triple antiplatelets for reducing dependency after ischaemic stroke tardis – isrctn47823388
DESCRIPTION
Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke TARDIS – ISRCTN47823388. TARDIS Team Philip Bath, Margaret Adrian University of Nottingham. www.tardistrial.org. Agenda: Morning. WelcomePhilip Bath 5 Aims/objectives/designPhilip Bath45 - PowerPoint PPT PresentationTRANSCRIPT
Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke
TARDIS – ISRCTN47823388
Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke
TARDIS – ISRCTN47823388
TARDIS TeamPhilip Bath, Margaret Adrian
University of Nottingham
www.tardistrial.org
Agenda: MorningAgenda: Morning
Welcome Philip Bath 5Aims/objectives/design Philip Bath 45Interventions/protocol Marg Adrian 40 Lunch
Agenda: AfternoonAgenda: Afternoon
Paperwork, data Marg Adrian 60SAEs / SUSARS Philip Bath 30Imaging Philip Bath 30 Tea
Site responsibilities Marg Adrian 45Data Monitoring Cttee Philip Bath 15Substudies Philip Bath 20 Tea
TARDIS: PeopleTARDIS: People
Patients Investigators Trial Steering Committee Trial Management Committee Data Monitoring Committee SAE / Events adjudication Neuroimaging staff Substudy staff
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Trial Steering CommitteeTrial 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 CommitteeTrial Management Committee
Philip Bath Chief Investigator Margaret Adrian Coordinator Tim England Medic Chamila GeeganageMedic Sandeep Ankolekar Medic TBA Statistician Wim Clarke Financial
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Other postsOther posts
Niki Sprigg Events adjudicator
TBA Neuroimaging
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Trial BodiesTrial Bodies
Funding The British Heart Foundation
Sponsor University of Nottingham
Adoption Stroke Research Network
Live Website www.tardistrial.org
Email [email protected]
TARDIS: IdentifiersTARDIS: Identifiers
ISRCTN: 47823388 EudraCT: 2007-006749 MHRA ref:03057/0027/001/0001 MREC ref: 08/H1102/112 Sponsor ref: 31350
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TARDIS: BackgroundTARDIS: Background
Philip Bath
www.tardistrial.org
AtherothrombosisAtherothrombosis
Cellular: Platelets White cells Endothelial cells
Soluble: Fibrinogen Thrombin
Antiplatelets and Stroke: MonotherapyAntiplatelets 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/TIAAcute ischaemic stroke/TIA
Stroke: Aspirin IST, CAST, MAST-I √ Dual PRoFESS (√) Triple ?
TIA: Aspirin APT √ AC FASTER (√)
Stroke prevention: AntiplateletsStroke prevention: Antiplatelets
Strategy RRR (%) Trial No.Aspirin (A) 18 ATT, ESPS II 18270Dipyridamole (D) 16 ESPS II 6602Clopidogrel (C) vs. A 7 CAPRIE 6431
AD vs. control 38 ESPS, ESPS II 9102AD vs. A 23 ESPS II, ESPRIT 9341AC vs. C ( 0) MATCH 7599AC vs. A (20) CHARISMA 15603AC vs. A (34) FASTER 392AD vs. C (- 1) PRoFESS 20332
ACD vs. A N/A Triple 2 17ACD vs. AD ? TARDIS
Platelet aggregation: In vitroPlatelet aggregation: In vitro
In blood from volunteersCombined 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 vivoPlatelet 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: DesignTriple 2 trial: Design
Randomised controlled trial Open label, blinded outcome, blinded adjudication
