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Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke TARDIS – ISRCTN47823388 TARDIS Team Philip Bath, Margaret Adrian University of Nottingham www.tardistrial.org Agenda: Morning Welcome Aims/objectives/design Interventions/protocol Lunch Philip Bath Philip Bath Marg Adrian 5 45 40 Agenda: Afternoon Paperwork, data SAEs / SUSARS Imaging Tea Marg Adrian Philip Bath Philip Bath 60 30 30 Site responsibilities Data Monitoring Cttee Substudies Tea Marg Adrian Philip Bath Philip Bath 45 15 20 TARDIS: People Patients Investigators Trial Steering Committee Trial Management Committee Data Monitoring Committee SAE / Events adjudication Neuroimaging staff Substudy staff www.tardistrial.org Trial Steering Committee Helen Rodgers NewcastleChair Philip Bath Nottingham Stan Heptinstall Nottingham Hugh Markus London Ossie Newell Nottingham Patient Tom Robinson Leicester Graham Venables Sheffield Independent Experts Sponsor’s representative Funder’s representative www.tardistrial.org Trial Management Committee Philip Bath Margaret Adrian Tim England Chamila Geeganage Sandeep Ankolekar TBA Wim Clarke Chief Investigator Coordinator Medic Medic Medic Statistician Financial www.tardistrial.org Other posts Niki Sprigg Events adjudicator TBA Neuroimaging www.tardistrial.org Trial Bodies Funding The British Heart Foundation Sponsor University of Nottingham Adoption Stroke Research Network Live Website www.tardistrial.org Email [email protected] TARDIS: Identifiers ISRCTN: EudraCT: MHRA ref: MREC ref: Sponsor ref: 47823388 2007-006749 03057/0027/001/0001 08/H1102/112 31350 www.tardistrial.org TARDIS: Background Philip Bath www.tardistrial.org Atherothrombosis Cellular: Platelets White cells Endothelial cells Soluble: Fibrinogen Thrombin Antiplatelets and Stroke: Monotherapy Aspirin: Inhibitor of cyclooxygenase Reduces recurrence (RRR) by 17% in patients with prior stroke or TIA Clopidogrel: Adenosine diphosphate (ADP) receptor antagonist Was slight more efficacious than aspirin in CAPRIE Dipyridamole: Inhibits red cell uptake of adenosine Reduced recurrence by 16% (vs placebo, ESPS II) Acute ischaemic stroke/TIA Stroke: Aspirin Dual Triple IST, CAST, MAST-I PRoFESS TIA: Aspirin APT AC FASTER √ (√) ? √ (√) Stroke prevention: Antiplatelets Strategy RRR (%) Aspirin (A) 18 Dipyridamole (D) 16 Clopidogrel (C) vs. A 7 Trial ATT, ESPS II ESPS II CAPRIE AD vs. control AD vs. A AC vs. C AC vs. A AC vs. A AD vs. C ESPS, 23 ( 0) (20) (34) (- 1) ESPS II 9102 ESPS II, ESPRIT 9341 MATCH 7599 CHARISMA 15603 FASTER 392 PRoFESS 20332 N/A ? Triple 2 TARDIS ACD vs. A ACD vs. AD 38 No. 18270 6602 6431 17 Platelet aggregation: In vitro In blood from volunteers Combined aspirin, AR-C69931 and dipyridamole reduce: Platelet aggregation (figures: ADP, PAF) Monocyte activation Neutrophil activation Platelet-monocyte conjugation Platelet-neutrophil conjugation Platelet p-selectin expression Zhao et al. Br J Pharm 2001;134:353-8 Platelet aggregation: Ex vivo In volunteers and patients with previous stroke Combined aspirin, AR-C69931 and dipyridamole (not different from aspirin/clopidogrel) reduce: Platelet aggregation (figures) Monocyte activation Neutrophil activation Platelet-monocyte conjugation Platelet-neutrophil conjugation Zhao et al. Thromb Haemost 2005;93:527-34 Triple 2 trial: Design Randomised controlled trial 50 patients, 1 centre Event: ischaemic stroke or TIA <5 years Primary outcome: tolerability (discontinuations) ACD vs. A (standard of care) Aspirin 75 mg od Clopidogrel 75 mg od Dipyridamole MR 200 mg bd Stopped early at n=17 Open label, blinded outcome, blinded adjudication Positive results of ESPRIT (AD > A) Total exposure 282 months ISRCTN83673558 Sprigg et al. PLoS 2008;3(8):e2852 Triple trial: Patient characteristics Number Age (years) Sex, male (%) 75 Event, stroke (%) Event trial (months)10 Lacunar syndrome (%) Hypertension (%) Diabetes (%) Aspirin 8 61 67 88 8 63 63 13 ACD 9 63 89 78 67 11 Sprigg et al. PLoS 2008;3(8):e2852 Triple trial: Discontinuations Aspirin n=8 ACD n=9 Exposure (mo) 144 138 Discontinuations bruising GI non-compliance 0 (0) 4 (44) 1 2 1 2p 0.08 Sprigg et al. PLoS 2008;3(8):e2852 Triple trial: Safety 2p Death 0 (0) SAEs treatment-related AEs Bleeding, any Recurrent stroke 0 2 0 0 Aspirin ACD n=8 n=9 1 (11) (0) 3 1 (25) 7 (0) 3 (0) 1 1.00 (33) 0.47 (77) (33) (11) 0.06 0.21 1.00 Sprigg et al. PLoS 2008;3(8):e2852 Adverse events: ordinal P<0.01 Sprigg et al. PLoS 2008;3(8):e2852 Triple trial: Other measures Aspirin Hb at end ACD 13.913.4 2p 0.76 Platelet agg. Monocyte act. Platelet-monocyte 84 165 118 70 96 74 BP, PP, HR, RPP No effects/differences 0.05 0.02 0.04 Sprigg et al. PLoS 2008;3(8):e2852 Triple trial: Conclusions Trial very underpowered Stopped early (17 vs. 50 patients) ACD (vs. A) Trends to increased discontinuations and AEs Reduced platelet aggregation, monocyte activation, platelet monocyte conjugates Patients at low risk of recurrence Long time after stroke, lacunars, young Benefit < hazard? Future trials should concentrate on high risk patients so benefit > hazard Sprigg et al. PLoS 2008;3(8):e2852 Triple therapy: Case series HistoryPrior Rx HT/PFO ICAS/HT/HL ICAS/IHD/HT IHD/HT/HL IHD/PE/HL DM/HL/HT IHD/HL DM/HT/HL IHD/ICAS/HT A A A A A C A A A Length AD AD AD AD W WA CD AC AD AD AD Status (months) 15 20 23 5 9 14 1 7 12 Stopped - PFO closed Continuing Continuing Continuing Stopped - further PE Continuing Stopped - haematuria Continuing Continuing No strokes on ACD Willmot et al. J Stroke CVD 2004;13:138-40 Triple therapy (SR): MI Geeganage et al. Unpublished Triple therapy (SR): Major bleeding Geeganage et al. Unpublished Triple therapy (SR): Absolute effects 12 10 8 Control Triple 6 4 2 si on sf u n Tr a M aj o r bl e ed th D ea V as cu la r ev en t M I 0 Geeganage et al. Unpublished Triple therapy (SR): Conclusions Short-term triple therapy: Reduces MI and vascular events Increases bleeding and transfusions Absolute event - efficacy>hazard Stroke: Minimal data on stroke events Minimal data on effects in stroke/TIA patients Need more data! Geeganage et al. Unpublished