl Salicylic Acid Asymptomatic intracerebral haemorrhage Brain Imaging Committee of SITS Cerebral oedema Computer Tomogram Computer Tomogram experienced physician Executive Committee of SITS (=Steering and monitoring committee of SITS-MOST) Electrocardiogram European Stroke Initiative Global Evaluation Scale Good Clinical Practice Haemorrhagic Infarct Intracerebral Haemorrhage International Coordinating Office Independent Ethics Committee Institutional Review Board International Stroke Thrombolysis Register Safe Implementation of Thrombolysis in Stroke intravenous Middle Cerebral Artery Monitoring study Safe Implementation of Thrombolysis in Stroke Magnetic Resonance Imaging modified Rankin Scale not applicable National Coordinator National Institute of Health s Stroke Scale National Institute of Neurological Disorders and Stroke Parenchymal Haemorrhage Parenchymal Haemorrhage, remote Tissue plasminogen activator, alteplase, Actilyse Serious Adverse Events Serious Adverse Reaction Source Data Monitoring Symptomatic Intracerebral Haemorrhage Safe Implementation of Thrombolysis in Stroke Brain Imaging Committee of SITS Executive Committee of SITS (=Steering and monitoring committee of SITS-MOST) SITS International Stroke Thrombolysis Register SITS Monitoring Study Summary of Product Characteristics (package insert) 16

17 III. Clinical Trial Protocol Summary SITS International Stroke Thrombolysis Register SITS-MOST Protocol date: Protocol version: Final Planned Study period: Q Q Name of active ingredient: Alteplase (Actilyse R ) Title of study: Observational study of safety and efficacy of intravenous rt-pa (0.9 mg/kg) within 3 hours of symptom onset in acute ischaemic stroke patients, according to the Summary of Product Characteristics (SPC). Investigators: International, multicentre trial Study center(s): Stroke Centres estimated Clinical phase: IV Objectives: To evaluate the safety and efficacy of intravenous rt-pa (0.9 mg/kg) within 3 hours of symptom onset in acute ischemic stroke Methodology: International, multicentre, open investigation within 3 h of acute ischaemic stroke comparing proportions of symptomatic intracerebral haemorrhage (SICH), death and independent patients at 3 months with active treatment outcome in a systematic review of randomised controlled trials of rt-pa. No. of subjects: total: >1000 each treatment: one treatment Diagnosis and main criteria for inclusion: Acute ischemic stroke within three hours after onset Test product: dose: mode of admin.: Duration of treatment: 1 hour Reference therapy: dose: mode of admin.: Outcome variables: Statistical methods: 0.9 mg/kg bodyweight, 10% bolus/ 1 min intravenous infusion Active treatment arm of previous randomised controlled trials of rt-pa N/A. N/A. Primary safety variables: SICH at 36 hours, mortality at 3 months Secondary efficacy variable: Independence for activities of daily living at 3 months Observational and descriptive analysis Outcome comparison: Historical comparison of proportions (incl. 95% confidence intervals) of patients with SICH, death and independence with outcome on active treatment in a systematic review of randomised controlled trials. 17

18 IV. STUDY FLOW CHART Trial Period: Baseline Treatment (0-60 min) Post treatment (2h after start of treatment) Follow-up Visit No: 1A 1B 1C Day of visit: (24 h after start of treatment) Informed consent X In-, exclusion criteria X Demographics X Medical history X Concomitant diagnoses X 7 (or stroke unit discharge) Previous treatment X CT / MR X X* (X**) NIHSS X X X X Blood pressure X X X X 90 (Final followup) Treatment delay X rt-pa administration X Concomitant treatment X X X mrs X Adverse drug reaction# X X X X X *with a time window of hours, or sooner, if clinically indicated **Optional, only needed in the interval 36 h to discharge in case of clinical deterioration are to be recorded at end of treatment # serious are to be reported immediately on a SAE form and faxed to BI local personnel (updated lists available on web site) and information of non-serious given in the registry directly. 18

19 1. Introduction 1.1 Stroke a growing disease Stroke is the third most common cause of death in industrialised countries after myocardial infarcts and tumour diseases 1. Stroke is also the most common cause of permanent disability. About 85% of all strokes are ischaemic, the remaining part haemorrhagic. One year after a total anterior circulation infarct, 60% of the patients have died and 35% have so severe neurological deficits that independent activities of daily living are restricted. With milder strokes, about 40% die or remain dependent 2. In 1998, over new strokes occurred within the European Union. The prevalence of stroke survivors was estimated to about 2.4 millions. Since the incidence of stroke is strongly age-related, the number of stroke victims is expected to increase substantially over the next decades when the proportion of the population over the age of 70 is estimated to grow from about 13% to 20% 3. Even within the next decade, the number of stroke victims is expected to increase by about 15%. The burden of stroke is heavy for the victims and for society. The yearly direct and indirect costs for stroke in Europe can be estimated to about 25 billion Euro. Since the stroke incidence is expected to be about in ten years, these cost might increase by about 10-15% if we do not succeed to prevent more strokes and improve the effect of acute stroke intervention. 1.2 Treatment strategies for stroke Until recently, there was no pharmacological treatment available for acute stroke. Several years attempts to clinically confirm experimental observations of neuroprotective effects of calcium antagonists, NMDA antagonists, glutamate release inhibitors, GABA agonists and other agents have failed until now 4. Appropriate management of stroke patients in stroke units have been shown to reduce death and dependency on others for activities of daily living. A modest effect on early stroke recurrence of aspirin was found in the International Stroke Trial (IST) 5 and the Chinese Acute Stroke Trial (CAST) 6. Hypertension control 7, treatment with ACE-inhibitors 8 (for hypertensive and normotensive), lipid lowering 9, aspirin 10, particularly in combination with dipyridamol 11, clopidogrel 12 and warfarin 13 for patients with atrial fibrillation may all prevent stroke, although the relative preventive effect may vary and the effect of combinations of these treatments is not sufficiently known. Rehabilitation and pharmacological approaches aimed to improve recovery are increasingly in focus but new strategies in clinical management will probably not be in clinical use for some time 14. Thrombolysis with rt-pa is the first evidence based treatment for acute stroke which aims to reduce the cerebrovascular lesion. It is now registered in Europe and US. 19

20 1.3 The rationale for thrombolytic treatment Thromboembolic occlusion of an artery leading to the brain or in the brain is a major cause of stroke. An occlusion of an artery leads to immediate drop of blood flow into the corresponding arterial territory. The size and site of the occlusion, and the efficiency of compensatory flow through collateral arteries determine the amplitude and the extension of the drop in the blood flow. If the flow is reduced to about 20 ml/100 g /minute (about 40% of the normal value), neurological symptoms occur. A blood flow below 10 ml/100 g/min is not compatible with cell survival, and the brain tissue is infarcted. Brain tissue with a blood flow between 10 and 20 ml/100g/min may survive for a few hours, but is likely to die if blood flow is not reestablished 15. Spontaneous reperfusion may occur through endogenous release of plasminogen activator which stimulates plasmin formation from plasminogen. For larger occlusions this release seems insufficient to induce reperfusion in time to avoid a cerebral lesion. Administration of plasminogen activator as an intravenous infusion thus is a method to enhance this endogenous procedure. Reperfusion of course should be done as early as possible to avoid a cerebral lesion and to avoid complications caused by ischaemic injury to blood vessel walls and the blood-brain barrier. 1.4 Evidence from randomised controlled trials In total, 17 randomised trials with 5,216 patients form the evidence base for thrombolysis in stroke. Of the data derived from these trials, 42% relate to streptokinase, 3% to intravenous urokinase and 5% to intra-arterial pro-urokinase. 50% of the data come from trials using intravenous rt-pa 16,17. Frequently, the results of all these trials and agents are discussed together which may give a more unfavourable impression of the effect of thrombolysis than if only intravenous rt-pa is studied. Whether there is true heterogeneity between thrombolytic agents is still not quite clarified, but there are differences between e.g. streptokinase and rt-pa in the effect on blood pressure (streptokinase reduces blood pressure) which may cause differential effects on collateral blood flow to the ischaemic area of the brain. For rt-pa, data from 2955 patients are available for analysis 18-25, of these 869 were included within three hours after onset of clinical symptoms. The results are more favourable for patients included within three hours compared to those included between three and six hours. The net benefit from intravenous rt-pa within 3 hours after stroke onset is approximately 1 fewer patient being dead or ADL dependent at follow up per ten treated. One fewer patient dies per 100 treated and 1 more suffers a symptomatic intracerebral haemorrhage per fourteen treated 17. This study aims to compare important outcome parameters with those observed in randomised controlled trials within three hours after symptoms onset. The parameters which were determined as primary outcome variables for SITS-MOST were mortality and frequency of intracerebral haemorrhages, and independence (the inverted value of death and dependency) as major secondary outcome variable. The proportions of patients with these outcomes in the 20

