monocentric randomized controlled prospective trial Prof. Dr. med. K. Faßbender, Dr. med. S. Walter

Transcription

1 Clinical Trial Protocol Synopsis Trial No.: - Title: Study Type: Investigator: Institute/ Department: Mobile Stroke-Unit for reduction of the response time in ischemic stroke monocentric randomized controlled prospective trial Prof. Dr. med. K. Faßbender, Dr. med. S. Walter University Hospital of the Saarland, Germany Kirrbergerstr. D Homburg/Saar Date of Protocol: Planned Dates of Trial Planned Study Period Start: November 17 th, 2008 (first patient in) End: after inclusion of 200 patients 24 months Objectives: The objective of this study is to collect data on the use of a Mobile Stroke Unit (an ambulance vehicle that includes all diagnostic tools, necessary for eventual pre-hospital thrombolysis), i.e. to investigate, whether the time to therapeutic decision can be reduced compared to optimized conventional clinical management. No. of subjects total: each treatment: Diagnosis and main criteria for inclusion: Stroke symptoms until call at least 30 min prior to the end of the approved time wondow for thrombolysis Test procedure: Diagnostic procedures in a Mobile Stroke Unit Reference Procedure: Primary efficacy endpoint: Secondary efficacy endpoints: Conventional stroke management Time between emergency call and therapy decision Time between emergency call and end of CT scan Time between emergency call and end of laboratory blood analysis Time between symptom onset and end of CT scan Time between symptom onset and end of laboratory blood analysis Time between symptom onset and therapy decision 1

2 Subgroup of stroke patients: - Number of patients with thrombolytic therapy - Time between emergency call and beginning of thrombolysis - Time between symptom onset and beginning of thrombolysis - Functional status at day 0, 1 and 7: mrs (total score) Barthel Index (total score) NIHSS (total score), mean/median, baseline change Safety endpoints - patient survival at day 7 - stroke-related and neurological deaths - symptomatic cerebral hemorrhage defined as any blood accumulation in the brain or intracranially associated with a clinical deterioration of 4 points of the NIHSS for which the hemorrhage has been identified as the dominating cause of the neurologic deterioration - symptomatic peripheral hemorrhage - symptomatic edema and cerebral herniation Further Variables to be assessed Statistical methods - epidemiological variables - time between symptom onset and emergency call - distances to be passed to reach the patient/hospital in km - continuously assessed RR level in the first 3 hours after emergency call - time until decision regarding differential RR management - length of stay in hospital 1-sided t-test at level alpha=0.025 for primary endpoint; interim analysis after 100 patients; exploratory tests for secondary endpoints. 2

3 Flow Chart Visit Hour/Day Window Baseline (= 1 st physician contact) D0 24 Hrs # 1 Hr D1 7 Days # 1 Day D7 MSU/ optimized x conventional SU Demographics x Medical History x Physical Exam. x In-/Exclusion x Criteria Informed Consent x and subject information Optional CT Scan x electronically sending Vital Signs x** x** Thrombolysis as x indicated Adverse Events x x x 12-Lead ECG x CT Scan ## x NIHSS* x x x Modified Rankin x x x Scale* Barthel Index* x x x Pat. Termination Record x # time after baseline ## CCT will be immediately performed in the case of neurological deterioration * subgroup of stroke patients ** permanent monitoring of vital signs including 3-lead ECG until end of Stroke Unit therapy (at least 24 hours) 3

4 Table of contents Clinical Trial Protocol Synopsis 1 Flow Chart 3 Table of Contents 4 1. INTRODUCTIONS MEDICAL BACKGROUND RATIONALE FOR PERFORING THE TRIAL BENEFIT/RISK ASSESSMENT 8 2. STUDY OBJECTIVES GENERAL AIM/PRIMARY OBJECTIVE PRIMARY EFFICACY ENDPOINT SECONDARY EFFICACY ENPOINTS SAFETY ENDPOINTS FURTHER VARIABLES TO BE ASSESSED 9 3. STUDY POPULATION NUMBER OF SUBJECTS PLANNED INCLUSION CRITERIA EXCLUSION CRITERIA PROCEDURES INVESTIGATIONAL PROCEDURES CONCOMITANT THERAPY AFTERTREATMENT OBSERVATIONS EFFICACY SAFETY INVESTIGATIONAL PLAN STUDY DESIGN AND PLAN STUDY PROCEDURES AT EACH VISIT VISIT SCHEDULE STATISTICS STATISTICAL DESIGN/MODEL NULL AND ALTERNATIVE HYPOTHESIS PLANNED ANALYSIS (EFFICACY) Primary analysis Secondary analysis Safety analysis Interim analysis HANDLING OF MISSING DATA RANDOMIZATION SAMPLES SIZE ISSUES ADMINISTRATIVE MATTERS ETHICS Institutional Review Board or Independent Ethics Committee Informed consent and Subject Information RECORDS Case Report Forms Source documents Direct access to source data/documents SIGNATURE PAGE(S) REFERENCES 21 4