Any Questions? TARDIS: Aims, objectives Philip Bath www.tardistrial.org TARDIS: Aims (PICO) To assess: Patients With acute TIA or ischaemci stroke Intervention Short-term addition of clopidogrel to standard dual antiplatelet therapy (AD) Comparator Standard dual antiplatelet therapy (AD) Outcomes Efficacy Safety – stroke and its severity bleeding and its severity www.tardistrial.org TARDIS: Predications Patients at high risk of recurrence Acute stroke Acute TIA (ABCD2>4, crescendo TIA) Efficacy: AD >> A; bleeding AD ~ A Efficacy: AC >> A; bleeding AC > A AD is standard of care in UK (NICE) Patients on AD still have strokes (‘failure’) Efficacy: ACD >> AD? Bleeding: ACD > AD? High risk patients: benefit > hazard www.tardistrial.org TARDIS: Design Prospective, randomised, open-label, blinded endpoint, parallel group controlled trial Reduce sources of bias: Randomised Concealment of allocation Blinded endpoint assessment Controlled ACD vs AD (open-label) Intention-to-treat www.tardistrial.org TARDIS: Design Start-up phase of main phase III trial 270 patients, 25+ SRN centres, 3 years Intervention: Addition of clopidogrel to standard antiplatelet therapy ACD vs. AD for one month Oral Aspirin 75 mg od Dipyridamole 200 mg bd MR Clopidogrel 75 mg od Nasogastric = (150 mg pr alt) 100 mg qds, liq/tab = www.tardistrial.org TARDIS: Outcomes (start-up) Primary outcome (day 30): SAEs 12% --> 30%, alpha 5%, power 90% Secondary (days 30, 90): Events: Stroke, Vascular, MI Function: mRS, BI, NIHSS Safety (days 30, 90): Death, SICH, major bleeding www.tardistrial.org TARDIS: Outcomes (main phase) Use ordinal outcome for stroke to: Shift analysis (as with mRS) Reduce sample size, potentially by ~25% Show effects of ACD on event severity Fatal stroke Non-fatal severe stroke Non-fatal mild stroke TIA No event www.tardistrial.org Any Questions? TARDIS: Trial interventions, protocol Margaret Adrian www.tardistrial.org TARDIS: Inclusion criteria Adults (aged >50) at high risk of recurrent ischaemic stroke, within 48hrs of onset: Acute non-cardioembolic ischaemic stroke Motor weakness and/or dysphasia present at randomisation Acute TIA with one or more of Crescendo TIA (>1 TIA within 1 week) AND/OR Taking dual antiplatelet therapy (aspirin/dipyridamole, aspirin/clopidogrel, clopidogrel/dipyridamole) AND/OR ABCD2 score >4 AND Motor weakness/or dysphasia lasting at least 10 minutes for the randomising event www.tardistrial.org ABCD2 score Definitions Stroke - WHO A clinical syndrome characterised by rapidly developing clinical symptoms and/or signs of focal (and at times global) loss of cerebral function with symptoms lasting for more than 24 hours or leading to death, with no apparent cause other than that of vascular origin’ Brain imaging required before trial entry TIA A sudden focal neurological deficit of the brain or eye, presumed to be of vascular origin and lasts less than 24 hours Brain imaging is not required before trial entry TARDIS: Exclusion criteria, 1 Age<50 Motor weakness and/or aphasia lasting <10 minutes Pure sensory, vertigo, dizziness, speech or visual symptoms without weakness Contraindications to, or intolerance of, aspirin, clopidogrel or dipyridamole Definite need for treatment with clopidogrel (e.g. recent MI - within 1yr) Pre-morbid dependency (mRS>2) No enteral access www.tardistrial.org TARDIS: Exclusion criteria, 2 TIA not fulfilling inclusion criteria Definite need for full dose oral (e.g. warfarin) or parenteral (e.g. heparin, GP IIb/IIIa inhibitor) anti-coagulation AF, recent MI Low dose heparin for DVT prophylaxis is allowed Thrombolysis within last 30 hours Severe high BP (BP>185/110 mmHg) Bleeding within 1 year (e.g. peptic ulcer, intracerebral haemorrhage) www.tardistrial.org TARDIS: Exclusion criteria, 3 Parenchymal haemorrhagic transformation (PH I/II), subarachnoid haemorrhage Other non ischaemic cause for weakness Known haemoglobin <10g/dL Known platelet count <100 x 1E9/L Known white cell count <3.5 x 1E9/L Planned surgery during 3 month follow-up (e.g. carotid endarterectomy) Concomitant acute coronary syndrome www.tardistrial.org TARDIS: Exclusion criteria, 4 Stroke secondary to a procedure e.g. carotid or coronary intervention Coma (GCS<8) Non-stroke life expectancy<6 months Dementia Participation in another drug trial Observational Not available for follow-up e.g. studies or non-drug trials are OK no fixed address, overseas visitor Females of childbearing potential, pregnancy or breastfeeding www.tardistrial.org TARDIS: Interventions / Trial Flow Stroke or TIA (<48) Triple Therapy (ACD) for 1 month (Randomised1:1) Dual Therapy (AD) for 1 month Assessment at days 7 and 35 for safety, efficacy, and tolerability 90 day central blinded telephone follow up and end of the trial www.tardistrial.org TARDIS: Trial Flow FBC Form Brain Imaging Form SAE / Outcome Form Hospital Events Form www.tardistrial.org TARDIS: Aspirin Dose: Loading dose: 300mg (whether or not already on aspirin) Maintenance dose: 25mg bd to 75mg od Protocol violation: maintained on 300mg aspirin Route Enteral (including via nasogastric tube): dispersible or crushed tablets Rectal: 150mg suppository alternate days Alternative if necessary All authorised UK brands may be used www.tardistrial.org TARDIS: Dipyridamole Dose: Oral: 200mg modified release (MR) bd Nasogastric tube (e.g. dysphagia): Dipyridamole suspension 75mg tds - 100mg qds Headache from dipyridamole: Wean up from daily MR 200mg or standard release 75mg od to MR 200mg bd Fixed combinations of A and D may be used E.g. Asasantin Retard (aspirin 25mg, dipyridamole 200mg MR bd) All authorised UK brands may be used www.tardistrial.org TARDIS: IMP - Clopidogrel Dose: Loading dose 300mg (day 0) Maintenance dose: 75mg od (days 1 to 30) Route: Enteral (including via nasogastric tube – tablets may be crushed) The IMP is defined by active substance only, so all authorised UK brands may be used www.tardistrial.org TARDIS: Discontinuation of IMP Should the participant discontinue any trial medication, they should remain in the study and take the remaining medications until the end of the trial