21 active (rt-pa) treatment arms (and consequently the basis for comparison with SITS-MOST) were 17,26,36 : Proportion 95% CI Symptomatic haemorrhage Mortality Independence Experiences from post-trial treatments Several open studies have been performed to address the issue of safety and efficacy of routine thrombolysis in acute stroke In the absence of control groups, the outcome of these studies must be compared with the results of randomised controlled trials. Such comparisons have been difficult since the baseline characteristics in most of the studies have not been comparable. This is illustrated by Katzan et al. 29 who reported the highest rate of cerebral haemorrhages of all studies. Initial stroke severity, the most important predictor of haemorrhagic complication risk was reported in only 40 % of all patients and in only 27 % of those with haemorrhage. In the 2000 review by Grond, only two studies 33, had characteristics which allowed comparisons with randomised controlled trials. The outcomes in these studies were very similar to the randomised trials. The major problem was that these studies were from expert centres and that consequently the question of risk and benefit of thrombolysis under routine conditions also outside expert centres has not been adequately answered. 1.6 Consensus at Karolinska Stroke Update 2000 The results of randomised controlled trials and post-trial experiences were discussed at the Karolinska Stroke Update consensus meeting in October It was concluded in the consensus statement (Attachment 5.1), that intravenous rt-pa within three hours after onset of symptoms in patients with acute ischaemic stroke is a highly effective evidence-based treatment (grade A evidence). The use of t-pa is supported by randomised controlled trials and meta-analyses. The risk of early fatal and symptomatic intracranial haemorrhage is increased but these hazards are offset by reduction in the proportion of patients being dead or dependent. Intravenous rt-pa within 6 hours after onset of 21

22 an ischaemic stroke seems to be beneficial, but the benefit is smaller while the risks are higher 33,34. Although there seem to be a consensus about the benefit of intravenous thrombolysis at least in expert centres, there is still some controversy about the ethics in randomising patients to placebo-controlled trial. The International Stroke Trial (IST-3) accepts randomisation within three hours at the investigator s discretion. Over 55% of the IST investigators were convinced that rt-pa was definitely beneficial, while about 31% were uncertain about its effect in that time interval. About 75% of the same investigators were uncertain of the effect of rt-pa in the 3-6 hour interval, and obviously ready to randomise these patients to rt-pa or placebo 35. A number of issues are still unanswered for thrombolysis in stroke Does aspirin use immediately prior to stroke increase the hazard of thrombolysis? - Does the risk-benefit ratio change with increasing age? - Is thrombolysis beneficial in lacunar stroke? - What features (clinical and radiological) indicate likelihood of benefit or risk (including stroke severity, infarct visibility, atrophy and leukoaraiosis on pre-treatment CT, other medical history, age etc. - What is the latest time window in individual patients and how do you know? - Does the absence of a blocked artery at the time thrombolysis treatment is being considered mean that there is no point in offering rt-pa? - What care environment is required to deliver rt-pa safely? - What should be done about blood pressure control prior to and during rt-pa? - Are short term benefits maintained in the long term? - Which dose of the drug and by what route of administration is best? - How cost-effective is this treatment? It could also be added that the effect of rt-pa in clinical routine, at least in non-expert centres is insufficiently known. 1.7 Rationale for a monitoring register the SITS-ISTR Safety and efficacy of a treatment may be different in the settings of randomised controlled trials and during implementation into clinical routine. Treatment may be in the hands of less experienced clinical centres, inclusion- and exclusion criteria may be less strictly followed and treatment outcome is generally not systematically monitored. The issue of monitoring of routine use of thrombolysis was discussed in the 2000 Karolinska Stroke update consensus statement on thrombolysis (5.1). Continuous auditing of the routine use of thrombolytic therapy was recommended. The SITS-ISTR was mentioned as an example for such routine monitoring. It was also stated that therapeutic use of thrombolysis outside randomised controlled trials must be subject to continuous quality control. SITS-ISTR is based on an initiative by former ECASS I & II investigators with the aim to safely transfer the experiences from randomised controlled trials into clinical routine. After registration of rt-pa for the stroke indication in Europe, SITS will strongly recommend that all 22

23 treatments of rt-pa will be done within the SITS-MOST study protocol. 23

24 1.8 Rationale for a monitoring study the SITS-MOST SITS-MOST has strict entry criteria, with a limit of maximally three hours from onset of symptoms to treatment. The aim of SITS-MOST is to evaluate the safety and efficacy of routine use of rt-pa for this well defined population in expert centres as well as new centres. It is also an aim of SITS-MOST to evaluate the effect of rt-pa within defined subgroups of this population, within experienced clinical centres and centres with less experience but highquality general stroke care, and to compare these results with those from randomised controlled trials. The central question is not a fundamental doubt about the efficacy of rt-pa in acute ischaemic stroke but that of conditions of prescription and safety in clinical routine use. There is concern that the risk of thrombolysis might be greater under routine conditions than under the optimal experimental conditions of controlled trials conducted exclusively in expert centres and that this higher risk might outweigh the benefit. Therefore, the question on risk and efficacy of thrombolytic treatment under routine conditions especially outside expert centres needs further elucidation in a European monitoring study focusing on the safety and efficacy in real medical practice. A further aim of SITS-MOST is to evaluate whether immediate feed back of a clinical centre s outcome data results in improved treatment safety and efficacy with time. It is reasonable to hypothesise that an immediate report system, based on an interactive web-site database, encourages selection of patients who are likely to benefit from the treatment and less likely to experience haemorrhagic complications. Because SITS-MOST arises from a requirement of the European Union regulatory authorities to perform a post-marketing surveillance study, centres in countries outside the European Union will not be included, at least initially. They may, of course contribute to the SITS registry. 24

25 2. SITS-MOST STUDY PROTOCOL 2.1 AIMS OF THE TRIAL Primary aim To assess whether alteplase treatment, given under clinical routine conditions as intravenous infusion within three hours after onset of acute ischaemic stroke, is at least as safe as in major randomised controlled trials, and for this purpose specifically evaluate - the incidence of symptomatic intracerebral haemorrhage within the h after thrombolysis treatment (SICH), - mortality at three months (mrs 6) Secondary aim: To assess whether alteplase treatment, given under clinical routine conditions as intravenous infusion within three hours after onset of acute ischaemic stroke, is at least as efficacious as in major randomised controlled trials, and for this purpose specifically evaluate - independence for activities of daily living at three months (functional independence, mrs 0-2) To adjust the above outcome variables to variations in baseline and demographic confounding factors the study will follow three strategies: - SICH, mortality and independence (mrs 0-2) in patient categories of mild, moderate and severe neurological deficit at baseline - the observed proportions on mrs compared to the predicted proportions of the individual patients (prognostic model, based on the placebo group of a rt-pa trials data base, attachment 5.6). - to develop in an explorative fashion a statistical risk management model by means of logistic regression to predict which patients may be at higher risk of e.g. intracerebral haemorrhage or mortality. A similar analysis will be performed for independent outcome on mrs. 2.2 STUDY DESIGN This is an open, multicentre, multinational, prospective, non-randomised observational study based on SITS International Stroke Thrombolysis Register. Centres who are qualified to administer intravenous thrombolysis in acute stroke are invited to participate. Patients who meet entry criteria will be followed until 3 months with symptomatic intracerebral 25

26 haemorrhage and death as main safety outcome and independence as secondary outcome. Study results will be open and continuously updated within the interactive web-site based report system. Overall results are evaluated every six months by the steering committee which may suggest modifications of study design or termination of the treatment for safety reasons. 2.3 TREATMENT Treatment product White, lyophilised powder of alteplase (rt-pa), trade name Actilyse and solvent (sterile, nonbacteriostatic water for injection. Under aseptic conditions the content of an injection vial of Actilyse (20, 50 or 100 mg) dry substance is dissolved with the provided solvent for injections according to the following table to obtain either a final concentration of 1 mg rt-pa/ml: For this the transfer cannulas provided with the packs of rt-pa 20 mg, 50 mg or 100 mg are to be used. rt-pa vial 20 mg 50 mg 100 mg Volume of solvent for injections to be added to dry powder to reach a final concentration of 1 mg alteplase/ml: 20 ml 50 ml 2 x 50 ml The reconstituted solution will be administered intravenously. It may be diluted further with sterile physiological saline solution (0.9 %) up to a minimal concentration of 0.2 mg/ml. Actilyse should not be stored above 25 o C and protected from light. Actilyse should be stored in the original package rt-pa dosage and treatment schedule The recombinant tissue plasminogen activator (rt-pa, alteplase, Actilyse ) is administrated as an intravenous infusion: 0.9 mg/kg (maximum rt-pa dose 90 mg), 10% given as bolus during 1 minute, remaining given as infusion over 1 hour. Treatment must be started within 3 hours after symptom onset. The treatment has to be performed in accordance with contraindications, precautions and warnings as described in the inclusion and exclusion criteria and the SPC provided by the manufacturer. 26

27 2.3.3 Concomitant therapy increased blood pressure Treatment of increased blood pressure should be considered if two readings 5-10 minutes apart reveal a systolic BP above 180 mm Hg or a diastolic BP above 105 mm Hg.. Appropriate drugs should be administered according to the patient needs and to local treatment schedules Concomitant therapy haemorrhage For the treatment of severe haemorrhage at a non-compressible site or the reversal of fibrinolysis during study drug administration appropriate measures according to the patients needs should be taken after stopping the infusion of trial medication. If these measures are insufficient, the administration of cryo-anti-haemophilic-globulin, fresh frozen plasma or fresh blood may be considered. If necessary, anti-fibrinolytics such as tranexamic acid (i.e. Ugurol or Cyklokapron ), aprotinin (i.e., Trasylol ) may also be considered according to the local treatment schedules Concomitant therapy overdose The relative fibrin specificity notwithstanding, a clinical significant reduction in fibrinogen and other blood coagulation components may occur after overdose. In most cases of overdose it is sufficient to await the physiological regeneration of these factors after the rt-pa therapy has been terminated. If however, severe bleeding results, the infusion of fresh frozen plasma or fresh blood is recommended and if necessary, synthetic antifibrinolytics may be administered Concomitant therapy anaphylactic reactions Anaphylactic reactions with rt-pa are uncommon. If an anaphylactic reaction occurs, the infusion should be discontinued and appropriate treatment initiated Precautions and warnings The following restrictions and interactions with respect to concomitant therapy apply: The risk of ICH can be increased if agents inhibiting coagulation, like heparin, are administered after treatment with rt-pa. Therefore, these co-medications are excluded within the first 24 hours of onset of the symptoms. Caution should be excercised in patients receiving prior treatment with antiplatelet agents, e.g. aspirin, since there is a greater risk of intracranial haemorrhage, although this may correlate more with the extent and severity of brain infarction Treatment compliance Treatment compliance is guaranteed by the invasive treatment procedure. The study medication will be administered as a single iv bolus followed by an intravenous infusion in one hour by the investigator or co-investigator. 27