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 Positive results of ESPRIT (AD > A)
Total exposure 282 months ISRCTN83673558
Sprigg et al. PLoS 2008;3(8):e2852
Triple trial: Patient characteristicsTriple trial: Patient characteristics
Aspirin ACDNumber 8 9Age (years) 61 63Sex, male (%) 75 67Event, stroke (%) 88 89Event trial (months) 10 8Lacunar syndrome (%) 63 78Hypertension (%) 63 67Diabetes (%) 13 11
Sprigg et al. PLoS 2008;3(8):e2852
Triple trial: DiscontinuationsTriple trial: Discontinuations
Aspirin ACD 2p n=8 n=9
Exposure (mo) 144 138
Discontinuations 0 (0) 4 (44) 0.08bruising 1GI 2non-compliance 1
Sprigg et al. PLoS 2008;3(8):e2852
Triple trial: SafetyTriple trial: Safety
Aspirin ACD2p
n=8 n=9
Death 0 (0) 1 (11) 1.00SAEs 0 (0) 3 (33) 0.47
treatment-related 1AEs 2 (25) 7 (77) 0.06Bleeding, any 0 (0) 3 (33) 0.21Recurrent stroke 0 (0) 1 (11) 1.00
Sprigg et al. PLoS 2008;3(8):e2852
Adverse events: ordinalAdverse events: ordinal
P<0.01
Sprigg et al. PLoS 2008;3(8):e2852
Triple trial: Other measuresTriple trial: Other measures
Aspirin ACD 2p
Hb at end 13.913.4 0.76
Platelet agg. 84 70 0.05Monocyte act. 165 96 0.02Platelet-monocyte 118 74 0.04
BP, PP, HR, RPP No effects/differences
Sprigg et al. PLoS 2008;3(8):e2852
Triple trial: ConclusionsTriple 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 seriesTriple therapy: Case series
History Prior Rx Length Status (months)
HT/PFO A AD 15 Stopped - PFO closedICAS/HT/HL A AD 20 ContinuingICAS/IHD/HT A AD 23 ContinuingIHD/HT/HL A AD 5 ContinuingIHD/PE/HL A W WA CD 9 Stopped - further PEDM/HL/HT C AC 14 ContinuingIHD/HL A AD 1 Stopped - haematuriaDM/HT/HL A AD 7 ContinuingIHD/ICAS/HT A AD 12 Continuing
No strokes on ACD
Willmot et al. J Stroke CVD 2004;13:138-40
Triple therapy (SR): MITriple therapy (SR): MI
Geeganage et al. Unpublished
Triple therapy (SR): Major bleedingTriple therapy (SR): Major bleeding
Geeganage et al. Unpublished
Triple therapy (SR): Absolute effectsTriple therapy (SR): Absolute effects
0
2
4
6
8
10
12
MI
Vascular event
Death
Major bleedTransfusion
ControlTriple
Geeganage et al. Unpublished
Triple therapy (SR): ConclusionsTriple 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?Any Questions?
TARDIS: Aims, objectivesTARDIS: Aims, objectives
Philip Bath
www.tardistrial.org
TARDIS: Aims (PICO)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 - stroke and its severity Safety – bleeding and its severity
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TARDIS: PredicationsTARDIS: 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
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TARDIS: DesignTARDIS: 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
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TARDIS: DesignTARDIS: 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 NasogastricAspirin 75 mg od = (150 mg pr alt)Dipyridamole 200 mg bd MR 100 mg qds, liq/tabClopidogrel 75 mg od =
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TARDIS: Outcomes (start-up)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
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TARDIS: Outcomes (main phase)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
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Any Questions?Any Questions?