at day 90, as completeness of follow-up is essential However, should they wish to do so, any participant is free to withdraw from the trial at any time and without giving reason Please notify the Trial Office 0115 823 0210 www.tardistrial.org TARDIS: Investigator’s discretion GI prophylaxis - PPI / H2 antagonist Potential negative interaction of most PPIs on clopidogrel After 30 days, the choice of antiplatelet therapy is up to the treating team E.g. A+D as recommended by NICE www.tardistrial.org TARDIS: Blood tests Baseline: FBC EDTA/whole blood Freeze Serum Centrifuge clotted sample, freeze EDTA/plasma Centrifuge, freeze Day 7: FBC Serum Plasma P-selectin Day 35: FBC P-selectin Collect, sent via post www.tardistrial.org TARDIS: SAEs and Outcome Events Record all SAEs, Outcome and bleeding events occurring within 90 days TIA Stroke MI - NSTEMI, STEMI Unstable angina PVD / Ischaemic limb Bleeding - minor, moderate, major SAEs including death from any cause www.tardistrial.org TARDIS TIMELINE *Clopidogrel 300mg loading dose on Day 0, then 75mg od Days 1 to 30 § Dipyridamole Aspirin 200mg MR bd Days 0 to 30 § 300mg loading dose (if not already received) on Day 0, then 75mg od Days 1 to 30 BASELINE DAY 0 Consent FBC Other bloods - P-selectin - Serum - Plasma Baseline form / Randomise Patient Details Form TCD Loading doses of IMP(s) DAY 3 ±1 TCD Antiplatelets continued at the discretion of the Investigator, e.g. aspirin and dipyridamole as per NICE guidelines § DAY 7 ±1 Day 7 form FBC Other bloods - P-selectin - Serum - Plasma DAY 35 ±3 DAY 90 ±7 Day 35 form FBC Central follow-up HOSPITAL EVENTS FORM - completed only for admitted patients FBC FORM - complete for Day 0, Day 7 and Day 35 FBC and any FBC relating to SAEs BRAIN IMAGING FORM - complete for any additional clinical head scans SAE / OUTCOME FORM - complete for any SAEs or outcomes (Bleeding events, Stroke, TIA, unstable angina, MI, new PVD or Ischaemic limb), death * Given to 50% of randomised patients § If dysphagic, then administer drugs via NG/PEG; clopidogrel, aspirin and standard release dipyridamole can be crushed, or use liquid dipyridamole at a dose range of 75mg tds to 100mg qds. Dispersible aspirin (via NG/PEG) or aspirin suppositories (rectal, 150mg alternate days) can be given. NB Patients must have enteral access at trial entry Patients with dipyridamole headache can reduce the dose (e.g. 200mg MR od, or 75mg od) and then wean up to a total of 400mg daily Mandatory In selected centres only www.tardistrial.org TARDIS: Trial status Stroke Research Network: trial adopted First patient randomized 7 April 2009 Site visits: 16 centres Actively recruiting centres: 3 Patients recruited: 13 10 stroke / 3 TIA Sites obtaining local R&D approval: >60 www.tardistrial.org TARDIS: New sites welcome! Scotland (9): Aberdeen Royal Infirmary Dundee Ninewells Fife Victoria Hospital Glasgow Royal Infirmary Glasgow Western Infirm. Inverness Raigmore Hosp. Lanarkshire Monklands Hosp Melrose Borders General Hosp Stirling Stirling Royal Infirm www.tardistrial.org Any questions? TARDIS: Forms and data entry Margaret Adrian www.tardistrial.org TARDIS: How many forms? Data Entry Forms: Baseline (randomisation) Additional Clinical Brain Imaging Hospital Events Serious Adverse Event/Outcome Day 7 Day 35 Day 90 Other Forms: Site responsibility (delegation) log Patient Details** FBC Blood sample freezer log Drug accountability form Screening Log Data query Data correction Fax cover sheet www.tardistrial.org TARDIS: Patient Details 1-page form: Fax to Nottingham Co-ordinating Centre with consent form/s www.tardistrial.org TARDIS: http://www.tardistrial.org TARDIS: Database Entry www.tardistrial.org TARDIS: Add a new patient www.tardistrial.org TARDIS: Check inclusion/exclusion www.tardistrial.org TARDIS: Baseline form completion Details of Patient and qualifying event (Stroke/TIA) Risk Factors and Past Medical History Current Medications Antithrombotic Antihypertensives Lipid Lowering Anti Gastric Acid medication Premorbid mRS Current Feeding ability Baseline BP x 2, ECG, BM, Temp, Weight GCS, NIHSS Baseline CT/MRI head result TCD Bloods (FBC result) Whether taking bloods for sub-studies www.tardistrial.org TARDIS: Baseline help 1 www.tardistrial.org TARDIS: Baseline validations TIA - weakness and/or dysphasia for minimum of 10mins STROKE - weakness and/or dysphasia must still be present Duration of symptoms ECG result AF? MI within last 12 mos Alteplase treatment within 30hrs Serious Bleed within last 12 mos www.tardistrial.org TARDIS: Error messages TARDIS: Baseline completion www.tardistrial.org TARDIS: Randomisation Result TARDIS: Additional Clinical Brain Imaging www.tardistrial.org TARDIS: Hospital Events TARDIS: SAE / Outcome TARDIS: SAE/Outcome www.tardistrial.org TARDIS: Day 7 • • SAEs: randomisation to D7 (or death) Antithrombotic meds • • • • • • • • • Doses taken since Day 0 (count blister pack) Other medications Two BP readings NIHSS, feeding ability Baseline scan (if done) Whether TCD undertaken at baseline and day 3 Bloods taken and FBC results for Day 7 Lipid results since onset Current disposition of patient- only use N/A if died TARDIS: Day 35 • • • • • • • SAEs: Day 7 to D35 (or death) Ask for empty blister pack to be returned for clopidogrel Other medications Two BP readings NIHSS, feeding ability Whether TCD undertaken at baseline and day 2 FBC: for Day 35 www.tardistrial.org TARDIS: Day 90 This will be undertaken by Nottingham Coordinating Centre - by telephone Assessor blinded to treatment Need full contact details of patient to enable follow-up www.tardistrial.org TARDIS: Site responsibility (delegation) log TARDIS: Patient Details TARDIS: Full Blood Count (FBC) www.tardistrial.org TARDIS: FBC results TARDIS: FBC results TARDIS: Blood sample freezer log TARDIS: Drug accountability log Add drug accountability form…… TARDIS: Screening Log Consecutive 31350 & 08093 TARDIS: Data Query / Correction TARDIS: Fax cover sheet TARDIS: Other information Within TARDIS Website: Frequently Asked Questions (FAQs) Demo Website (demoinv1 / nottingham / 8888) Data Entry Forms Contact