28 2.4 STUDY POPULATION Patients presenting with acute stroke symptoms for which thrombolysis treatment can be initiated within 3 hours after stroke onset Inclusion criteria - Female or male inpatients - Age years - Clinical diagnosis of ischaemic stroke causing a measurable neurological deficit defined as impairment of language, motor function, cognition, gaze, vision and/or neglect. Ischaemic stroke is defined as an event characterised by sudden onset of acute focal neurological deficit, presumed to be caused by cerebral ischaemia, after CT scan exclusion of haemorrhage - Onset of symptoms within 3 hours prior to initiation of thrombolysis treatment - Stroke symptoms present for at least 30 minutes and has not significantly improved before treatment. Symptoms must be distinguishable from an episode of generalized ischaemia (i.e. syncope), seizure, or migraine disorder - Patients are willing to receive thrombolysis treatment and to give informed consent with regard to retrieval of data and follow up procedures, according to the regulations in participating countries - Willingness and ability to comply with the study protocol Exclusion criteria The cerebral CT exclusion criteria are: Evidence of intracranial haemorrhage (ICH) on the CT-scan. The general exclusion criteria are: Symptoms of ischaemic attack began more than 3 hours prior to infusion start or when time of symptom onset is unknown. Minor neurological deficit or symptoms rapidly improving before start of infusion. Severe stroke as assessed clinically (e.g. NIHSS>25) and/or by appropriate imaging techniques. Seizure at onset of stroke Symptoms suggestive of subarachnoid haemorrhage, even if the CT-scan is normal. Administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory 28

29 Patients with any history of prior stroke and concomitant diabetes Prior stroke within the last 3 months Platelet count of below 100,000/mm 3. Systolic blood pressure >185 mmhg or diastolic blood pressure >110 mmhg, or aggressive management (IV medication) necessary to reduce BP to these limits. Blood glucose <50 or > 400 mg/dl. Known haemorrhagic diathesis Patients receiving oral anticoagulants, e.g. warfarin sodium Manifest or recent severe or dangerous bleeding Known history of or suspected intracranial haemorrhage Suspected subarachnoid haemorrhage or condition after subarachnoid haemorrhage from aneurysm Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery) Haemorrhagic retinopathy,e.g. in diabetes (vision disturbances may indicate haemorrhagic retinopathy) Recent (less than 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture. Bacterial endocarditis, pericarditis. Acute pancreatitis Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial- aneurysm, arterial/venous malformation Neoplasm with increased bleeding risk Severe liver disease, including hepatic failure, cirrhosis, portal hypertension oesophageal varices) and active hepatitis Major surgery or significant trauma in past 3 months Consent/assent Ethics Committee approval is not unconditionally required but this may vary between participating countries. If ethics committee approval and written or oral consent is requested, a patient information letter and a consent form is attached (attachment 5.2), as appropriate. Alternatively, patients must consent on treatment, retrieval of study data in the database, monitoring of source data and on follow up procedures. Consent may be given orally, if not otherwise requested according to national laws and regulations, and must be documented in the patient hospital files Level of care Thrombolysis treatment should be given at a semi-intensive care unit within a stroke unit, or an intensive care unit or semi-intensive care unit in close collaboration with the stroke unit, under the responsibility of an experienced stroke neurologist/stroke physician. This stroke neurologist/stroke physician should have personal experience from thrombolysis treatment in stroke or must have passed the SITS educational programme. 29

30 Patients should never be included into SITS-MOST unless the level of care is at least semiintensive and the treatment is under the responsibility of an experienced stroke neurologist/stroke physician according to the definition in Section and Patients should be continuously or repeatedly monitored during the first 24 hours for changes of neurological symptoms, degree of consciousness, blood pressure, ECG, oxygen saturation and body temperature. 2.5 OUTCOME MEASURES Outcome will be evaluated for all patients included in SITS-MOST Primary safety outcome variables: - SICH within h after start of thrombolysis treatment - death within three months (mrs = 6) Secondary efficacy outcome variable: - mrs 0-2 at three months (independence) Further clinical variables of interest - NIHSS improvement 4 points at 2 hours, 24 hours, 7 days (or day of discharge) post treatment initiation - SICH occurring after 36 hours but within 7 days - asymptomatic intracerebral haemorrhage (AICH), intracranial haemorrhage (ICH), and cerebral oedema (COED) at CT follow up hours after thrombolysis treatment - any of the following events reported within the first seven days after treatment: death, SICH, AICH, major extracranial haemorrhage, recurrent ischaemic stroke - mrs score of 0 (cured) - mrs score of 0-1 (favourable outcome) - global effect classification at 2 hours, 24 hours, 7 days (or day of discharge) post treatment initiation - delays of management time from onset of symptoms start of treatment time from onset of symptoms arrival at hospital time from arrival at hospital start of treatment time from arrival at hospital - start of CT scan time from start of CT scan CT scan report time from CT scan report start of treatment - diffusion/perfusion deficit at baseline as predictor of outcome (if available) - correlation of reperfusion on MR/TCD and clinical improvement at 24h / 3 months (if 30

31 available) - outcome according to (2.1.a) included in agreement with entry criteria and with complete data entry - outcome according to (2.1.a) with adjustment for baseline prognostic variables - outcome according to (2.1.a) in previous ECASS centres with current use of thrombolysis in clinical routine, versus other centres - correlation between blood pressure and outcome - baseline characteristics of responders (improvement at 2h (NIHSS) / 24h (NIHSS)/ 7d (NIHSS) / 3 months (mrs)) - baseline characteristics of patients with SICH - baseline characteristics of non-responders (no improvement at 2h (NIHSS)/ - / 24h (NIHSS / 7d (NIHSS) / 3 months (mrs)) - incidence of intracerebral haemorrhage (symptomatic and asymptomatic) and haemorrhagic infarcts - outcome in Oxford Community Stroke Project (OCSP) classification stroke - subtypes - outcome in etiological subgroups (TOAST criteria) Procedure for evaluation of occurrence of symptomatic intracerebral haemorrhage Symptomatic intracerebral haemorrhage, SICH, is defined as 'Intracerebral haemorrhage (parenchymatous haemorrhage type 2, PH2), at the hours post-treatment scan combined with neurological deterioration leading to an increase of 4 points on the NIH Stroke Scale'. Parenchymatous haemorrhage type 2 is defined in The evaluation of haemorrhage will be done using the CT scan performed between hours after start of treatment. SICH is defined by the presence of PH2 when the NIHSS score has increased by 4 points from baseline or the lowest NIHSS value after baseline to 24 hours. In addition to SICH, the occurrence of PH2 among SITS patients compared to RCT:s will be evaluated Procedure for evaluation of mortality Eventually, evaluation of mortality should be done as a (preparative) part of the three months efficacy follow up. Each investigator, who receives information about the death of a patient should enter this information in the SITS-MOST register, so it can be found before the start of the follow-up procedure. If no such information is present, the follow up procedure should start with investigation of survival over official population registers (if available) or by contact with the investigator or other medical professional (e.g., general practitioner). Death within 90 days will be classified according to cause: ICH, PH, COED, COED + ICH, other cerebral death, undetermined cerebral cause of death, non-cerebral death or unknown cause of death Procedure for evaluation of independence/ modified Rankin scale

32 A modified Rankin score, mrs, of 0-2 is defined as functional independence (independence for activities of daily living). Evaluation of mrs will be performed 3 months after stroke onset, by telephone interview with the patient or carer, or by letter reply form. 2.6 Investigational procedures National Institute of Health Stroke Scale, NIHSS The NIH stroke scale, NIHSS, is described in Attachment 5.3 and at the SITS website The scores are entered in the on-line entry form. All SITS-MOST investigators must study the NIHSS educational video and pass the certification video Modified Rankin Scale, mrs The modified Rankin scale, mrs, is described in Attachment 5.4 and the questions to answer are specified at the on-line entry form Global Evaluation Scale, GES The Global Evaluation Scale, GES, is described in Attachment 5.5 and the questions to answer are specified at the on-line entry form Brain CT/MR scan (See also 2.5.3) All CT/MR scans are reviewed at the participating centre according to the local routine procedure and the outcome of the evaluation is entered in the database. External review CT/MR scans will be subjected to external review by the Brain Imaging Committee (BRIC) in case of a clinical deterioration defined as an increase of 4 points on the NIH stroke scale or death, and/or if the local centre identifies a parenchymatous haemorrhage type 2 (PH2; PHr2). If possible, CT/MR scans evaluated by the local centre will be submitted for review in digital format on CD-ROM. If this is not possible, these CT/MR scans will be digitalised centrally, and saved in the SITS imaging data base. In addition, the Steering Committee, in agreement with the Sponsor, can decide to review a random sample of CT/MR scans if source data monitoring raises concern about the quality of data entry. Baseline readings 32