5 11. APPENDICES 23 APPENDIX 11.1: NATIONAL INSTITUTE OF HEALTH STROKE 23 SCORE, NIHSS APPENDIX 11.2: MODIFIED RANKIN SCALE, mrs 25 APPENDIX 11.3: BARTHEL INDEX 26 APPENDIX 11.4: CASE REPORT FORM 27 APPENDIX 11:5. ADVERSE EVENT FORM 30 5

6 1. INTRODUCTION 1.1 MEDICAL BACKGROUND Stroke is the most common cause of permanent disability, the second most common cause of dementia and the third most common cause of death in elderly in industrialized countries. Approximately 85 % of all strokes are due to cerebral ischemia, whereas 15% are due to cerebral hemorrhage. In 1998, over new strokes occurred within the European Union. Since the incidence of stroke is strongly age-related, the number of stroke victims is expected to increase substantially over the next decades as the proportion of the subjects older than 70 is estimated to grow from about 13 % to 20 % (Wahlgren 2001; The European stroke initiative, 2000). Within the next 8 years the yearly direct costs for stroke can be estimated to about 27 billion only in Germany (Kolominsky-Rabas et al., 2006). Due to the increased incidence in the future, these costs are expected to increase by about % within the next 10 years. The main causes of ischemic stroke are thromboembolic occlusion of cerebral vessels by embolism of the heart or of the brain feeding arteries. This occlusion of a cerebral artery leads to an immediate drop of the blood flow in the corresponding arterial territory. This reduced blood flow leads to the known neurological symptoms of the affected brain area. Animal experiments show that a massive cellular death occurs within minutes after the occlusion of an intracerebral artery in the centre of the ischemic lesion (infarction core). The region surrounding this area (penumbra) is at high risk by a functionally reduced blood flow. By improving the blood flow, this area could potentially be rescued and therefore represents the focus of every stroke therapy. Aggravatingly, the first irreversible cellular death in the penumbra starts as early as 30 minutes to 1 hour after stroke onset (Astrup et al., 1981; Heiss et al., 1983; Garcia et al., 1995; Watanabe et al., 1977; Siesjo et al., 1992; Hossmann 1994; Hu et al., 2001). Based on these data, a causal therapy of ischemic stroke appears only possible, if the cerebral blood flow is re-established within the very first hours after symptom onset (Dyker et al., 1998; Kasner et al., 1997; Adams et al., 1996; Brott et al., 1992; Del Zoppo et al., 1996; Zivin, 1998). Currently, systemic thrombolysis with the recombinant tissue plasminogen activator (rt-pa), which is approved in Germany since 2000, represents the first evidence-based and the only causal treatment for acute ischemic stroke. The therapy should be performed as early as possible to minimize the cerebral injury and to avoid complications (i.e., hemorrhagie). Treatment with rt-pa has been studied in 6 large randomized placebo-controlled multi-centre studies (The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study 6

7 Group, 1995; Hacke et al. 1995; Hacke et al., 1998; Clark et al., 2000). Meta-analysis of these studies showed that a thrombolytic therapy within the first 3 hours results in a significant reduction of disability or death (Hacke et al., 1998; 2004). 1.2 RATIONALE FOR PERFORMING THE TRIAL The chances to save the brain tissue by a thrombolytic therapy exponentially decrease with passing time. In most cases, the patient is examined by an emergency physician, but the beginning of the final thrombolysis therapy is delayed by a variety of factors, like delivery to the hospital, neurologist re-examinations, and delay in blood analysis or CT scan. Due to this, a therapy decision is possible within the first 3 hours only in a minority of the stroke patients. This contributes to the low lysis rate of only 4-7 % of all stroke patients. The odds ratio (OR) of a favourable 3-month outcome of stroke therapy converges against 1 in the first 4 hours in favour of the rt-pa group (Fig.1, Hacke et al., 2004). Meta-analyses demonstrate that a reduction of time until the beginning of the thrombolytic therapy has the best potential to reduce the disabling effects of a stroke. The rational of this study is to investigate whether a Mobile Stroke Unit contributes to a better stroke management by saving precious time until a therapeutic decision is made, according to the concept time is brain. Fig. 1: Dependency of the success of thrombolysis therapy on time until start of therapy (Hacke et al., 2004). 7