list Working Practice Documents (WPDs) Telephone: 0115 823 0210 (plus answerphone) www.tardistrial.org Any questions? TARDIS: Outcome events, Serious Adverse Events, and pharmacovigilance Philip Bath www.tardistrial.org TARDIS: Outcome events / SAEs All Events and SAEs within final follow-up (90 +/- 10 days of enrollment) will be collected Events and SAEs will be collected using same online form to avoid confusion Data will be adjudicated by blinded observer Insufficient information follow-up questions Events: Vascular: stroke, TIA, MI, angina, death Bleeding SAEs www.tardistrial.org TARDIS: SAE / Event form www.tardistrial.org TARDIS: Stroke/TIA information Stroke: Clinical – symptoms, signs, outcome Imaging - CT and/or MR (send images) TIA: Clinical – symptoms, signs (nil new), length, not a mimic www.tardistrial.org TARDIS: Stroke event www.tardistrial.org TARDIS: MI/angina information Myocardial infarction: Clinical – chest pain, tachycardia, pale, sweaty, nausea, duration, … Biochemistry – enzyme levels (troponin, CK) ECG – new q waves, ST elevation, … (fax it) Angina, unstable / stable: Clinical – symptoms Biochemistry – enzyme levels ECG – no new q wave, ST depression www.tardistrial.org Definitions: Acute Coronary Syndromes Acute cardiac chest pain No ST segment elevation ST segment elevation Cardiac enzymes not elevated Elevated cardiac enzymes Elevated cardiac enzymes UNSTABLE ANGINA (including new onset angina, angina at rest and increasing angina) NSTEMI Non-ST elevation myocardial infarction STEMI ST elevation myocardial infarction TARDIS: Bleeding, definition 1 Major bleed: Fatal bleeding; and/or Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome; and/or Bleeding causing fall in Hb >2 g/l (1.24 mmol/l) or more, or leading to transfusion of >2 units of whole blood or red cells All major bleeds are an SAE www.tardistrial.org TARDIS: Bleeding, definition 2 Moderate bleed: Not major; and Bleeding causing fall in Hb <2 g/l (1.24 mmol/l), and leading to no transfusion, or transfusion of only 1 unit of whole blood or red cells Moderate bleeds may or may not be a SAE depending on other criteria, e.g. hospitalisation, disabling The CC will sort this out www.tardistrial.org TARDIS: Bleeding, definition 3 Mild bleed: Not major or moderate; and Comprising bruising, ecchymoses, gingival bleed or similar other type bleeding Mild bleeds cannot constitute a serious adverse event www.tardistrial.org TARDIS: Bleeding information Clinical Organ – brain, joint, muscular, occular, pericardial, retropeironeal, skin, spine, … Transfusion – how many/no (Outcome) Haematology – change in levels www.tardistrial.org Pharmacovigilance: Question What is it? 1. The science and activities to monitor drug interactions 2. The science and activities to detect, assess, understand and prevent adverse drug effects Pharmacovigilance: Answer What is it? 1. The science and activities to monitor drug interactions 2. The science and activities to detect, assess, understand and prevent adverse drug effects TARDIS: Adverse events We will not collect AEs: Clopidogrel is already licensed Considerable information is already known about it CAPRIE, CURE, CREDA, CHARISMA, … (S)AE: Recording - Question What should be recorded? 1. Any untoward medical occurrence to a patient after (s)he has signed the informed consent 2. Operations/procedures occurring during the trial, but scheduled prior to trial enrolment 3. Illnesses recorded at screening visit 4. Significant laboratory abnormalities (S)AE: Recording - Answer What should be recorded? 1. Any untoward medical occurrence to a patient after (s)he has signed the informed consent 2. Operations/procedures occurring during the trial, but scheduled prior to trial enrolment 3. Illnesses recorded at screening visit 4. Significant laboratory abnormalities Adverse event: Definition Any untoward medical occurrence in a study subject administered an intervention and which does not necessarily have a causal relationship with this treatment Reporting an adverse event is NOT limited to NOR implies a causal relationship A medical or surgical procedure is not an AE, the reason for the procedure is! Abnormal laboritory values are AEs if ‘clinically significant’, lead to treatment change, are a SAE, or are a safety risk SAE: Components - Question Any untoward medical occurrence that? 1. Results in death 2. Is life-threatening 3. Requires inpatient hospitalisation or prolongation of existing hospitalisation 4. Is an adverse event assessed as severe 5. Results in persistent or significant disability/incapacity 6. Is a congenital anomaly/birth defect 7. Is medically important SAE: Components - Answer Any untoward medical occurrence that? 1. Results in death 2. Is life-threatening 3. Requires inpatient hospitalisation or prolongation of existing hospitalisation 4. Is an adverse event assessed as severe 5. Results in persistent or significant disability/incapacity 6. Is a congenital anomaly/birth defect 7. Is medically important SAE: Life-threatening Refers to an event in which the patient was at risk of death at the time of the event Does not refer to an event which hypothetically might have caused death if it had been more severe SAE: Medically important Serious adverse events that may jeopardise the patient or may require medical or surgical intervention to prevent one of the other serious outcomes Examples: Allergic bronchospasm requiring intensive treatment in A&E Convulsion not resulting in in-patient hospitalisation An abnormal lab value which needs active out-patient management SAE: Required information – Quest. 1. 2. 3. 4. 5. 6. 7. Causality Prognosis Patient’s address Intensity Outcome Hospital cost Action taken SAE: Required information - Answer 1. 2. 3. 4. 5. 6. 