TARDIS: Trial interventions, protocolTARDIS: Trial interventions, protocol
Margaret Adrian
www.tardistrial.org
TARDIS: Inclusion criteriaTARDIS: 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
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ABCD2 scoreABCD2 score
DefinitionsDefinitions
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, 1TARDIS: 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
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TARDIS: Exclusion criteria, 2TARDIS: 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)
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TARDIS: Exclusion criteria, 3TARDIS: 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
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TARDIS: Exclusion criteria, 4TARDIS: 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 studies or non-drug trials are OK Not available for follow-up
e.g. no fixed address, overseas visitor Females of childbearing potential, pregnancy
or breastfeedingwww.tardistrial.org
TARDIS: Interventions / Trial FlowTARDIS: Interventions / Trial Flow
Stroke orTIA (<48)
Dual Therapy(AD) for 1 month
Triple Therapy(ACD) for 1 month
(Randomised 1:1)
Assessment at days 7 and 35 forsafety, efficacy, and tolerability
90 day central blinded telephonefollow up and end of the trial
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TARDIS: Trial FlowTARDIS: Trial Flow
Hospital Events Form
FBC Form
Brain Imaging Form
SAE / Outcome Form
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TARDIS: AspirinTARDIS: 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
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TARDIS: DipyridamoleTARDIS: 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
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TARDIS: IMP - ClopidogrelTARDIS: 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
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TARDIS: Discontinuation of IMPTARDIS: 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
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TARDIS: Investigator’s discretionTARDIS: 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
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TARDIS: Blood testsTARDIS: Blood tests
Baseline: FBC EDTA/whole blood
Freeze Serum
Centrifuge clotted sample, freeze
EDTA/plasma Centrifuge, freeze
P-selectin Collect, sent via post
Day 7: FBC Serum Plasma P-selectin
Day 35: FBC
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TARDIS: SAEs and Outcome EventsTARDIS: 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
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TARDIS TIMELINETARDIS TIMELINE
BASELINE DAY 0
ConsentFBC
Other bloods
- P-selectin - Serum - PlasmaBaseline form / RandomisePatient Details FormTCD
Loading doses of IMP(s)
DAY 7 ±1
Day 7 formFBC
Other bloods
- P-selectin - Serum - Plasma
DAY 35 ±3
Day 35 formFBC
DAY 90 ±7
Central follow-up
DAY 3 ±1
TCD
Aspirin
*Clopidogrel
Dipyridamole
300mg loading dose on Day 0, then 75mg od Days 1 to 30 §
* 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
200mg MR bd Days 0 to 30 §
300mg loading dose (if not already received) on Day 0, then 75mg od Days 1 to 30 §
Antiplatelets continued at the discretion of the Investigator,
e.g. aspirin and dipyridamole as per NICE guidelines
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
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TARDIS: Trial statusTARDIS: 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
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TARDIS: New sites welcome!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 StirlingStirling Royal Infirmwww.tardistrial.org
Any questions?Any questions?
TARDIS: Forms and data entryTARDIS: Forms and data entry
Margaret Adrian
www.tardistrial.org
TARDIS: How many forms? 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
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TARDIS: Patient DetailsTARDIS: Patient Details
1-page form: Fax to Nottingham
Co-ordinating Centre with consent form/s
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TARDIS: http://www.tardistrial.orgTARDIS: http://www.tardistrial.org
TARDIS: Database EntryTARDIS: Database Entry
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TARDIS: Add a new patientTARDIS: Add a new patient
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TARDIS: Check inclusion/exclusionTARDIS: Check inclusion/exclusion
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TARDIS: Baseline form completionTARDIS: 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
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1
TARDIS: Baseline helpTARDIS: Baseline help
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MI within last 12 mos
Alteplase treatment within 30hrs
AF?
Duration of symptoms
ECG result
Serious Bleed within last 12 mos
TIA - weakness and/or dysphasia for minimum of 10mins
STROKE - weakness and/or dysphasia must still be present
TARDIS: Baseline validationsTARDIS: Baseline validations
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TARDIS: Error messagesTARDIS: Error messages
TARDIS: Baseline completionTARDIS: Baseline completion
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TARDIS: Randomisation ResultTARDIS: Randomisation Result
TARDIS: Additional Clinical Brain ImagingTARDIS: Additional Clinical Brain Imaging
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TARDIS: Hospital EventsTARDIS: Hospital Events
TARDIS: SAE / OutcomeTARDIS: SAE / Outcome
TARDIS: SAE/OutcomeTARDIS: SAE/Outcome
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TARDIS: Day 7 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 35TARDIS: 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
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TARDIS: Day 90TARDIS: 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
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TARDIS: Site responsibility (delegation) logTARDIS: Site responsibility (delegation) log
TARDIS: Patient DetailsTARDIS: Patient Details
TARDIS: Full Blood Count (FBC)TARDIS: Full Blood Count (FBC)
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TARDIS: FBC resultsTARDIS: FBC results
TARDIS: FBC resultsTARDIS: FBC results
TARDIS: Blood sample freezer logTARDIS: Blood sample freezer log
Add drug accountability form……
TARDIS: Drug accountability logTARDIS: Drug accountability log
31350 & 08093
Consecutive
TARDIS: Screening LogTARDIS: Screening Log
TARDIS: Data Query / CorrectionTARDIS: Data Query / Correction
TARDIS: Fax cover sheetTARDIS: Fax cover sheet
TARDIS: Other informationTARDIS: 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)
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Any questions?Any questions?