8 1.3 BENEFIT/RISK ASSESSMENT As outlined above, the reduction of time until beginning of thrombolytic therapy is the most important means to reduce the disabling consequences of ischemic stroke. In contrast, there is no evidence that a CT scan and other diagnostic procedures in an ambulance at the site, where the patient is found, is less effective or has more complications than in a hospital. Therefore, the benefit/risk assessment argues for such a clinical trial to prove the efficacy of the concept of a Mobile Stroke Unit in the clinical practice. 2. STUDY OBJECTIVES 2.1. GENERAL AIM/PRIMARY OBJECTIVE The objective of this study is to collect data on the use of a Mobile Stroke Unit (an ambulance vehicle that includes all diagnostic tools, necessary for eventual pre-hospital thrombolysis), i.e. to investigate, whether the time to therapeutic decision can be reduced compared to optimized conventional clinical management. 2.2 PRIMARY EFFICACY ENDPOINT Time between emergency call and therapy decision 2.3 SECONDARY EFFICACY ENDPOINTS Time between emergency call and end of CT scan Time between emergency call and end of laboratory blood analysis Time between symptom onset and end of CT scan Time between symptom onset and end of laboratory blood analysis Time between symptom onset and therapy decision Subgroup of stroke patients: o Number of patients with thrombolytic therapy o Time between emergency call and beginning of thrombolysis o Time between symptom onset and beginning of thrombolysis o Functional status at day 0, 1 and 7: mrs (total score) Barthel Index (total score) NIHSS (total score), mean/median, baseline change 8

9 2.4 SAFETY ENDPOINTS - Patient survival at day 7 - Stroke-related and neurological deaths - Symptomatic cerebral hemorrhage defined as any blood accumulation in the brain or intracranially associated with a clinical deterioration of 4 points of the NIHSS for which the hemorrhage has been identified as the dominating cause of the neurologic deterioration - Symptomatic peripheral hemorrhage - Cerebral herniation rate and symptomatic edemas 2.5 FURTHER VARIABLES TO BE ASSESSED - Epidemiological variables - Time between symptom onset and emergency call - Distances to be passed to reach the patient/hospital in km - Continuously RR level in the first 3 hours after emergency call - Time until decisions regarding differential RR management - Length of stay in hospital 3. STUDY POPULATION 3.1 NUMBER OF SUBJECTS PLANNED Two hundred patients will be enrolled (100 patients per treatment group). The study will be started November, 17 th INCLUSION CRITERIA The following inclusion criteria are designed for patients participating in the diagnostic stroke management. They do not correlate with the criteria for performing a thrombolysis therapy, as these criteria are clearly documented and followed in this trial in case of thrombolysis. Age between 18 and 80 years Onset of symptoms until call 2.5 hours (and not after awakening) 9

10 Clinical signs of ischemic stroke with suddenly occurring, measurable neurological deficits defined as impairment of language, motor function, facial palsy or asymmetry Patient is willing to participate voluntarily and to sign a written informed consent. Informed consent will be obtained from each patient or the subject s legally authorized representative or relative. Patients who are unable to sign but who are able to understand the meaning of participation in the study may give an oral witnessed informed consent. These patients have to make undoubtfully clear that they are willing to participate voluntarily and must be able to understand an explanation of the contents of the information sheet. 3.3 EXCLUSION CRITERIA As the main purpose of the trial is the analysis of optimized stroke diagnostic management, the following exclusion criteria will be applied for all patients participating in this trial: Symptoms of cerebral ischemia persisting longer than 2.5 hours prior to emergency call Age younger than 18 or older than 80 years Non-acute onset of symptoms No focal stroke-like symptoms Pregnant patients In those cases, where thrombolytic therapy can be performed, the exclusion criteria are according to the approval of the use of rt-pa in Germany. 4. PROCEDURES 4.1. INVESTIGATIONAL PROCEDURES Therapy of acute stroke in an optimized conventional way (ambulance transport to a hospital stroke unit, diagnostic procedures and possible stroke treatment with thrombolysis) versus with a Mobile Stroke Unit (diagnostic procedures and possible stroke treatment beginning in the ambulance) will be compared. The trial shall be performed in the Saarland, where the Emergency Medical Service is ideally controlled by one centralized management. Incoming emergency calls will be evaluated by the central emergency coordinating office according to the modified Rossier stroke scale (Nor et al., 2005). A list of 4 questions 10