7. Causality Prognosis Patient’s address Intensity Outcome Hospital cost Action taken SAE: Causality to intervention Definitely Probably Possibly Unlikely Not related Temporal relationship Re-challenge Other aetiology v. strong strong suggestive weak none v. strong strong N/A N/A N/A none unlikely equally likely likely v. likely SAE: Intensity Severe Incapacitating Prevents daily activities Not a measure of seriousness Moderate Uncomfortable Impairs daily activities Mild Minimal discomfort Non-intefering with daily activities SAE: Serious or Severe ‘Severe’ A medical judgement used to describe intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction) The event itself, however, may be of relatively minor medical significance (e.g. ‘severe headache’). So severity does not mean serious ‘Serious’ Based on event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning Serves as a guide for defining regulatory reporting obligations SAE: Outcome Recovered Not yet recovered Used Died for chronic conditions SAE: Outcome - Question What is important when recording a SAE with fatal outcome? 1. Death should be the primary SAE event 2. Death is an outcome 3. Provide a clinicial summary describing the symptoms/events preceding death 4. Provide the autopsy report when available SAE: Outcome - Answer What is important when recording a SAE with fatal outcome? 1. Death should be the primary SAE event 2. Death is an outcome 3. Provide a clinicial summary describing the symptoms/events preceding death 4. Provide the autopsy report when available So, death is an outcome, not an event! SAE: Action taken Treatment: None, i.e. continued Interrupted Discontinued SUSAR, 1 Suspected Unexpected Serious Adverse Reaction: Unexpected Unlikely in context of antiplatelet agents Serious – needs to meet criteria for serious Fatal Life threatening Disabling Hospitalisation (admission or prolongation) Teratogenic Medically important SUSAR, 2 Reaction Suspected drug reaction Not just a consequence or complication of stroke Requires notification to Trial Office <24 hours TARDIS should generate very few, if any, SUSARs SAE: Example - Question A patient experiences myocardial infarction with chest pain, dyspnoea, diaphoresis, ECG changes, enzyme changes, and jaundice. What SAE(s) should be recorded? 1. Record all diagnoses and symptoms as SAEs 2. Only record the overall diagnosis of MI as an SAE 3. Record MI and jaundice as SAEs SAE: Example - Answer A patient experiences myocardial infarction with chest pain, dyspnoea, diaphoresis, ECG changes, enzyme changes, and jaundice. What SAE(s) should be recorded? 1. Record all diagnoses and symptoms as SAEs 2. Only record the overall diagnosis of MI as an SAE 3. Record MI and jaundice as SAEs SAE: Coding Example Investigator term Verbatim, raw term Standard term Headache, head pain cephalgia Headache Please look for standard term in available list TARDIS: SAE questions, 1 When did it start? Before / during / after Fatal? Y/N Life-threatening? Y/N Hospitalisation? Y/N Disabling? Y/N Birth defect? Y/N Medically important? Y/N Category? Stroke / MI / Bleed / SAE Describe? www.tardistrial.org TARDIS: SAE questions, 2 Date/time began? Nature? Single / Multiple Intensity? Mild / Moderate / Severe Relationship? Definitely not / … / definite Action? Continue/Missed/Stopped Outcome? Recovered / … / Died www.tardistrial.org TARDIS: SAE questions, 3 Diagnostic evidence *As much info. as possible Pathology Radiology ECG Bacteriology Biochemistry Haematology Clinical Comment www.tardistrial.org TARDIS: SAE questions, 4 Event Limb weakness Speech disturbance Sensory disturbance Visual field loss Posterior circulation Other Length of symptoms Severity Brain imaging Type Stroke / TIA / N/A Y/N Y/N Y/N Y/N Y/N Describe ABCD2 bands ABCD2 / NIHSS score / ? IS/HTI/ICH/? www.tardistrial.org TARDIS: SAE questions, 5 Event Chest pain SOB Sweating Nausea/vomit ECG date ECG changes Enzyme date Enzymes UA / NSTEMI / STEMI / N/A Y/N Y/N Y/N Y/N Ts inv / ST el / ST dep / Q wave Trop I/Trop T/CK/CKMB/ND www.tardistrial.org TARDIS: SAE questions, 6 Bleed Minor / Moderate / Major / N/A Blood transfusion 0/ 1/ 2/ 3/ 4/ 5/ 6/ >6 units Where CNS Respiratory CV Retroperitoneal GI Skin GU Other MS Ocular www.tardistrial.org TARDIS: SAE questions, 7 SAE preferred term Cardiovascular CNS Cutaneous Gastrointestinal Genito-urinary Haematological Immunological Musculoskeletal Respiratory Other / miscellaneous AF/ bradycardis/… Agitation/ anxiety/… Bullous/ eczema/… Abdo pain/ colitis/… Sex dys./ incont./… Anaemia/ agran/… Anaphylactic/… Arthritis/… Bronchospasm/… www.tardistrial.org TARDIS: SAE questions, 8 SUSAR If fatal, cause Y/N IS, IHD, PAD, VTE, other vasc, non vasc, major bleed date www.tardistrial.org SAE: Problems in trials Failure to report Select inappropriate SAE type Too little diagnostic evidence submitted (or available) Chase other hospitals, fax available information Failure to report promptly SAE: >48 hours of knowledge SUSAR: >24 hours of knowledge If uncertain, ask TARDIS CC Any questions? TARDIS: Imaging Philip Bath www.tardistrial.org Introduction Importance of CT in classification of stroke Classification of stroke type Type of stroke Compatibility with presenting stroke Mass effect Cerebral atrophy White matter disease Previous stroke Quiz CT scans Usually don’t diagnose stroke (clinical) Useful in determining type of stroke Ischaemic Haemorrhagic CT scans in ischaemic strokes can be normal early after onset or with very small lacunar strokes (normal scan does not exclude stroke) Haemorrhagic strokes always abnormal if done acutely / sub-acutely Give other information e.g atrophy TARIS: Baseline form BASELINE CT OR MRI HEAD Date of scan (dd/mm/yyyy) Type of scan? Please complete with regards to the baseline head scan? / CT / MRI No scan NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STROKE - NO BLOOD ISCHAEMIC STROKE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STROKE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Stroke - head scan required before randomisation TIA - no scan required www.tardistrial.org Haemorrhagic Transformation of Infarction (HTI) ISCHAEMIC STROKE MINOR BLOOD = ISCHAEMIC STROKE MAJOR BLOOD = Haemorrhagic Infarct (HI): petechial infarction without space occupying effect. Parenchymal Haemorrhage (PH): haemorrhage with mass effect. HI1 - small petechiae HI2 - more confluent petechiae PH1 - <30% of the infarcted area with mild space occupying effect PH2 - >30% of the infarcted area with significant space occupying effect. www.tardistrial.org Haemorrhagic Transformation of Infarction (HTI) ISCHAEMIC STROKE MINOR BLOOD = ISCHAEMIC STROKE MAJOR BLOOD = Haemorrhagic Infarct (HI): petechial infarction without space occupying effect. Parenchymal Haemorrhage (PH): haemorrhage with mass effect HI1 - small petechiae HI2 - more confluent petechiae PH1 - <30% of the infarcted area with mild space occupying effect PH2 - >30% of the infarcted area with significant space occupying effect. www.tardistrial.org TARDIS: Baseline form √ BASELINE CT OR MRI HEAD Date of scan (dd/mm/yyyy) Type of scan? Please complete with regards to the baseline head scan? / CT / MRI No scan NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STROKE - NO BLOOD ISCHAEMIC STROKE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STROKE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) www.tardistrial.org TARDIS: Baseline form √ BASELINE CT OR MRI HEAD Date of scan (dd/mm/yyyy) / Type of scan? CT Please complete with regards to the baseline head scan? / MRI No scan NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STROKE - NO BLOOD ISCHAEMIC STROKE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STROKE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) www.tardistrial.org CT scans - Ischaemic stroke CT scans - Haemorrhagic stroke TARDIS: Day 7 Form - Imaging BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible Comments/reason for no scan Report available No scan / / YES : NO www.tardistrial.org TARDIS: Day 7 Form - Imaging BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible Comments/reason for no scan / / YES : NO TARDIS: CT scan - lesion Choose ‘normal’ if… ‘Normal scan’ ‘Normal for age’ ‘no intracranial abnormalities’ Choose ‘no lesion explaining symptoms’ lesion on the wrong side or if only old strokes, atrophy and white matter change mentioned www.tardistrial.org TARDIS: CT scan - lesion Choose ‘Ischaemic Stroke - no blood’ if…. Do not choose this if words like ‘old’, ‘mature’, go with the words ‘infarct’ or ‘hypodensity’ ‘hypodensity’, ‘infarct’, ‘infarction’, ‘low attenuation’ +/- ‘acute’,‘recent’, ‘subacute’, ‘patchy’, ‘subtle’ Instead choose ‘no lesion explaining symptoms’ Choose ‘Ischaemic stroke - minor blood’ If any of the top descriptions plus ‘haemorrhage’, ‘blood’, ‘bleeding’, ‘haemorrhagic transformation’, ‘petechial haemorrhage’ major blood / PH1,PH2 should have been excluded - but if ‘large’/’significant’ blood, then ask. www.tardistrial.org TARDIS: CT scan - lesion Choose ‘OTHER’ if… Most commonly tumour If there is something mentioned in the scan that you don’t understand or you are not sure if it explains the presentation, ask… If they mention a stroke AND another lesion, ask… www.tardistrial.org TARDIS: CT scan - compatible with presentation? BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible Comments/reason for no scan / / YES : NO TARDIS: CT scan - compatible with presentation? Remember - left sided lesions cause right sided symptoms and vice versa Bearing that in mind… If acute stroke evident, say yes If normal scan, say yes (as long as clinical diagnosis remains stroke) If old strokes/other lesions, ask! www.tardistrial.org TARDIS: Mass effect BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible Comments/reason for no scan / / YES : NO Mass effect TARDIS: CT scan - mass effect Chose yes if… ‘mass effect’, ‘midline shift’, ‘ventricular effacement’ If it says these are not present or there is no mention of them, chose no Please note that hydrocephalus is NOT mass effect www.tardistrial.org Mass effect v hydrocephalus TARDIS: Cerebral Atrophy BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible Comments/reason for no scan / / YES : NO Atrophy TARDIS: CT scans - atrophy Answer yes if… “Atrophy” or “involutional change” If no mention or ‘age appropriate’ and the patient is under 60, say no www.tardistrial.org TARDIS: Leukoariosis BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible Comments/reason for no scan / / YES : NO CT scan - periventricular white matter lucency TARDIS: CT scan - periventricular white matter lucency Choose yes if… “periventricular white matter lucency”, “leukoaraiosis”, “white matter disease”, “white matter change”, “small vessel disease”, “small vessel ischaemia.” If the report says these are absent or not mentioned, say no. www.tardistrial.org TARDIS: CT scan - previous strokes BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible Comments/reason for no scan / / YES : NO TARDIS: CT scan - previous strokes Choose yes if… “old”, or “mature” infarcts If they are not mentioned, or are noted to be absent absent, say no. www.tardistrial.org TARDIS: Most important of all If you don’t understand the scan report, please ask a doctor The more you do, and the more you ask, the more you will get used to the terminology www.tardistrial.org Test number 1 78 year old patient with right sided weakness and aphasia. CT report: There is extensive infarction affecting the entire MCA territory on the left with a hyperdense MCA. There is associated midline shift. There is some high intensity change within the infarction, suggestive of petechial bleeding. Case 1 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 1 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 1 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 1 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 1 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 1 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 1 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Test number 2 70 year old patient with sudden onset right sided weakness. CT report: There is evidence of multiple well-established old infarction in both cerebral hemispheres. There is an area of hypodensity in the region of the left internal capsule which may represent more recent ischaemia. There is extensive leukoaraiosis and atrophy. Case 2 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 2 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 2 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 