33 The CTs will be evaluated with respect to haemorrhage, any decrease in x-ray attenuation indicating a major acute ischaemic injury in the symptomatic vascular territory, or other pathology. Preferably, CTA (CT angiography) imaging will be performed for identification of cerebral artery occlusion. Day 1 readings (22-36 hours after start of treatment) The CTs will be evaluated with respect to infarct size. Intracerebral haemorrhage, ICH, will be classified according to the following definitions : HI 1: small petechiae along the margins of the infarct HI 2: a more confluent petechiae within the infarct area but without space-occupying effect PH 1: blood clot(s) not exceeding 30% of the infarct area with some mild space-occupying effect PH 2: blood clots exceeding 30% of the infarct area with significant space occupying effect PHr 1: small or medium sized blood clots located remote from the actual infarct; a mild space occupying effect could be present PHr 2: large confluent dense blood clots in an area remote from the actual infarct; significant space occupying effect may be present Cerebral oedema, COED, will be classified according to the following criteria COED 1: Focal brain swelling up to one third of the hemisphere COED 2: Focal brain swelling greater than one third of the hemisphere COED 3: Brain swelling with midline shift If intracerebral haemorrhage and intracerebral oedema occur simultaneously, an estimation will be done of their relative contribution to the space-occupying process. If CTA has been performed at baseline, a follow up examination is preferred at day Brain MR scanning (optional) Brain MR scanning is optional. Participating centres may use diffusion- and perfusion weighted MR and MR-angiography to characterise the cerebrovascular lesion at baseline and at follow up. Further instructions are available at the on-line data entry form. MR imaging may replace CT imaging for evaluation of inclusion criteria and for follow up where appropriate. The imaging technology should be consistent between baseline reading and follow up Criteria for stopping treatment Each patient may terminate the study prematurely without giving any reason. If possible, the patient should discuss her/his decision with the investigator. The investigator may terminate the administration of study drug prematurely for any medical reason. Reason, date and clock time of termination have to be documented. The patients should be asked to participate in follow-up, in particular the final central telephone/letter follow up. If the patient categorically declines to participate in follow up, at least survival should be evaluated according to available 33

34 registers and any additional information be collected from general practitioner or other. Patient records for whom trial treatment or participation in the trial was terminated prematurely, will be included in the source data monitoring procedure as for other patient records. 2.7 PLANNED ANALYSES Primary and secondary outcome analyses The proportion of patients with primary and secondary outcome events, i.e., the incidence of SICH at the hour CT follow up, mortality and independence, will be compared with the corresponding proportions in the rt-pa arms of the relevant randomised controlled trials (0-3 hour cohorts) according to a systematic review of randomised controlled trials (RCT). The relevant proportions (and their 95% confidence intervals) are : Event (in RCT) Proportion 95% CI SICH 8.6% (40/465) Mortality 17.3% (83/479) Independence 50,1% (233/465) The corresponding proportions and their 95% confidence intervals will be determined for SITS-MOST : Event (in SITS-MOST) Proportion 95% CI SICH SITS(SICH) SITS(SICH) 95% CI Mortality SITS(MORT) SITS(MORT) 95% CI Independence SITS(INDEP) SITS(INDEP) 95% CI Figure 1a and 2a (page 9) show the number of patients required to ascertain that the upper confidence limit of the point estimate of SICH and death is below the corresponding upper confidence limit in the systematic review. Figure 3a shows the corresponding figure for independence with regard to lower confidence limits. Figure 1b, 2b and 3b (page 9) show the number of patients required to exclude worsening of safety and efficacy, i.e., to exclude that an observed difference in events between SITS- MOST and RCT, and its 95% CI is greater than 0 (for SICH and death) or lower than 0 (for independence). It should be noted that such statistical bounds are not necessarily identical with the clinical thresholds around which the benefit/risk ratio is expected to fall one side or the other. 34

35 Hence, these statistical bounds cannot be the only basis of the decision rules, especially given the nature of the historical comparison. Therefore also all relevant descriptive statistics for the safety and efficacy measures, along with their respective 95% confidence intervals will be presented taken into account. Furthermore it should be noted that conclusions about outcomes are difficult to draw unless at least 1000 patients have been included in the study Further evaluations of interest Will be performed according to

36 2.8 SCHEDULE OF STUDY PROCEDURES An overview of the schedule of study procedures is shown on page 18. Visit 1A, Day 1, baseline: The following procedures are included in visit 1A: Informed consent Inclusion and exclusion criteria Inclusion procedure Demographic and baseline data Medical history Concomitant diagnoses Previous treatment CT scan / MR scan NIHSS Visit 1B, Day 1, treatment: Treatment delay documentation Administration of alteplase Concomitant treatment BP measured at end of treatment Visit 1C, Day 1, 2 h after treatment initiation NIHSS Adverse drug reaction recording Visit 2, 24 hours after treatment initiation CT scan (with a time window of hours) NIHSS Concomitant treatment Adverse drug reaction recording Visit 3, 7 days after treatment initiation (or upon discharge from stroke unit) (CT, optional, only needed if clinical worsening) NIHSS Concomitant treatment Adverse drug reaction recording 36

37 Visit 4, 90 days after treatment initiation, final follow up mrs 2.9 Patient identification and monitoring of source data Patient identification Within SITS-MOST, patients are identified through two different procedures, which may vary between participating countries. 1) Date of birth (and if available personal ID number) and full name (family and first): This alternative is preferable if in agreement with data integrity regulations. Data entry in SITS meets high data integrity safety requirements with encrypted data entry and appropriate log-in procedure. 2) SITS-generated code number, based on date of initial data entry, centre and number of patients treated in a centre a specific day The local investigator must enter this code number into the patient s hospital record, and save a list of code numbers with corresponding patient identities (so that source data may be retrieved) Source data monitoring Sample source data monitoring (SDM) within SITS-MOST will be organised by the National Coordinator in each country, together with the assistance of monitoring support provided by the sponsor. It is emphasised that a particular level of SDM, unusual for a post-marketing surveillance trial, has been agreed with the EU authority. Source data monitoring, - Will occur in at least 10% of the patients entered in SITS-MOST. The allocation to source data monitoring will be made centrally by SITS. As far as possible, all centres in SITS- MOST will be visited at least once during the study period. - Should be agreed with the local coordinator at least 14 days before the visit - The local coordinator must open the local centre s list of patients appointed for monitoring at the SITS website so the monitor can follow the data entered there and compare with the hospital files - patient s identity on the list and the hospital record - a note in the hospital file that the patient was included in SITS-MOST and (if appropriate) the ID code - date of thrombolysis treatment and the dose given - exact time of stroke onset and of start of treatment - Global Evaluation Score in SITS database with comment in hospital discharge note or hospital note at 7 days - Reports on imaging studies performed within h after thrombolysis, and, if 37

38 available, for scans performed later during the first week after onset of stroke - the Monitor will make a report on line, according to a procedure set up within the registry - If the Monitor s report includes notes of disagreement between SITS data base and the hospital records, the National Coordinator and the Steering Committee will be informed as appropriate. - Monitoring will also occur, in agreement with the National Co-ordinator should the automatic data QA checks suggest evidence of error, omission or non-compliance with the protocol Centre eligibility Previous ECASS centres have all participated in trial related education on various aspects of thrombolysis management in stroke. Those which also continued to use thrombolysis in clinical routine form a specific category of SITS-MOST centres with solid experience from the procedure. Since future thrombolysis treatment of stroke cannot rely on the comparatively few ECASS centres, it is expected and requested that centres with less previous experience now also join SITS-MOST. The National Coordinator will accept participation of a centre according to the principles in and General requirements for SITS-MOST centres - the centre must have solid experience from acute stroke treatment and have a direct link with the hospital s emergency unit (the doctor on call at the emergency unit must have the authority to initiate thrombolysis acute management, or must have immediate access to a colleague with this authority) - the centre must have a stroke unit, i.e., a ward specialised in acute stroke management, which is under the medical responsibility of a stroke profiled and stroke experienced neurologist or physician, leading a multidisciplinary team including a trained stroke nurse and usually also consisting of physiotherapist, occupational therapist, speach therapist, social worker and a neuropsychologist - during thrombolysis and the first day after admission, patients must be admitted to semiintensive or intensive care (preferably but not necessarily within the stroke unit), i.e., constant nurse in the room during procedures, qualified to monitor level of consciousness and neurological impairment, and monitoring equipment for blood pressure, pulse rate, ECG, oxygen saturation and body temperature - the rehabilitation team must have a policy of early evaluation/intervention, including the first day, and the patient must be admitted to the standard stroke care level after the first day (if necessary) - the SITS-MOST investigators (= owners of SITS access codes) and radiologists (= responsible for evaluation of CT scan) must have participated in an educational programme for thrombolysis in stroke and for the SITS-MOST protocol (more extensive for new centres than for active ECASS centres) 38