TARDIS: Outcome events, Serious Adverse Events, and pharmacovigilance
TARDIS: Outcome events, Serious Adverse Events, and pharmacovigilance
Philip Bath
www.tardistrial.org
TARDIS: Outcome events / SAEsTARDIS: 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
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TARDIS: SAE / Event formTARDIS: SAE / Event formwww.tardistrial.org
TARDIS: Stroke/TIA informationTARDIS: 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
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TARDIS: Stroke eventTARDIS: Stroke eventwww.tardistrial.org
TARDIS: MI/angina informationTARDIS: 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
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Acute cardiac chest pain
No ST segment elevation ST segment elevation
Elevated cardiac enzymes Elevated cardiac enzymesCardiac enzymes not elevated
NSTEMI Non-ST elevation myocardial
infarction
UNSTABLE ANGINA (including new onset angina, angina at rest and increasing
angina)
STEMIST elevation myocardial
infarction
Definitions: Acute Coronary SyndromesDefinitions: Acute Coronary Syndromes
TARDIS: Bleeding, definition 1TARDIS: 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 2TARDIS: 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 outwww.tardistrial.org
TARDIS: Bleeding, definition 3TARDIS: 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
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TARDIS: Bleeding informationTARDIS: Bleeding information
Clinical Organ – brain, joint, muscular, occular, pericardial,
retropeironeal, skin, spine, … Transfusion – how many/no (Outcome)
Haematology – change in levels
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Pharmacovigilance: QuestionPharmacovigilance: 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: AnswerPharmacovigilance: 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 eventsTARDIS: 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(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 visit4. Significant laboratory abnormalities
(S)AE: Recording - Answer(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 visit4. Significant laboratory abnormalities
Adverse event: DefinitionAdverse 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 - QuestionSAE: Components - Question
Any untoward medical occurrence that?1. Results in death2. Is life-threatening3. Requires inpatient hospitalisation or
prolongation of existing hospitalisation4. Is an adverse event assessed as severe5. Results in persistent or significant
disability/incapacity6. Is a congenital anomaly/birth defect7. Is medically important
SAE: Components - AnswerSAE: Components - Answer
Any untoward medical occurrence that?1. Results in death2. Is life-threatening3. Requires inpatient hospitalisation or
prolongation of existing hospitalisation4. Is an adverse event assessed as severe5. Results in persistent or significant
disability/incapacity6. Is a congenital anomaly/birth defect7. Is medically important
SAE: Life-threateningSAE: 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 importantSAE: 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.SAE: Required information – Quest.
1. Causality2. Prognosis3. Patient’s address4. Intensity5. Outcome6. Hospital cost7. Action taken
SAE: Required information - AnswerSAE: Required information - Answer
1. Causality2. Prognosis3. Patient’s address4. Intensity5. Outcome6. Hospital cost7. Action taken
SAE: Causality to interventionSAE: Causality to intervention
Temporal Re-challenge Other relationship aetiology
Definitely v. strong v. strong noneProbably strong strong unlikelyPossibly suggestive N/A equally likelyUnlikely weak N/A likelyNot related none N/A v. likely
SAE: IntensitySAE: 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 SevereSAE: 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: OutcomeSAE: Outcome
Recovered Not yet recovered
Used for chronic conditions Died
SAE: Outcome - QuestionSAE: Outcome - Question
What is important when recording a SAE with fatal outcome?
1. Death should be the primary SAE event2. Death is an outcome3. Provide a clinicial summary describing the
symptoms/events preceding death4. Provide the autopsy report when available
SAE: Outcome - AnswerSAE: Outcome - Answer
What is important when recording a SAE with fatal outcome?