2 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 2 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 2 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Case 2 - answers BASELINE CT/MRI SCAN (performed prior to rand omisation) CT/MRI scan performed before randomisation? Date and time of scan (dd/mm/yyyy hh:mm) The result of the scan CT / MRI No scan / : NOT DONE BECAUSE TIA NORMAL NO LESION EXPLAINING SYMPTOMS ISCHAEMIC STRO KE - NO BLOOD ISCHAEMIC STRO KE - MINOR BLOOD (HI1 OR HI2) ISCHAEMIC STRO KE - MAJOR BLOOD (PH1 OR PH2) OTHER (E.G. TUMOUR, ABCESS) Is the sca n compatible with the presenting event? YES NO Is there evidence of mass effect YES NO Is there evidence of cerebral atrophy YES NO Is there evidence of periventicular white matter lucency (e.g. leukoariosis)? YES NO Is there evidence of previous strokes? YES NO Have you uploaded the scan? (If no, please do so as soon as pos sible) YES NO Has a further (clinical) scan been done since randomisation? YES NO If yes, date and time (dd/mm/yyyy hh:mm) If yes, have you uploaded the scan? If no, please do so as soon as possible / / YES : NO Comments/reason for no scan www.tardistrial.org Any questions? TARDIS: Site responsibilities and trial files Margaret Adrian www.tardistrial.org Record Keeping Documents individually and collectively permit the evaluation of the trial and the quality of the data produced. Documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of GCP and all applicable regulatory requirements ICH GCP 8.1 What do we mean by records? Site file Case record form Medical notes Site File Contact List / Investigator Site Personnel Study Documentation Regulatory Approved Documents Signed Agreement Study Medication/Laboratory Recruitment Screening log/signed consent forms SAE/SUSAR Report Monitoring Reports Miscellaneous Case Record Form (CRF) Accurate and legible Changes Consistent with source documents Document all visits/tests Document and explain all deviations Patient medical notes Stickers Copy of PIS/consent GP letter Trial medication Serious Adverse Events Storage of records Confidential Archiving TARDIS is sponsored by The University of Nottingham Conclusion A simple and accurate paper trial is essential to demonstrate the validity and integrity of study conduct Any Questions? TARDIS: Trial monitoring Margaret Adrian www.tardistrial.org Purpose of monitoring To verify that: The rights and well being of human subjects are protected The reported trial data are accurate, complete, and verifiable from source documents The conduct of the trial is in compliance with the protocol, GCP and regulatory requirements Types of monitoring in clinical trials Approaches to trial monitoring should be appropriate to the trial and should be proportionate to its: Size Complexity Risks, both to the participants and the results Trial Oversight Committees The funding body or sponsor may specify particular oversight arrangements, but even if they do not, some form of oversight is strongly recommended for all trials, although the appropriate structures will vary according to the size, complexity and risks associated with the trial Commonly employed oversight committees: Trial Steering Committee (TSC) Trial Management Committee (TMC) Data Monitoring Committee (DMC) Trial Steering Committee (TSC) Roles: Provide overall supervision of the trial Ensure that trial is being conducted according to GCP and the relevant regulations Agree the trial protocol and any protocol amendments Provide advice to the investigators on all aspects of the trial Have independent members, including Chair Decide on continuation, change or termination of the trial Trial Management Committee (TMC) Composition: Individuals responsible for the day-to-day management of trial Chief investigator, trial manager, statistician, coordinators, data manager Roles: Monitor all aspects of the conduct and progress of the trial Ensure that the protocol is adhered to and take appropriate action to safeguard participants and the quality of the trial itself Coordinating centre monitoring Day-to-day monitoring should be carried out by those responsible for running a trial Typically includes following checks: Data consistent with adherence to protocol CRF’s are only completed by authorised staff No key missing data Data appear to be valid (range, consistency) Review of recruitment rates, withdrawals and losses to follow-up Central monitoring Central monitoring is defined as: ‘Centralised procedures for quality control of trial data’ These may include: Statistical checks over time and across different data items to identify unusual data patterns within and across centers External validation of selected data items Central monitoring Central collection of copies of radiographs, scans, or pathology reports which permit the study coordinators to verify independently key criteria for eligibility or outcome With the participant’s consent, national vital statistics services may be used for the corroboration of the existence of the subject or the verification of mortality outcomes Central monitoring Using stroke registers to confirm information on eligibility or outcomes Central monitoring of data using statistical techniques for identification of unusual patterns of data Can be used to identify sites or contributors that may be deviating from the protocol Participant consent may be confirmed by the collection of a copy of the consent form at the coordinating centre, with measures to ensure confidentiality On-site monitoring, 1 On-site visits provide the opportunity to: Educate staff about the trial Understand the protocol and trial procedures Verify that site staff have access to the necessary documents to conduct the trial Confirm that required pharmacy and laboratory resources are in place On-site monitoring, 2 On-site visits provide the opportunity to (continued): Check adherence to the protocol and GCP Verify selected data and SAEs recorded in CRFs as compared with data in clinical records to identify errors of omission as well as inaccuracies Confirm that written consent was obtained If copies