39 Previous ECASS centres with current rt-pa protocols ( Active ECASS centres ) To qualify for the category of Active ECASS centre the centre should have participated in ECASS I or II and thereafter established thrombolysis treatment as a clinical routine method. A hospital protocol for stroke thrombolysis must exist and patients must have been treated with thrombolysis during year Other centres ( New thrombolysis centres ) These centres should meet the general requirements according to Investigators should be participating in the extended educational programme (Appendix 5.8) Investigators and local users All the following investigators and local users will receive an access code for data entry in SITS-MOST. All must have participated in the SITS-MOST educational programme (Appendix 5.8) or educational material available on the SITS website. Local coordinator The overall responsibility for inclusion of patients, data entry, and compliance with the study protocol relies with the Local Coordinator. The Local Coordinator must be a stroke neurologist or stroke physician with solid stroke experience. Local user The local user is appointed by the Local Coordinator to enter data in SITS-MOST 2.11 Administrative and ethical matters The trial will be carried out in compliance with the protocol, the principles laid down in the Declaration of Helsinki (version 1996), in accordance with the ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP) and in accordance with applicable regulatory requirements Regulating authorities, Institutional Review Boards or Independent Ethics Committees Since SITS-MOST is a monitoring study of a treatment approved for routine use approval of the study protocol by ethics committees is not unconditionally required. In case such evaluation will be required in some of the member countries, the following text under and will apply. All patients in the study must consent that their data be included in the data base, and that study staff is authorised to contact them or their carers for follow up. 39

40 The trial will not be initiated before the protocol and informed consent and subject information form have been reviewed and received approval / favourable opinion from regulating authorities, the local Institutional Review Board (IRB) or an Independent Ethics Committee (IEC). Should a protocol amendment be made that needs IRB / IEC approval, the changes in the protocol will not be instituted until the amendment and revised informed consent (if appropriate) has been reviewed and received approval / favourable opinion from the local IRB or IEC. A protocol amendment intended to eliminate an apparent immediate hazard to subjects may be implemented immediately providing that the appropriate regulatory authorities and IRB / EC are notified as soon as possible and an approval is requested. Protocol amendments only for logistical or administrative changes may be implemented immediately; the IRB /IEC needs to be informed only. It should be noted that PMS may need either EC approval or only notification, according to local requirements. The constitution of the IRB or IEC must meet the requirements of the participating countries. A list of the IRB / IEC members, with names and qualifications, will be requested. If such a list is unavailable, the investigator must provide the name and address of the IRB/IEC along with a statement from the IRB/IEC that it is organised according to GCP and the applicable laws and regulations. The IRB or IEC must also perform all duties outlined by the requirements of the participating country(ies). For studies conducted under a US IND, the requirements outlined in the US Code of Federal Regulations must also be met. National regulatory approval may/may not be required for SITS-MOST depending on health authority requirements. This should be ascertained for each member state Informed Consent and Subject Information Prior to subject participation in the trial, written or oral informed consent will be obtained from each subject (or the subject s legally accepted representative) according to the regulatory and legal requirements of the participating country. The procedure is further detailed under If written consent is used, each signature must be dated by each signatory and the informed consent and any additional subject information form retained by the investigator as part of the study records. A signed copy of the informed consent and any additional subject information must be given to each subject or the subject s legally authorised representative. The subject must be informed that his / her medical records may be examined by authorised monitors or by appropriate IEC / IRB members and by inspectors from regulatory authorities. Should a protocol amendment be made, the subject consent form and subject information form may need to be revised to reflect the changes to the protocol. It is the responsibility of the investigator to ensure that an amended consent form is reviewed and received approval / favourable opinion from the IRB or IEC, and that it is signed by all subjects subsequently entered in the trial and those currently in the trial, if affected by the amendment Safety evaluation A continuous safety monitoring (using confidence graphs for all safety endpoints) will be done by the ICO. 40

41 In case that any observed rate of serious drug related (as rated by the investigator) events like PH, symptomatic ICH or death will reach an incidence which is significantly different from what can be expected from the NINDS study or from the meta-analysis on all rt-pa trials in the 0-3 hrs cohort (i.e. the incidence is outside the 95% confidence interval calculated from those trials) the Steering Committee will carefully evaluate the data and make a recommendation. A regular evaluation of safety outcomes will be done every six months by the Steering Committee. This will include the proportion of patients with adverse events, especially SICH and death, and their 95% confidence intervals. A written report will be issued by the Steering Committee and will be made available to Boehringer-Ingelheim. Other data from SITS-MOST will be made available for Boehringer-Ingelheim for regulatory purposes, as decided by the Steering Committee. All serious expected and unexpected adverse drug reactions will be reported to the respective regulatory authorities according to established regulatory requirement, i.e. on an expedited basis. An adverse event is considered to be an adverse drug reaction (ADR) if there is a reasonable causal relationship between administration of the drug and the event and if for marketed medical products there is a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylactics, diagnosis, or therapy of disease or for the modification of physiological function. The reaction could be associated with the rt- PA treatment if it occurs during the treatment and in the posttreatment period when the patient is hospitalised. Events which are believed not reasonably related to the drug administration will not be reported. Serious adverse drug reactions must be reported immediately to the local BI Monitor/Clinical Safety Officer. Any non-serious adverse events occurring concomitantly with the serious ADR are to be reported on the same form. Serious adverse drug reactions will be reported by the physician using the BI Serious Adverse Event Report form for Clinical Trials (See attachment 5.9), which will be available by PDF file from the Case Record Form website or from BI Monitors. The BI Corporate Medicine Standard Operating Procedures for the reporting of Adverse Events in Clinical Trials will apply for the expedited reporting of serious adverse reactions in SITS-MOST. A copy is available for inspection by National Co-ordinators from the BI Monitors. Non-serious adverse reactions will be collected for reporting purposes to local authorities and EMEA. The information of these non-serious adverse drug reactions will be entered directly in the SITS-MOST registry by the physician. The reactions are thus reported on a continuous basis but revealed to the authorities in the end of the study. Responsibility of the sponsor and of the physician: The sponsor takes the responsibility to inform the authorities of all serious adverse drug reactions reported to the SITS-MOST registry on an ongoing basis in accordance to the regulations. Moreover will the sponsor collect information of all non-serious adverse drug reactions occurring in the study and report these to the authorities in the end of the study. The obligation of the physician to report all the ADR is thus taken over by the sponsor. Data regarding adverse drug reactions and other safety data (e.g. SICH) will be transferred monthly to the sponsor, whereby a separate BI study database with the non-serious adverse drug reactions is not required. 41

42 Definitions; An Adverse event (AE) is any untoward medical occurrence, including an exacerbation of a preexisting condition in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event is serious if it result in death is immediately life-threatening results in persistant or significant disability/incapacity requires or prolongs patient hospitalisation is a congenital anomality/birth defect is considered as serious, when based upon appropriate medical judgement they may jeopardise the patient and may require medical or surgical intervention to prevent one of the other seriousness criteria from occurring. 42

43 Drug accountability Since this is a non-randomised study of the efficacy and safety of clinical routine use of thrombolysis, no specific study drug will be administered. Drugs are provided and managed according to the usual hospital routine Data entry All data will be entered on-line through the SITS website. A paper version of the entry form will be provided if necessary. The data item names used in the registry are shown in Attachment 5.7. Each investigator/study nurse will receive a personal access code which must be kept secret and used only by the owner. All data entry from a centre can be made by each member of the local team, but once the data entry is confirmed (i.e., can not be changed), the person who made the confirmation will be identified on the data entry form Database Ownership and Data Transfer The SITS-MOST patient data will be owned jointly by the SITS-ISTR Registry and by Boehringer Ingelheim. The database will be located and under the control of the SITS-MOST Coordinators and the Steering Committee. However, Boehringer Ingelheim as study sponsor has a legal obligation to provide specific analyses and reports to the regulatory authorities including responses to ad hoc or post hoc questions arising from the presentation of data. Data transfer to the Boehringer Ingelheim alteplase project database will occur on a regular fourweekly basis Financing The financing of SITS-MOST will be an obligation for Boehringer-Ingelheim (BI) according to a contractual agreement between BI and SITS. This is not described in this protocol Insurance There is no study-specific insurance since alteplase is given within an approved indication (PMS-observational study), according to the Summary of Product Characteristics for Actilyse. Patients who receive rt-pa treatment outside the product-specific labelling applying to this protocol and who sustain a serious adverse reaction are not indemnified STUDY TERMINATION, CONFIDENTIALITY AND PUBLICATION POLICY Study termination 43

44 The Steering Committee will terminate the trial if one of the following conditions applies: - safety reasons according to decision by regulatory authority/ethics committee Statement of confidentiality Individual subject medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited with the exceptions noted below. Subject confidentiality will be further ensured by utilising subject identification code numbers to correspond to treatment data in the computer files. Such medical information may be given to the subject s personal physician or to other appropriate medical personnel responsible for the subject s welfare. Data generated as a result of this trial are to be available for inspection on request by the participating physicians, the sponsor s representatives, by the IRB or IEC and the regulatory health authorities. All results, including primary and secondary outcomes for own centre, own country and all countries, will be available for users of SITS as continuously updated reports. These reports are only for internal use within SITS. All external oral or written reports must be approved by the Steering Committee according to the publication policy (Section ). Confidential safety reports will be written jointly with the sponsor for the European regulatory authority based upon the agreed 6-monthly analyses of the SITS-MOST database, coinciding with the sponsor s obligations to provide the Authority with regular Periodic Safety Update Reports Publication policy Manuscripts based on the results of the study will be submitted to a peer-reviewed medical journal. The steering committee will appoint a writing committee who will publish the manuscripts in the name of all investigators. A list of all investigators will be included in the original manuscript. The policy for secondary manuscripts will be decided by the Steering Committee. Boehringer Ingelheim will be allowed review and comment on all manuscripts arising from SITS-MOST prior to publication but in all respects encourages the publication of data from the study. 44