11 (abruptly occurring symptoms; symptoms persisting less than 2.5 hours; age between 18 and 80 years and one of the following neurological deficits: paralysis of arm or leg, facial paralysis, aphasia or dysarthria) will be asked and in the case of 4 positive answers, the patient is a possible candidate for the trial. According to the randomization plan, the coordinator will dispose the Mobile Stroke Unit or initiate an optimized conventional stroke management - as control condition. In the optimized conventional clinical management (OCCM): After performing patient s medical history, physical examination and emergency treatment by the emergency physician, the patient will be transported to the Department of Neurology, University Hospital of the Saarland. The delivery of the patient will directly take place at the CT scanner. The neurologist on duty will perform a second medical history, physical examination, while the blood will be drawn by the assisting nurse. CT scan will be performed, while the blood will be analyzed by point of care technique (PTT/INR; blood glucose, blood count, liver and pancreas enzymes), placed close to the CT scanner. Additionally the blood will be sent in parallel to the hospital central laboratory for conventional laboratory analysis. Depending on the results, a thrombolytic therapy will be initiated directly at the CT. Thereafter, the patient will be transported to the hospital Stroke Unit, where monitoring and further treatment will be continued. The patient will be asked for his consent to participate in this trial. A denegation will neither have any influence on diagnostic nor therapeutic procedures. In the Mobile Stroke Unit (MSU) procedure: Conventional Emergency Medical Service together with the MSU will meet at the side, where the patient is found. The MSU is an ambulance, equipped with a neurologist and neuroradiologist and includes CT scanner and point of care laboratory unit (Fassbender et al., 2003). The patient s medical history and the physical examination will be directly performed by the neurologist. CT scan analysis will be performed by the neuroradiologist, while the neurologist will analyze the blood samples with the point of care laboratory unit (PTT/INR; blood glucose, blood count, liver and pancreas enzymes). If the inclusion and exclusion criteria are fulfilled, the thrombolytic therapy will directly be started by the neurologist. A possible thrombolytic therapy will be performed under the current inclusion and exclusion criteria that are associated with the rt-pa drug approval in Europe. After performance of the acute therapy, the patient will be transported to 11

12 the Department of Neurology, University Hospital of the Saarland. After delivery, he/she will be monitored on the hospital s Stroke Unit. The patient will be asked for his/her agreement to participate in this trial. A denegation will not have any influence on either diagnostic or therapeutical procedures. In the case of denegation the patient will be treated in the conventional way as described above. General study conditions: the observation period will last 7 ( 1) days after stroke onset. The study will be conducted at the Department of Neurology, University Hospital of the Saarland. The Department has a stroke unit and 24-hours access to an adequate CT scanner. The two different procedure types must be performed by a physician specialized in neurological intensive care. The study will be performed in cooperation with the Department of Neuroradiology, University Hospital of the Saarland, the Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital of the Saarland, the Institute for Clinical Chemistry, University Hospital of the Saarland and with the Rettungszweckverband Saar 4.2 CONCOMITANT THERAPY Every drug therapy may be given according to patient needs. 4.3 AFTERTREATMENT The aim of the study is to investigate the stroke diagnostic process management. Neither the performance of further diagnostics nor stroke therapy will be influenced or changed by participation in the trial. All patients participating will be admitted to every necessary diagnostic or therapeutic procedure including rehabilitative treatment. 12