of the form are not held in the coordinating centre Source documentation All electronic data should be supported by source documentation Source documentation is any form of documentation on which the initial information is written, regardless of what it has been written on All forms of source documentation will need to be filed and retained Minimum information Centre No, Recruit ID, Recruit Initials Source documentation The following are all considered forms of source documentation: Medical records Nursing records Drug chart Paper CRF’s CT/MRI reports Diagnostic investigational reports Findings from site monitoring visits Document Control - Version Numbers Stroke onset time not clearly documented in medical records Absence of documents Lack of Delegation of responsibilities Site files non-existent/not up to date Inconsistent dates and times Limited written entries in medical records Failure to report SAE’s Each page of a CRF must have unique trial identifier and the dated and signed by investigator Any Questions? TARDIS: Data Monitoring Philip Bath www.tardistrial.org TARDIS: Data Monitoring, 1 Composition: Professor Ian Ford (Chair, Glasgow) Biostatistician, Dr Cathie Sudlow (Edinburgh) Stroke neurologist, antiplatelets (ATT) Dr Matthew Walters (Glasgow) Clinical trialist (IMAGES, WOSCOPS, …) Pharmacologist, stroke trialist Mr Michael Tracy (Nottingham) TARDIS statistician www.tardistrial.org TARDIS: Data Monitoring, 2 Roles: Safeguard interests of participants Assess safety and efficacy Monitor trial conduct Respond to any investigator concerns Consider requests for release of data Advice potential funder(s) of main phase Perform extra interim analyses as needed Consider results of any other studies/trials Recommend: continuation, change or stop TARDIS: Data Monitoring, 3 Modus operandi: 6 monthly assessments of data Data tables prepared by trial statistician Teleconference (or meeting) Open then closed session Minuted Report to Chair of TSC (Helen Rodgers), cc CI (PB) Closed session confidential www.tardistrial.org TARDIS: Data Monitoring, 4 Roles: Review accruing unblinded trial data Assess whether there are any safety issues that participants’ should be informed of Assess whether trial should continue or not Be independent of investigators, funder & sponsor Make recommendations to the TSC TARDIS: Data Monitoring, 4 Trials status: Timelines Recruitment Patients, centres, patients/centre Data completeness, quality Patients: Baseline features Balance by treatment groups Outcomes TARDIS: Data Monitoring, 5 Data: Modified Rankin Scale Stroke (ischaemic and haemorrhage) Bleeding: major SICH (<2%) Death SAEs www.tardistrial.org Any Questions? TARDIS: Sub-studies Philip Bath www.tardistrial.org TARDIS: Sub-studies Transcranial Doppler: Centres with TCD machines and staff already trained in their use MCA monitoring of emboli P-Selectin: Aspirin / clopidogrel resistance Pharmacogenetics: Antiplatelet effects/resistance by genotype Serum & Plasma samples: For future testing www.tardistrial.org Any Questions? And many thanks for attending TARDIS: Inclusion criteria Adults at high risk of recurrent ischaemic stroke: Acute non-cardioembolic ischaemic stroke (<48 hours of onset) Acute TIA (<48 hours of onset) with an ABCD2 score >5 (stroke rate at 13 weeks>10%). (All TIAs and strokes must have motor weakness lasting at least 10 minutes) www.tardistrial.org TARDIS: Exclusion criteria Age<50; Motor weakness lasting <10 minutes Pure sensory, vertigo or dizziness, speech or visual disturbance symptoms Intolerance/contraindications to A, C, or D Definite need for C Pre-morbid dependency (mRS>3) No enteral access Parenchymal haemorrhage (PH I/II) TIA not fulfilling inclusion criteria AF/cardioembolic stroke BP>185/110 mmHg Recent PU, ICH Planned surgery within 3 months www.tardistrial.org TARDIS: Substudies - biomarkers TCD emboli (baseline, day 2)? As in CARESS At Leicester & Nottingham LAD; but limited power (or do as pilot) Platelet function (baseline, day 7) All centres P-selectin (fixed blood) Central assay Nottingham Also VerifyNow (PoC) at Nottingham Pharmacogenetics Antiplatelet efefcts, resistance www.tardistrial.org TARDIS: Trial status MREC approval MHRA approval Local SSI/R&D ongoing UKSRN Adoption ongoing UK investigator meeting 23-24/03/09 Start April 2009 www.tardistrial.org Resistant stroke/TIA Non-cardioembolic stroke/TIA with recurrence: On mono antiplatelet therapy Add another antiplatelet (A->AD, C->?) [But should be on two already (NICE)] On dual antiplatelet therapy? Anticoagulation Ineffective in SPIRIT, WARSS, ESPRIT Mixed anticoagulation and antiplatelet (WA) No trial data (but ineffective in cardioembolic stroke) Triple (W) antiplatelet therapy No trial data Triple 2 trial: Logistics TSA grant Trial manager Trent LRN Research Nurses Identify, recruit patients; perform measurements Trent LRN TCD equipment? NHS Treatment Costs: Clopidogrel NHS Indirect Costs: Blood counts Triple therapy: Systematic review Aim: Safety and efficacy of triple vs. conventional antiplatelet therapy in the prevention of vascular events Methods: Electronic searches Cochrane Review Manager Geeganage et al. Unpublished Triple therapy: Systematic review RCTs Trials 12; patients 10,538 ACS/PCI 11; stroke/TIA 1 Observational studies Studies 7; patients 20,167 Treatment Start Length Geeganage et al. Unpublished Triple therapy (SR): Results - RCTs T N E OR CI Efficacy MI 10 Ischaemic stroke Vascular 9795 3 9 783 3684 9595 0.71 6 852 0.56-0.90 3.02 0.60-15.23 0.73 0.58-0.92 Safety Death Bleed major Bleed minor Transfusion Thrombocytopen. 9 10 8 6 5 9595 9820 8864 8874 6541 103 156 242 192 25 0.87 1.24 1.52 1.52 9.45 0.59-1.29 0.90-1.73 1.17-1.97 1.13-2.05 2.53-33.34 Geeganage et al. Unpublished Triple therapy (SR): Results - OSs T Efficacy MI 4 Ischaemic stroke 0 Vascular 4 Safety Death 6 Bleed major 7 Bleed minor 3 Transfusion 1 Thrombocytopen. 2 N E OR CI 8240 327 0.46 0.25-0.85 8240 430 0.44 0.25-0.79 11923 71 20004 316 5477 191 4809 61 3311 12 0.34 1.57 1.08 1.44 0.79 0.18-0.64 1.11-2.22 0.63-1.88 0.45-4.62 0.21-3.01 Geeganage et al. Unpublished