45 3. References 1 WHO Task Force. Stroke Recommendations on stroke prevention, diagnosis and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders. Stroke 1989; 20 (10): Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifyable subtypes of cerebral infarction. Lancet 1991; Wahlgren NG. Introduction to Stroke Update. In Wahlgren NG, ed. update on Stroke Therapy , Karolinska Stroke Update, Stockholm, 2001, Lees KR. Update on Neuroprotection. In: Wahlgren NG, ed. update on Stroke Therapy , Karolinska Stroke Update, Stockholm, 2001, International Stroke Trialists Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among patients with acute ischaemic stroke. Lancet : CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebocontrolled trial of early aspirin use in patients with acute ischaemic stroke 7 Sever PS, Mackay JA. The hypertension trials. J Hypertens 1995; 14: S Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B, Davies R, Östergren J, Probstfield J. Use of ramipril in preventing stroke: double blind randomised trial. BMJ Mar 23;324(7339): Amarenco P. Hypercholesterolaemia, lipid lowering agents and the risk of brain infarction. In: Wahlgren NG, ed. update on Stroke Therapy , Karolinska Stroke Update, Stockholm, 2001, Antithrombotic Trialists Collaboration. Prevention of death, myocardial infarction and stroke by antiplatelet therapy: Collaborative meta-analysis of 266 trials involving patients at risk of occlusive vascular events. 11 Diener HC, Cunha L, Forbes C, Sivenius j, Smets P, Lowenthal A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: CAPRIE Steering Committee. A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342: Johansson BB. Can we enhance relearning after stroke? In: Wahlgren NG, von Arbin M, eds. Update on Stroke Therapy , Karolinska Stroke Update, Stockholm, 1999, Hossman KA. Pathophysiology of cerebral infarction. In: Wilken PJ, Bruyn GW, Klawans HL, eds.handbook of Clinical Neurology, Vol 53. Amsterdam, Elsevier Science Publishers 1988, Wardlow J. Updated systematic review of randomised trials of rt-pa in acute stroke. In: Wahlgren NG, ed. update on Stroke Therapy , Karolinska Stroke Update, Stockholm, 2001, Wardlow, del Zoppo G, Yamahuchi T. Thrombolytic therapy in acute ischaemic stroke. Part 1. Thrombolysis versus control. In : Warlow C, Van Gijn J, Sandercock P, eds. Stroke module of the Cochrane database of Systematic Reviews. The cochrane Collaboration; Issue 4. Oxford: Update Software, Mori E, Yoneda Y, Tabuchi M, et al. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology 1992; 42: Haley EC, Brott TG, Sheppard GL, et al. Pilot Randomized Trial of Tissue Plasminogen Activator in Acute Iscemic Stroke. Stroke 1993; 24: Yamaguchi T, Hayakawa T, Kiuchi H, Japanese Thrombolysis Study Group. Intravenous Tissue Plasminogen Activator Ameliorates the Outcome of Hyperacute Embolic Stroke. Cerebrovasc Dis 1993; 3: European Cooperative Acute Stroke Study (ECASS): Intravenous thrombolysis with 45

46 recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995;274: The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group: Tissue Plasminogen Activator for Acute Ischaemic Stroke. The New Engl J Med 1995;333: Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P, for the Second European- Australasian Acute Stroke Study Investigators: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998;352: Clark WM, Wissman S, Albers GW, et al, for the ATLANTIS Study investigators: Recombinant tissue-type plasminogen activator (Alteplase) for ischaemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomised controlled trial. JAMA 1999;282: Clark WM, Albers GW, Madden KP, Hamilton S, for the Thrombolytic Therapy in Acute Ischaemic Stroke Study Investigators: The rrt-pa (Alteplase) 0- to 6- hour Acute Stroke Trial, Part A (A027g). Results of a double-blind, placebo-controlled, multicentre study. Stroke 2000;31: Wardlaw J. Personal information 27 Chiu D, Krieger D, Villar-Cordova C, Kasner SE, Morgenstern LB, Bratina PL, Yatsu FM, Grotta JC. Intravenous tissue plasminogen activator for acute ischemic stroke. Feasibility, Safety and efficacy in the first year of clinical practice. Stroke. 1998;29: Trouillas P, Nighoghossian N, Derex L, Adeleine P, Honnorat J, Neuschwander P, Riche G, Getenet JC, Li W, Froment JC, Turjman F, Malicier D, Fournier G, Gabry AL, Ledoux X, Berthezène Y, Ffrench P, Dechavanne M. Thrombolysis with intravenous rtpa in a series of 100 cases of acute carotid territory stroke. Determination of etiological, topographic, and radiological outcome factors. Stroke 1998;29: Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL, Hinchey JA, Hammel JP, Qu A, Sila CA. Use of tissue-type plasminogen activator for acute ischemic stroke. The Cleveland experience. JAMA 2000;283: Schmülling S, Grond M, Rudolf J, Heiss WD. One-year follow-up in acute stroke patients treated with rtpa in clinical routine. Stroke 2000;31: Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke. The standard treatment with alteplase to reverse stroke (STARS) study. JAMA 2000;283: Tanne D, Demchuk A., Kasner SE, Grond M, Hanson S, Hamilton S, Buchan AM, Wang DZ, Wechsler LR, Zweifler R, Levine SR, for the t-pa in acute stroke collaborators. A large multinational investigation to predict t-pa related symptomatic ICH in patients with acute ischemic stroke.stroke 30, 248, Grond M. Systematic review of post-trial experiences. In: Wahlgren NG, ed. update on Stroke Therapy , Karolinska Stroke Update, Stockholm, 2001, Kaste M, Thomassen L, Grond M, Hacke W, Holtås S, Lindley R, Roine R, Wahlgren NG, Wardlow J, for the Karolinska Stroke Update Consensus Group: Thrombolysis Karolinska Stroke Update Consensus Statement In Wahlgren NG, ed., Karolinska Stroke Update 2000/2001, Kaste M, Thomassen L, Grond M, Hacke W, Holtås S, Lindley R, Roine R, Wahlgren NG, Wardlow J, for the Karolinska Stroke Update Consensus Group: Thrombolysis Karolinska Stroke Update Consensus Statement Stroke 35 Lindley R. Thrombolytic therapy in acute stroke: Controversies and unresolved issues. In: In: Wahlgren NG, ed. update on Stroke Therapy , Karolinska Stroke Update, Stockholm, 2001, Schellinger, PD, Fiebach JB, Mohr A, Ringleb PA, Jensen O, Hacke W. Thrombolytic therapy for ischemic stroke- a review. Part I Intravenous thrombolysis. Crit Care Med 2001, 29:

47 4. Signature page On behalf of the SITS Steering Committee: Name date Nils G Wahlgren, M.D. Ph.D. Organisation/Department On behalf of the sponsor: Department of Neurology Karolinska Hospital S Stockholm Sweden Phone Fax Team Member Medicine: Name Organisation/Department date Michael Humphreys MB ChB FFPM Boehringer Ingelheim Limited Ellesfield Avenue Bracknell Berkshire, RG 12 7 RR, UK Phone Fax Trial Statistician: Name date Erich Bluhmki, PhD Organisation/Department BI Pharma GmbH & Co. KG Medical Data Services Birkendorfer Strasse 65 D Biberach an der Riss Germany Phone Fax

48 5 Attachments 5.1 Karolinska Stroke Update Consensus statement on Thrombolysis, October Patient information and Informed Consent Form 5.3 NIHSS 5.4 Rankin Scale 5.5 Global Evaluation Scale 5.6 Statistical considerations 5.7 Data Entry Form 5.8 Educational programme outline 5.9 Boehringer Ingelheim Serious Adverse Event Report Form for Clinical Trials (to be used for reporting Serious Adverse Reactions in SITS- MOST) 48

49 5.1 Karolinska Stroke Update Consensus statement on Thrombolysis This consensus statement was proposed by the chairpersons, Professor Markku Kaste, Helsinki, Finland and Dr Lars Thomassen, Bergen, Norway together with the speakers in this session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations. The speakers in this session were Professor Werner Hacke, Heidelberg, Germany, Dr Joanna Wardlow, Edinburgh, United Kingdom, Dr Martin Grond, Cologne, Germany, Professor Stig Holtås, Lund, Sweden, Associate Professor Nils Gunnar Wahlgren, Stockholm, Sweden, Dr Risto Roine, Helsinki, Finland and Dr Richard Lindley, Edinburgh, United Kingdom 1 Intravenous rt-pa within 3 hours after the onset of symptoms in patients with acute ischaemic stroke is a highly effective evidence-based treatment (grade A evidence). The use of rt-pa is supported by results from randomised controlled trials and metaanalyses. The risk of early fatal and symptomatic intracerebral haemorrhage is increased, but these hazards are offset by reduction in the proportion of patients being dead or dependent. According to meta-analyses, for patients given rt-pa within 3 hours of ischaemic stroke approximately 1 out of 10 more will be independent, 1 of 14 will suffer symptomatic haemorrhage and 1 in 100 fewer may die as a result of the treatment (grade A evidence). Overall, the net benefit of rt-pa given within 3 hours of onset will result in one more independent survivor for every 10 patients treated Intravenous rt-pa within 6 hours after the onset of an ischaemic stroke seems to be beneficial, but the benefit is smaller while the risks are higher. The use of rt-pa up to 6 hours is supported by the results of meta-analyses (grade B evidence). 3 The therapeutic use of intravenous rt-pa is recommended within 3 hours in selected patients in acute ischaemic stroke (grade A evidence), but may also be beneficial up to 6 hours (grade B evidence) and possibly even longer in certain subgroups of stroke patients such as basilar artery occlusion (grade C evidence). 4 Outside randomised controlled trials, the therapeutic use of intravenous rt-pa must be subject to continuous quality control. It is recommended that the use of intravenous rt- PA follows the recommendations of published guidelines, with local modifications as appropriate. In most open studies the safety and efficacy of intravenous rt-pa in routine clinical practice is comparable to randomised studies. However, there is an obvious need for continuous education and for trained local stroke specialists to be responsible for a safe stroke thrombolysis service. 5 The evidence strongly supports that rt-pa is made available for routine clinical use to treat stroke patients in adequately qualified centres. The development of hospital services designed to deliver early thrombolysis 24 hours a day for acute ischaemic stroke is encouraged. Continuous auditing of the routine use of thrombolytic therapy in stroke is advisable. For example, the International Stroke Thrombolysis Register (SITS) is an on-line monitoring system designed for auditing safety and efficacy of routine therapeutic use of rt-pa in acute ischaemic stroke, and could be used for such a purpose. 49