13 5. OBSERVATIONS In this study, 2 follow-up visits are planned. The last examination takes place at Day 7 1 day. BP: Blood pressure will be measured at baseline. Further BP monitoring will take place in the following order: every 30 minutes until hour 3 (i. e. after 30, 60, 90, 120, 150, 180 minutes) and then every hour for the first 24 hours. ECG: Resting 12-lead ECG readings are to be taken at baseline and if needed. 3-lead ECG will be taken permanently during Stroke Unit monitoring. CT: A cerebral CT scan must be performed and evaluated prior to the initiation of treatment. A second CT scan must be performed after a possible thrombolysis therapy. Others CT scans are optional and will be performed only in case of clinical deterioration. Adverse events (AE): AE (free reporting by the patient to standardized questions of the visiting physician every day during the hospital stay, and later at each examination) will be documented until the hospital discharge (date of onset, date of last occurrence, intensity, etc.). Efficacy parameters: The NIH Stroke Scale, the Modified Rankin Scale and the Barthel Index will be performed at baseline, at Day 1 and at Day 7. The patient termination record will be performed on Day EFFICACY The main goal of this study is to assess efficacy of a MSU to reduce the time until treatment decision. For the list of further endpoints see chapter SAFETY For the list of safety endpoints see chapter 2.5. For the assessment of safety, incidences and severity of adverse events will be assessed at all visits. Stroke-related and neurological complications (including the cerebral herniation and 13

14 symptomatic edema, death, symptomatic cerebral or peripheral bleedings) will be evaluated. Haemorrhagic events will be classified as HI type I or II or as PH type I or II. HI 1 is defined as small petechiae along the margins of the infarct. HI 2 represents more confluent petechiae within the infarcted area but without space-occupying effect. PH 1 is defined as blood clot not exceeding 30 % of the infarcted area with some mild spaceoccupying effect. PH 2 represents dense blood clots exceeding 30 % of the infarcted area with significant space-occupying effect (Lyden et al., 1989). 6. INVESTIGATIONAL PLAN 6.1 STUDY DESIGN AND PLAN This is a monocentric, randomized controlled prospective trial in patients with stroke symptoms. Emergency Call Study inclusion Yes No Weekly Randomisation OCCM MSU procedure Fig. 2: After emergency call, the centralized Emergency Medical Service of the Saarland will ask standard questions regarding history and symptoms of the patient. If inclusion criteria are fulfilled, either the OCCM or the MSU procedure will be initiated according to the randomization plan. 14

15 6.2 STUDY PROCEDURES AT EACH VISIT Three visits will be conducted during the study. At visit 1 (baseline) the documentation of demographics, medical history, physical examination, in-/exclusion criteria for thrombolysis, vital signs, concomitant therapy, 12-lead ECG, permanent 3-lead ECG, in the stroke subgroup: adverse events in the case of thrombolysis, NIH Stroke Scale, the modified Rankin Scale, Barthel Index and performance of a cerebral CT scan. A visit 2 (24 hours), heart rate, blood pressure, 3-lead ECG will be monitored until end of Stroke Unit therapy. The documentation of adverse events and of concomitant medication will be done. In the stroke subgroup: the NIH Stroke Scale, modified Rankin Scale, Barthel Index will be performed. In the case of thrombolytic therapy, a CT scan will be performed (acceptable time window for CT: -2 to +12 hours). At visit 3 (day 7), the documentation of adverse events and of concomitant medication will be done. In the stroke subgroup: the NIH Stroke Scale, modified Rankin Scale, Barthel Index will be performed. The patient termination record will be filled in. 6.3 VISIT SCHEDULE For visit 1 (D0) there is no time window. For visit 2 (D1), a window between +1 and 1 hour is acceptable. For visit 3 (D7), a window between +1 and 1 day is acceptable. 15

16 7. STATISTICS The objective of this study is to test the hypothesis whether the use of a MSU can save precious time in stroke treatment to improve thrombolytic therapy compared to OCCM. 7.1 STATISTICAL DESIGN/MODEL This is a mono-centre, prospective, randomized, parallel-group study. The use of MSU will be compared to OCCM. For practical reasons, use of MSU or OCCM is randomized on a weekly basis. The primary endpoint is the time between emergency call and therapy decision. 7.2 NULL AND ALTERNATIVE HYPOTHESIS The primary objective of the study, showing that use of MSU is superior to OCCM with regard to the time until a therapy decision, will be tested using the hypotheses given below: H 0 : μ MSU - μ OCCM 0 min versus H 1 : μ MSU - μ OCCM < 0 min, where μ MSU represents the average time between emergency call and therapy decision for the MSU, and μ OCCM represents the average time between emergency call and therapy decision for the OCCM. 7.3 PLANNED ANALYSIS Primary analysis It is expected that the time between emergency call and therapy decision follows roughly a normal distribution and that the standard deviations for both procedures are comparable. Consequently, testing of the null hypothesis above will be performed using a one-sided t-test at an alpha level (Type I error rate) of In the case that the assumptions about the primary endpoint are clearly not met, the non-parametric Wilcoxon rank sum test will be applied instead Secondary analysis Baseline characteristics of the patients in both treatment arms will be tabulated. All secondary endpoints related to time intervals, such as time between symptom onset and end of CT scan, time between symptom onset and end of laboratory blood analysis, time between symptom onset and therapy decision, time between emergency call and end of CT scan, time between emergency call and end of laboratory blood analysis, subgroup of stroke patients: o time between symptom onset and beginning of thrombolysis 16