1. Death should be the primary SAE event2. Death is an outcome3. Provide a clinicial summary describing
the symptoms/events preceding death4. Provide the autopsy report when
available
So, death is an outcome, not an event!
SAE: Action takenSAE: Action taken
Treatment:
None, i.e. continued
Interrupted
Discontinued
SUSAR, 1SUSAR, 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, 2SUSAR, 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 - QuestionSAE: 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 SAEs2. Only record the overall diagnosis of MI as an
SAE3. Record MI and jaundice as SAEs
SAE: Example - AnswerSAE: 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 SAEs2. Only record the overall diagnosis of MI as an
SAE3. Record MI and jaundice as SAEs
SAE: CodingSAE: Coding
Example
Investigator term Headache, head painVerbatim, raw term cephalgia
Standard term Headache
Please look for standard term in available list
TARDIS: SAE questions, 1TARDIS: SAE questions, 1
When did it start? Before / during / after
Fatal? Y/NLife-threatening?Y/NHospitalisation? Y/NDisabling? Y/NBirth defect? Y/NMedically important? Y/NCategory? Stroke / MI / Bleed / SAEDescribe?
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TARDIS: SAE questions, 2TARDIS: SAE questions, 2
Date/time began?Nature? Single / MultipleIntensity? Mild / Moderate / SevereRelationship? Definitely not / … /
definiteAction? Continue/Missed/StoppedOutcome? Recovered / … / Died
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TARDIS: SAE questions, 3TARDIS: SAE questions, 3
Diagnostic evidence *As much info. as possible
PathologyRadiologyECGBacteriologyBiochemistryHaematologyClinicalComment
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TARDIS: SAE questions, 4TARDIS: SAE questions, 4
Event Stroke / TIA / N/ALimb weakness Y/NSpeech disturbance Y/NSensory disturbance Y/NVisual field loss Y/NPosterior circulation Y/NOther DescribeLength of symptoms ABCD2 bandsSeverity ABCD2 / NIHSS
score / ?Brain imagingType IS/HTI/ICH/?
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TARDIS: SAE questions, 5TARDIS: SAE questions, 5
Event UA / NSTEMI / STEMI / N/AChest pain Y/NSOB Y/NSweating Y/NNausea/vomit Y/NECG dateECG changes Ts inv / ST el / ST dep / Q
waveEnzyme dateEnzymes Trop I/Trop T/CK/CKMB/ND
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TARDIS: SAE questions, 6TARDIS: SAE questions, 6
Bleed Minor / Moderate / Major / N/ABlood transfusion 0/ 1/ 2/ 3/ 4/ 5/ 6/ >6 unitsWhereCNS RespiratoryCV RetroperitonealGI SkinGU OtherMSOcular
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TARDIS: SAE questions, 7TARDIS: SAE questions, 7
SAE preferred term Cardiovascular AF/ bradycardis/… CNS Agitation/ anxiety/… Cutaneous Bullous/ eczema/… Gastrointestinal Abdo pain/ colitis/… Genito-urinary Sex dys./ incont./… Haematological Anaemia/ agran/… Immunological Anaphylactic/… Musculoskeletal Arthritis/… Respiratory Bronchospasm/… Other / miscellaneous www.tardistrial.org
TARDIS: SAE questions, 8TARDIS: SAE questions, 8
SUSAR Y/N
If fatal, cause IS, IHD, PAD, VTE, other vasc, non vasc, major
bleed date
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SAE: Problems in trialsSAE: 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?Any questions?
TARDIS: ImagingTARDIS: Imaging
Philip Bath
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IntroductionIntroduction
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 scansCT 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 formTARIS: Baseline form
BASELINE CT OR MRI HEAD
Date of scan (dd/mm/yyyy) / /
Type of scan? CT MRI No scan
Please complete with regards to the baseline head 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 randomisationTIA - no scan required
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Haemorrhagic Transformation of Infarction (HTI)Haemorrhagic Transformation of Infarction (HTI)ISCHAEMIC STROKE MINOR BLOOD =
Haemorrhagic Infarct (HI): petechial infarction without space occupying effect.