50 6 The heterogeneity for good outcome in meta-analyses implies that more data are needed on how to identify the patients most likely to benefit and least likely to be harmed by thrombolysis. The role of patient characteristics including age, sex, stroke severity, stroke subtype, concomitant disease, drug treatments, strategies for blood pressure control, prior antiplatelet therapy and antiplatelet and anticoagulation therapy after thrombolysis should be further evaluated in future trials, meta-analyses, phase IV studies and SITS. 7 It is recommended that future trials of safety and efficacy of thrombolysis should assess modern imaging techniques as a part of the protocol to help in patient selection and in monitoring of the effects of therapy. For example, MR diffusion and perfusion weighted imaging may reveal in individual patients brain tissue at risk but salvageable with thrombolysis within a 3 hour time window and possibly even longer (grade C evidence). Other imaging modalities including perfusion CT, MR angiography, SPECT and TCD may also help in selecting patients, in verifying recanalization of the occluded artery and in detecting change of infarct size (grade C evidence). 8 It is strongly recommended that one of the main targets in future randomised trials should be to try to extend the time window beyond 3 hours after stroke onset as this would increase the proportion of patients who may benefit from therapy. This would have an important public health impact in Europe. It is also recommended that new thrombolytic agents, and thrombolysis together with neuroprotective agents, should be evaluated in future randomised trials to try to increase the effectiveness and to decrease the risks involved in thrombolysis. 9 Future studies should include collection of data to allow the assessment of the impact on health economics and on quality of life of rt-pa in acute is haemic stroke. The public should be educated of the value of early expert assessment and treatment. 50

51 5.2 Patient information and Informed Consent Form applies only if Ethics Committee approval is required within a member country and if written informed consent is requested. Otherwise consent/assent rules in apply Patient information: Invitation to participate in a clinical study of alteplase, a treatment to dissolve blood clots in acute stroke (this text can be modified in agreement with local ethics committees) Your doctor and the medical staff have concluded that your symptoms are caused by a blood clot occluding one of the arteries in the brain and that this may result in a disabling stroke unless the blood circulation in the brain is restored. Alteplase is a treatment which is routinely used after heart attacks. It has also proven effective in acute stroke, in particular if treatment is started within 3 hours after onset of symptoms. Alteplase dissolves blood clots, and by using this effect in acute stroke, the blood circulation can be restored for many patients. Treatment is approved by regulating authorities within the European Union, on the condition that treatment safety is monitored within the present study protocol. Alteplase does not always cause blood clots to dissolve, because they vary in size and composition. Alteplase treatment can cause bleeding in the brain, which sometimes can be serious and result in clinical deterioration. Nevertheless, alteplase is a highly efficient treatment, and may cause symptom relief or substantial improvement during treatment or in the hours after. In randomised controlled trials, the net benefit of the treatment was 10 more patients independent in their daily life activities of 100 patients treated, compared to those who did not receive active treatment. Of those 100 patients seven more patients experienced symptomatic intracerebral haemorrhage. To increase treatment benefit and to reduce risks, treatment should start as soon as possible after stroke onset. Treatment is given via a drip into a vein over one hour. You will be closely looked after during the first 24 hours, but otherwise treated in exactly the same way stroke patients are taken care of if they have not received alteplase. In addition to the brain scan performed at you arrival, a follow up brain scan will be done between 22 and 36 hours after treatment. This study, SITS Monitoring study, is of active treatment only. There is no control treatment. Studies with placebo control have already shown that alteplase is effective. The purpose of this study is to evaluate if treatment is as effective when given as routine treatment. You may decline to participate in this study. If you decide to do so, you will receive the standard treatment given to stroke patients at your hospital. If you accept to participate in the study, you have the right to withdraw your participation at any time. If you withdraw, your existing data will remain in the register. If you are willing, then you recovery will also still be recorded. For this purpose, a member of our team will see you or call you after about three months. Data about your stroke, your treatment and the treatment effect will be saved in a database 51

52 and the information will be entered over internet in a way that will not disclose your identity to anyone outside the study, except for auditing by authorities. The data may be treated statistically and reported in scientific publications, but your identity will not be revealed. Consent form: I have received written and oral information about the SITS-MOST study and I accept to participate. I also accept that my hospital record may be reviewed by study members outside of my hospital and by authorities for assessment of the study quality. Place and date: Patient signature: Alternative, witnessed oral consent if patient is unable to write: I have witnessed (patient name) give oral consent to participate in the SITS-MOST study and for study members outside of this hospital or authorities to review the hospital record for assessment of the study quality. Place and date: Witness: Alternative, relative s or carers consent, if patient is unable to communicate: I have received written and oral information about the SITS-MOST study and I believe that (patient name) would accept to participate if he/she would have been able to communicate. I also believe that he/she would accept that the hospital record may be reviewed by study members outside of this hospital and by authorities for assessment of the study quality. Place and date: Relative or carer (indicate which): 52

53 5.3 National Institute of Health Stroke Score, NIHSS 1a.Level of consciousness 1b. Ask patient the month and their age 1c.Ask patient to open/close eyes and form/release fist 2.Best gaze (only horisontal eye movements) 3. Visual field testing 4. Facial paresis (Ask patient to show teeth or raise eyebrows and close eyes tightly) 3 5a.Motor function - right arm 5b. Motor Function - left arm 6a. Motor Function - right leg 6b. Motor Function left leg 7. Limb ataxia 8. Sensory (use pinprick to test arms, legs trunk and face, compare side to side) 9. Best language (describe picture, name items) 10. Dysarthria (read several words) 0 Alert 1 Not alert, but arousable with minimal stimulation 2 Not alert, requires repeated stimulation to attend 3 Coma 0 Answers both correctly 1 Answers one correctly 2 Both incorrect 0 Obeys both correctly 1 Obeyrs one correctly 2 Both incorrect 0 Normal 1 Partial gaze palsy 2 Forced gaze deviation 0 No visual field loss 1 Partial hemianopia 2 Complete hemianopia 3 Bilateral hemianopia (blind, incl. Cortical blindness) 0 Normal symmetrical movement 1 Minor paralysis (flattened nasolabial fold, asymmetry on smiling), asymmetriskt leende) 2 Partial paralysis (total or near total paralysis of lower face) Complete paralysis of one or both sides (abscence of facial movement in the upper and lower face) 0 Normal (extends arm 90º or 45º for 10 sec without drift) 1 Drift 2 Some effort against gravity 3 No effort against gravity 4 No movement 9 Untestable (joint fused or limb amputated) 0 Normal (extends arm 90º or 45º for 10 sec without drift) 1 Drift 2 Some effort against gravity 3 No effort against gravity 4 No movement 9 Untestable (joint fused or limb amputated) 0 Normal (holds leg in 30º position for 5 sec without drift) 1 Drift 2 Some effort against gravity 3 No effort against gravity 4 No movement 9 Untestable (joint fused or limb amputated) 0 Normal (holds leg in 30º position for 5 sec without drift) 1 Drift 2 Some effort against gravity 3 No effort against gravity 4 No movement 9 Untestable (joint fused or limb amputated) 0 No ataxia 1 Present in one limb 2 Present in two limbs 0 Normal 1 Mild to moderate decrease in sensation 2 Severe to total sensory loss 0 No aphasia 1 Mild to moderate aphasia 2 Severe aphasia 3 Mute 0 Normal articulation 1 Mild to moderate slurring of words 2 Near unintelligible or unable to speak 9 Intubated or other physical barrier 0 Normal 1 Inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities 11. Extinction and inattention (use visual double stimulation or sensory double stimulation) 2 Severe hemi-inattention or hemi-inattention to more than one modality 53

54 5.4 Modified Rankin Scale, mrs Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend own bodily needs without assistance 5 Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6 Dead Total (0-6): 54

55 5.5 Global evaluation scale, GES Has a change in the patient s clinical condition occurred after treatment? Check one alternative: Much better +2 Better +1 Unchanged 0 Worse -1 Much worse -2 Dead -3 55