17 o time between emergency call and beginning of thrombolysis, will be analysed in the same way as the primary endpoint. The number of patients with thrombolytic therapy will be compared between treatment arms by means of Fisher's exact test. The functional status of patients' on days 0, 1 and 7 according to the mrs and the Barthel Index will be tabulated (each category) and compared between treatment arms by means of the 2 -test. For the NIHSS (total score) the t-test (or Wilcoxon rank sum test) will be used to compare the treatment arms Safety analysis Incidence and severity of AEs will be described for all included patients by treatment arm and by MedDRA classification Interim analysis After roughly 100 included patients an interim analysis will be performed. Using the East software (version 4) with Lan-DeMets spending functions and O'Brien-Fleming boundaries the study would be stopped for futility (accepting the null hypothesis) if the p-value in the interim analysis is greater than 0.4, and the study would be stopped for proven superiority if the p-value is less than With this group-sequential plan the boundary for the final analysis is If it turns out in the interim analysis that the standard deviation of the primary endpoint is considerably greater than the expected 30 min, then the total sample size may be increased HANDLING OF MISSING DATA All efforts will be made to collect complete information according to the protocol. This refers to all included patients. No missing values regarding survival status are expected. However, the last-observation-carried-forward (LOCF) method will be applied in the sense that data from the previous day or measurement will substitute the missing data. In case of missing values due to death, the worst score principle will be applied. 17

18 7.5. RANDOMISATION Eligible patients will be included into the trial. Study procedures will be weekly randomized (in blocks of four), with an equal allocation ratio to either MSU or OCCM. 7.6 SAMPLES SIZE ISSUES From recent emergency cases in the same Stroke Unit in which the study will be conducted, it can be expected that the standard deviation of the time between emergency call and therapy decision will be 30 min. With this assumption 100 patients per group are necessary to detect an advantage of 14 min by the use of an MSU compared to the optimized conventional clinical procedure in a one-sided t-test at alpha-level with 90% power. 8. ADMINISTRATIVE MATTERS The trial will be carried out in compliance with the protocol, the principles laid down in the Declaration of Helsinki, last revised version, in accordance with the ICH Harmonized Tripartite Guideline for Good Clinical Practice and in accordance with applicable regulatory requirements. 8.1 ETHICS Institutional Legal Department and Independent Ethics Committee The protocol and informed consent and subject information form have already been reviewed and accepted by the local Independent Ethics Committee of the Medical Association of the Saarland, which is regularly involved in the ethical aspects of clinical trials at the University of the Saarland and by the clinical and university legal Departments Informed Consent and Subject Information Prior to subject participation in the trial, a written informed consent will be obtained from each subject (or the subject s legally accepted representative) or deferred in exceptional circumstances according to the regulatory and legal requirements. A signed copy of the 18

19 informed consent and any additional subject information must be given to each subject or the subject s legally authorized representative. 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 and may have to be signed by all subjects subsequently entered in the trial and those currently in the trial, if affected by the amendment. 8.2 RECORDS Case Report Forms Case report forms for individual subjects will be provided by and remains with the main investigator. Case report forms are used to record clinical trial data and are an integral part of the trial. The case report forms, therefore, must be legible and complete. The case report form includes more information than necessary for the trial due to the required quality management of the University Hospital of the Saarland Source documents Case report forms, progress notes and copies of laboratory and medical test results must be available at all times for inspection by health authorities. Source documents provide evidence for the existence of the subject and substantiate the integrity of the data collected. Source documents are filed at the investigator s site. Documented data include: Subject identification (initials, gender, date of birth) Subject participation in the trial (trial number, patient number, data informed consent given) Dates of subject s visits Medical history Adverse events (AE onset and end) Direct access to source data/documents Case report forms and all source documents, including progress notes and copies of laboratory and medical test results must be available at all times for review by health authorities. 19