HI1 - small petechiaeHI2 - more confluent petechiae
ISCHAEMIC STROKE MAJOR BLOOD =
Parenchymal Haemorrhage (PH): haemorrhage with mass effect.
PH1 - <30% of the infarcted area with mild space occupying effectPH2 - >30% of the infarcted area with significant space occupying effect.
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Haemorrhagic Transformation of Infarction (HTI)Haemorrhagic Transformation of Infarction (HTI)ISCHAEMIC STROKE MINOR BLOOD =
Haemorrhagic Infarct (HI): petechial infarction without space occupying effect.
HI1 - small petechiaeHI2 - more confluent petechiae
ISCHAEMIC STROKE MAJOR BLOOD =
Parenchymal Haemorrhage (PH): haemorrhage with mass effect
PH1 - <30% of the infarcted area with mild space occupying effectPH2 - >30% of the infarcted area with significant space occupying effect.
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TARDIS: Baseline formTARDIS: Baseline form
BASELINE CT OR MRI HEAD
Date of scan (dd/mm/yyyy) / /
Type of scan? CT MRI No scan
Please complete with regards to the baseline head 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)
√
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TARDIS: Baseline formTARDIS: Baseline form
BASELINE CT OR MRI HEAD
Date of scan (dd/mm/yyyy) / /
Type of scan? CT MRI No scan
Please complete with regards to the baseline head 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)
√
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CT scans - Ischaemic strokeCT scans - Ischaemic stroke
CT scans - Haemorrhagic strokeCT scans - Haemorrhagic stroke
TARDIS: Day 7 Form - ImagingTARDIS: Day 7 Form - Imaging
Report available
BASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
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TARDIS: Day 7 Form - ImagingTARDIS: Day 7 Form - ImagingBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
TARDIS: CT scan - lesionTARDIS: 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
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TARDIS: CT scan - lesionTARDIS: CT scan - lesion
Choose ‘Ischaemic Stroke - no blood’ if…. ‘hypodensity’, ‘infarct’, ‘infarction’, ‘low attenuation’ +/- ‘acute’,‘recent’, ‘subacute’, ‘patchy’, ‘subtle’
Do not choose this if words like ‘old’, ‘mature’, go with the words ‘infarct’ or ‘hypodensity’ 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.
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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…
TARDIS: CT scan - lesionTARDIS: CT scan - lesion
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BASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
TARDIS: CT scan - compatible with presentation?TARDIS: CT scan - compatible with presentation?
TARDIS: CT scan - compatible with presentation?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!
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TARDIS: Mass effectTARDIS: Mass effectBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
Mass effectMass effect
TARDIS: CT scan - mass effectTARDIS: 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
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Mass effect v hydrocephalusMass effect v hydrocephalus
TARDIS: Cerebral AtrophyTARDIS: Cerebral AtrophyBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
AtrophyAtrophy
TARDIS: CT scans - atrophyTARDIS: CT scans - atrophy
Answer yes if…
“Atrophy” or “involutional change”
If no mention or ‘age appropriate’ and the patient is under 60, say no
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TARDIS: LeukoariosisTARDIS: LeukoariosisBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
CT scan - periventricular white matter lucencyCT scan - periventricular white matter lucency
TARDIS: CT scan - periventricular white matter lucencyTARDIS: 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.
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BASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
TARDIS: CT scan - previous strokesTARDIS: CT scan - previous strokes
TARDIS: CT scan - previous strokesTARDIS: 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.
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TARDIS: Most important of allTARDIS: 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
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Test number 1Test 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 - answersCase 1 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
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Case 1 - answersCase 1 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
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Case 1 - answersCase 1 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 1 - answersCase 1 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 1 - answersCase 1 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 1 - answersCase 1 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 1 - answersCase 1 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Test number 2Test 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 - answersCase 2 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 2 - answersCase 2 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 2 - answersCase 2 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 2 - answersCase 2 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 2 - answersCase 2 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 2 - answersCase 2 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Case 2 - answersCase 2 - answersBASELINE CT/MRI SCAN (performed prior to randomisation)
CT/MRI scan performed before randomisation? CT MRI No scan
Date and time of scan (dd/mm/yyyy hh:mm) / / :
The result of the 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)
Is the scan compatible with the presenting event?