56 5.6 Statistical considerations Accepting historical comparisons, the numbers of patients required in SITS-MOST to verify that the proportions of SICH, death and independence is equal or better than in RCT are shown in Figures 1a, 2a and 3a on page This outcome if present if the 95% confidence interval of the SITS proportions are lower than the upper confidence limit for SICH and mortality and higher than the lower confidence interval for independence. An alternative outcome evaluation is to exclude that the proportion of events in SITS-MOST is worse than in RCTs. This evaluation will be performed if the analysis in thre previous paragraph fails to prove at least equality. The numbers of patients required in SITS-MOST for this purpose is shown in Figures 1b, 2b and 3b on page Exclusion of worsening of SICH, mortality and independence compared to RCT (and evidence of improvement) The number of patients required to exclude that the proportions of SICH, mortality and independence is worse than in RCT is illustrated in Figures 1b, 2b and 3b on page The numbers of patients required to prove an inprovement compared to RCT are shown in Figures 4-6 on page 12. An experimental / explorative hypothesis of worsening of the outcome variables in SITS- MOST compared to RCT will be tested as follows. Different levels of worsening can be analysed. As examples, 4% higher proportion of SICH, 5% higher mortality and 6% lower proportion of independent patients are calculated below. Analyses of improvements of the SITS results compared to RCT:s will be performed using the same method. To provide a statistically significant difference between these proportions (of 4%, 5% and 6%, respectively) in SITS and RCT, the 95% confidence interval (CI) of the difference must exclude the value of 0. The Standard Error for the difference in proportions is SE (Diff) = (((RCT(100-RCT))/N(RCT)) + ((SITS(100-SITS))/N(SITS))) Or, using the known RCT data SE (Diff) = ((SITS(100-SITS))/N(SITS))) (for SICH) SE (Diff) = ((SITS(100-SITS))/N(SITS))) (for Mortality) SE (Diff) = ((SITS(100-SITS))/N(SITS))) (for Independence) The 95% CI for the difference is then 95% CI = ±1.96 * ((SITS(100-SITS))/N(SITS))) (for SICH) 95% CI = ±1.96 * ((SITS(100-SITS))/N(SITS))) (for Mortality) 56

57 95% CI = ±1.96 * ((SITS(100-SITS))/N(SITS))) (for Independence) To exclude the value of 0, the observed difference (any increase of the proportions of SICH and mortality or lowering of the proportion of independence, in SITS_MOST compared to RCT) minus the lower part of the 95% CI must exceed 0, i.e. DIFF (SICH, SITS-RCT) * ((SITS(100-SITS))/N(SITS))) > 0 DIFF (Mortality, SITS-RCT) * ((SITS(100-SITS))/N(SITS))) > 0 DIFF (Independence, SITS-RCT) * ((SITS(100-SITS))/N(SITS))) > 0 The absolute minimum of patients with this method to prove worsening of SICH, mortality and independence under the exemplified conditions are 447, 494 and 620, respectively. With a SITS sample size of 1000, the differences in proportions, and the 95% CI:s between SITS and RCT could be outlined as follows: for SICH: Proportions of symptomatic haemorrhage per 100 patients treated and 95% confidence intervals (CI) RCT (true) SITS (hypothetical) Difference SITS RCT Proportion 95% CI Proportion 95% CI Proportion 95% CI * n (RCT) = 465; n (SITS) = 1000 the 95% confidence interval for a 4% difference in proportions with a SITS sample size of 1000 excludes the value of 0 (no difference), meaning that a 4% higher proportion of symptomatic haemorrhage is detectable with a sample size of 1000 for mortality: Mortality per 100 patients treated and 95% confidence intervals (CI) RCT (true) SITS (hypothetical) Difference SITS RCT Proportion 95% CI Proportion 95% CI Proportion 95% CI * n (RCT) = 465; n (SITS) = 1000 the 95% confidence interval for a 5% difference in mortality with a SITS sample size of 1000 excludes the value of 0 (no difference), meaning that a 5% lower mortality is detectable with a sample size of

58 for independence: Proportions of independent patients per 100 treated and 95% confidence intervals (CI) RCT (true) SITS (hypothetical) Difference SITS RCT Proportion 95% CI Proportion 95% CI Proportion 95% CI * n (RCT) = 465; n (SITS) = 1000 the 95% confidence interval for a 6% difference in proportions with a SITS sample size of 1000 excludes the value of 0 (no difference), meaning that a 6% lower proportion of independence is detectable with a sample size of 1000 Prognostic model approach: An additional analysis of the secondary efficacy outcome variable is forseen. The design of this investigation will be a prospective one sample comparison of actual treatment response versus predicted placebo response based on a prognostic model (ordinal logistic regression). To compare the outcome of rt-pa treatment for each individual patient the outcome at day 90 on the entire modified Rankin Scale (mrs) will be predicted based on the placebo population of the existing rt-pa database (N=2799) at Boehringer Ingelheim. The actual observed outcome at day 90 for each treated patient on the entire mrs will be compared with the predicted outcome at day 90 based on the prognosis of each patient. To predict the individual outcome on placebo the relevant baseline characteristics found in a meta-analysis based on individual data of the rt-pa database were selected. The coefficients taken from an ordinal logistic regression model based on the placebo population (N=1304) of the rt-pa database will be applied for the individual prediction. The prognosis at day 90 in terms of the cumulative probabilities Pr( mrs i), i = 0,..., 6 for each individual patient to be included in the trial is given below. (1) Pr( mrs 0) Pr( mrs 1) Pr( mrs 2) 1 Pr( mrs 3) = 1+ exp( Y ) Pr( mrs 4) Pr( mrs 5) Pr( mrs 6), where 58

59 Y time age sysbp glucose NIHSS stroke diabetes CHF ASA hypertension atrial fibrillation In general, the probability for each category on the mrs at day 90 is given by Pr( mrs = i) = Pr( mrs i) Pr( mrs i + 1) for i = 0,..., 5 and Pr( mrs = 6) = Pr( mrs 6). Simulations revealed that the predicted outcome on mrs at day 90 for each individual patient should be based on the 75 th percentile of probabilities from the ordinal logistic regression model. E.g., the placebo prognosis on the mrs at day 90 for a patient with the individual profile - time from stroke onset to treatment (time) = 205 min - age (age) = 70 - systolic blood pressure (sysbp) = 184 mmhg - glucose level at baseline (glucose) = 141 mg/dl - NIHSS on admission (NIHSS) = 14 - without prior stroke (stroke), coded = 0 - without prior diabetes (diabetes), coded = 0 - without prior CHF (CHF), coded = 0 - without prior ASA (ASA), coded = 0 - without prior hypertension (hypertension), coded = 0 - with prior atrial fibrillation (atrial fibrillation), coded = 1 would be predicted according to formula (1) with the following probabilities for the different mrs categories at day 90. MRS % 15% 13% 20% 27% 7% 12% 75% 59

60 The placebo prognosis on the ordinal mrs for this patient would then be mrs 2 based on the 75 th percentile rule; the minimal predicted score on mrs would be 2. If the same patient would have an NIHSS on admission of 24 instead of 14 his prognosis under placebo according to formula (1) would worsen to a minimal predicted score on the mrs of 4 based on the predicted probabilities on the ordinal mrs and the 75 th percentile rule: MRS % 3 % 4 % 9% 26% 13% 44% 75% The 75 th percentile guarantees a hit rate (minimal predicted score on mrs observation on mrs) of at least 80%, i.e. the requirement for an acceptable prognosis Success of rt-pa is defined if the observed outcome on mrs at day 90 of a patient is better than the placebo prognosis of that patient. The success rate in the placebo population (N=1304) of the rt-pa database is 15% with a corresponding hit rate of 85%. It has to be noted that the prognostic model as given in formula (1) is experimental and can be refined, if further placebo data as part of other previous or new stroke trials, meeting the SPC population of rt-pa, would become available. The placebo effect in the prognostic modelling of about 15% could be adapted, if new historical placebo 0-3 hrs data in rt-pa eligible patients would be become available. In such a case, one would have to rerun the prognostic modelling and recalculate the placebo response. From there one could correct the sample size, if necessary. The predicted placebo response for the prognostic model is derived from the placebo groups in the 0-3 hrs time-window of NINDS A & B, ECASS II and ATLANTIS. 60

61 5.7 Data entry form Code PID TFN TSO TAF TAH TBI TBR TTR STOP AGE GEN RBS RF CM SBPB DBPB SBPA DBPA SBPH DBPH GLB NTB NTA NTA NTE MG WEST MGKE MGKW ICAY IMAY Data item name Patient identity Treatment file name Time of stroke onset Time of arrival at first (non-treating) hospital Time of arrival at treating hospital Time of Brain Imaging Study Time of Brain Imaging Report Time of Treatment No treatment given Age Gender Rankin grade before stroke Risk factors Concomitant medication SBP before DBP before SBP after DBP after SBP 24h DBP 24h Glucose before NIH before NIH after NIH 24 h NIH 7d Dose mg Estimated weight Dose mg/kg Dose mg/kg CT h MR h 61

62 ICEY CT extra (late deterioration) IMEY MR extra (late deterioration) SUB Subgroup of stroke GLOD Global outcome 24h GLOE Global outcome 7d SICH SICH 22-36h SAE SAE SAET Time of SAE ADR ADR ADRT Time of ADR R3M Rankin 3m TD Time of death CD Primary cause of death 62

63 5.8 Educational programme outline One day information course for local coordinators Stroke diagnosis and classification (practical examples): NIHSS MRS GES Inclusion & Exclusion criteria Patient information and consent CT early infarct diagnosis Alteplase, mechanistic aspects Management of thrombolysis patient from door to needle & from needle to door Potential complications and to manage them Data entry in SITS 63

64 5.9 Serious Adverse Form to be used in reporting serious drug reaction 64