20 20

21 10. REFERENCES Adams et al., 1996; Guidelines for thrombolic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke: Stroke 1996; 27: Astrup et al.,thresholds in cerebral ischemia: the ischemic penumbra. Stroke 1981; 12: Brott et al., Urgent therapy for stroke. Stroke 1992; 23: Clark et al., The rt-pa (alteplase) (1 to 6 hour acute stroke trial) part A (A0267g): results of a double-blind, placebo controlled, multicenter study. Stroke 2000;31: Dyker et al., Duration of neuroprotective treatment of acute ischemic stroke. Stroke 1998; 29: Del Zoppo et al.,thrombolytic therapy in stroke: Possibilities and hasards? Stroke 1996; 17: Fassbender et al., Mobile Stroke Unit for hyperacute stroke treatment. Stroke 2003; 34: e44. Garcia et al., Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 1995; 26: Hacke et al., for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Stroke Study (ECASS. JAMA 1995; 274: Hacke et al.,randomised double-blind placebo-controlled trial of thrombolic therapy with intravenous alteplase in acute ischaemic stroke. (ECASS II) Lancet 1998; 352: Hacke et al., Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-pa stroke trials. Lancet 2004; 363: Heiss et al. Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 1983; 14: Hossmann KA.; Viability thresholds and the penumbra of focal ischemia. Annual Neurology 1994; 36: Hu et al.; Protein aggregation after focal brain ischemia and reperfusion. J Cereb Blood Flow Metab 2001; 21: Kasner et al. Emergency Identification and Treatment of acute ischemic stroke. Annuals of Emergency Medicine, 1997; 30: Kolominsky-Rabas et al., Lifetime cost of ischemic stroke in Germany: results and national projections from a population-based stroke registry: the Erlangen stroke project. Stroke 2006; 37: Lyden, P.D. et al., Tissue plasminogen activator-mediated thrombolysis of cerebral emboli and its effect on hemorrhagic infarction rabbits. Neurology, 1989 (39): 703 Nor Azlisham et al.; The recognition of stroke in the emergency room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet Neurology 2005; 4:

22 Siesjo et al., Pathophysiology and treatment of focus cerebral ischemia, Pathophysiology. Journal of Neurosurgery 1992; 77: The European stroke initiative: Recommendations for stroke management. Cerebrovasc dis 2000 (10 (suppl 3)): 1-34 The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995 (333(24)): Wahlgren NG, Introduction to stroke update. In Wahlgren NG, ed. Update on Stroke Therapy , Karoloinska Stroke Update, Stockholm, 2001:17-19 Watanabe et al., Experimental regionalcerebral ischemia in the middle cerebral artery territory in primates. II. Stroke 1977; 8: Zivin JA, Factors determining the therapeutic window for stroke. Journal of Neurology 1998; 50:

23 APPENDIX 11.1: 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 first 2. Best gaze (only horizontal eye movements) 3. Visual field testing 4. Facial paresis (Ask patient to show teeth or raise eyebrows and close eyes tightly) 5a. Motor Function Right arm 5b. Motor function Left arm 0 Alert 1 Non 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 Obeys one correctly 2 Both incorrect 0 Normal 1 Partial gaze palsy 2 Forced gaze deviation 0 No visual field loss 1 Partial hemianopsia 2 Complete hemianopsia 3 Bilateral hemianopsia (blind, incl. Cortical blindness) 0 Normal symmetrical movement 1 Minor paralysis /flattened nasolabial fold, asymmetry on 2 Partial paralysis (total or near total paralysis of lower face) 3 Complete paralysis of one or both sides (absence of facial movement in the upper and lower face) 0 Normal (extends arm 90 or 45 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 90 or 45 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) 6a. Motor Function 0 Normal (holds leg in 30 positon for 23

24 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) 11. Extinction an inattention (use visual double simulation or sensory double stimulation) 5sec 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 30 positon for 5sec 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 2 Severe hemi-inattention or hemiinattention to more than one modality 24

25 APPENDIX 11.2: 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): 25

26 APPENDIX 11.3: Barthel Index Item Score Categories 0 Incontinent or needs enemas Bowels 5 Occasional incontinence (< once per week) 10 Continent 0 Incontinent/unable to manage catheter Bladder 5 Occasional accident (< once per day) 10 Continent Grooming 0 Needs help with shaving, washing, hair or teeth 5 Independent 0 Dependent Toiler use 5 Needs some help 10 Independent on, off, dressing and cleaning 0 Dependence Feeding 5 Needs some help (e. g. with cutting, spreading) 10 Independent 0 Unable and no sitting balance Transfer (e. g. 5 Needs major help bed to chair) 10 Needs minor help 15 Independent 0 Unable Mobility 5 Wheelchair independent indoors 10 Walks with help or supervision 15 Independent (but may use aid) 0 Dependent Dressing 5 Needs some help 10 Independent including fasteners 0 Unable Stairs 5 Needs some help or supervision 10 Indepent up and down Bathing 0 Dependent 5 Independent in bath or shower Total

27 APPENDIX 11.4: Case Report Form name address date of birth N o medical record residential from - to length (days) ward family physician after awakening Yes No date symptoms start symptoms place symptoms distance to hospital in km referral (self, emergency physician/emt, family physician/neurologist, ext. hospital, UKH) emergency call 1 st physician contact mode hospital arrival (emergency/family physician/neurologist) 1 st CCT/cMRI hosp. central lab results point of care results therapy decision weight thrombolysis i.v./i.a. start thrombolysis end thrombolysis decision diff. RR management place of start diff. RR management (hospital vs. mobile ICU) Rankin before stroke NIHSS day 0 Rankin day 0 Barthel day 0 swallowing problems day 0 NIHSS day 1 Rankin day 1 Barthel day 1 swallowing problems day 1 NIHSS day 7 Rankin day 7 Barthel day 7 swallowing problems day7 NIHSS discharge Rankin discharge Barthel discharge swallowing problems discharge 27

28 BP: hour 1 (min): 0 30 hour 2 (min): 0 30 hour 3 (min): 0 30 Risk factors: hypertension nicotine abuse (py) DM HLP atrial fibrillation CHD prior cardiac infarction cardiac failure biol. valvular transplant mech. valvular transplant ACVB coronary stent arterial obstructive disease glaucoma contraceptive prior TIA stenosis of ICA right % % left prior stroke ICA stent Diagnostics: <24h EC duplex EC doppler TCD cmri TTE/TEE MRA CTA DSA >24h EC duplex EC doppler TCD cmri TTE/TEE MRA CTA DSA Interventions: TEA ICA stent other stent PTA planned stent planned TEA operative decompression date intubation date urethral catheter nasogastric stomach tube PEG Complications: re-stroke cerebral oedema seizure haem. transform. haemorrhage with >4 pts NIHSS change incarceration stroke-caused death pneumonia sepsis thrombosis/pulm. embolism periph haemorrrhage amentia depression decubitus ulcer other 28

29 Second. prophylaxis: ASS Clopidogrel Aggrenox Marcumar Heparin sc Lipid lowering drugs hypertension adjustment Time intervals: emergency call end CT emergency call end conventional blood analysis emergency call - end point of care blood analysis emergency call therapy decision emergency call thrombolysis emergency call start diff. RR symptom onset - end CT symptom onset - end conventional blood analysis symptom onset - end point of care blood analysis symptom onset - therapy decision symptom onset - thrombolysis symptom onset - start diff. RR 29

30 APPENDIX 11.5: Adverse Events ADVERSE EVENTS Record below any new event None If the patient has concluded participation in the trial and experienced no adverse events, mark this box. Serious and significant adverse events must also be reported immediately according to SAE procedures. Date of event * If ongoing, record cont* in this column Onset (ddmonyy) End* (ddmonyy) Intensity of event 1= mild 2=moderate 3=severe Recording the most severe intensity Therapy for event 0=no 1=yes If yes, record on Concomitant Therapy page Action taken with trial drug due to event 1=continued 2=reduced 3=discontinued 4=increased 5=completed acc. protocol 6=discont & reintroduced 7=NA (see facing page) Outcome of event 1=recovered 2=not yet recovered 3=sequelae 4=fatal 5=unknown Was event serious? 0=no 1=yes 3=no, but significant If yes, enter appropriate code(s) ** Example: Headaches 06 Dec 02 cont Description of the above recorded events if necessary (refer to event by above line number) Causal relationship Is there a reasonable causal relationship between the event and the test drug? *** 0=no 1=yes ** 1= results in death 2=immediately life-threatening 3=persistentor significant disability/incapacity 4=requires or prolongs patient hospitalisation 5=congenital anomaly/birth defect 8=other comparable medical criteria (specify under description) *** Medical judgement including kind and pattern of reaction, reasonableness of time relationship, patients clinical status, co-medication etc. 30