YES NO
Is there e vide nc e o f mas s effect YES NO
Is there e vide nc e o f cer e bral atrophy YES NO
Is there e vide nc e o f pe rive ntic ular white matter luc e nc y (e .g . leu koa rios is)?
YES NO
Is there e vide nc e o f pre viou s st roke s ? YES NO
Have you uploa ded the sc an? (If no, pleas e do so as s oo n as pos s ible)
YES NO
Has a furthe r (c linical) s c an be e n do ne s inc e rando misat ion?
YES NO
If ye s , dat e and time (dd/mm /yyyy hh :mm) / / :
If ye s , have you uploa ded the sc an? If no , ple ase d o s o as s o on as pos s ible
YES NO
Com ment s /reaso n fo r no sc an
www.tardistrial.org
Any questions?Any questions?
TARDIS: Site responsibilities and trial filesTARDIS: Site responsibilities and trial files
Margaret Adrian
www.tardistrial.org
Record KeepingRecord 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?What do we mean by records?
Site file
Case record form
Medical notes
Site FileSite 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)Case Record Form (CRF)
Accurate and legible Changes Consistent with source documents Document all visits/tests Document and explain all deviations
Patient medical notesPatient medical notes
Stickers
Copy of PIS/consent
GP letter
Trial medication
Serious Adverse Events
Storage of recordsStorage of records
Confidential
Archiving
TARDIS is sponsored by The University of Nottingham
ConclusionConclusion
A simple and accurate paper trial is essential to demonstrate the validity and integrity of study conduct
Any Questions?Any Questions?
TARDIS: Trial monitoringTARDIS: Trial monitoring
Margaret Adrian
www.tardistrial.org
Purpose of monitoringPurpose 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 trialsTypes 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 CommitteesTrial 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)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)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 monitoringCoordinating 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 monitoringCentral 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 monitoringCentral 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 monitoringCentral 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, 1On-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, 2On-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 documentationSource 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 documentationSource 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 visitsFindings 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?Any Questions?
TARDIS: Data MonitoringTARDIS: Data Monitoring
Philip Bath
www.tardistrial.org
TARDIS: Data Monitoring, 1TARDIS: Data Monitoring, 1
Composition: Professor Ian Ford (Chair, Glasgow)
Biostatistician, trialist (IMAGES, WOSCOPS, …) Dr Cathie Sudlow (Edinburgh)
Stroke neurologist, antiplatelets (ATT) Dr Matthew Walters (Glasgow)
Clinical Pharmacologist, stroke trialist
Mr Michael Tracy (Nottingham) TARDIS statistician
www.tardistrial.org
TARDIS: Data Monitoring, 2TARDIS: 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, 3TARDIS: 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, 4TARDIS: 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, 4TARDIS: 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, 5TARDIS: Data Monitoring, 5
Data: Modified Rankin Scale Stroke (ischaemic and haemorrhage) Bleeding: major SICH (<2%) Death SAEs
www.tardistrial.org
Any Questions?Any Questions?
TARDIS: Sub-studiesTARDIS: Sub-studies
Philip Bath
www.tardistrial.org
TARDIS: Sub-studiesTARDIS: 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
Any Questions?
And many thanks for attending
TARDIS: Inclusion criteriaTARDIS: 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 criteriaTARDIS: 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 - biomarkersTARDIS: 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 statusTARDIS: Trial status
MREC approval MHRA approval
Local SSI/R&D ongoing
UKSRN Adoption ongoing
UK investigator meeting 23-24/03/09
Start April 2009www.tardistrial.org
Resistant stroke/TIAResistant 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 (W)
Ineffective in SPIRIT, WARSS, ESPRIT Mixed anticoagulation and antiplatelet (WA)
No trial data (but ineffective in cardioembolic stroke) Triple antiplatelet therapy
No trial data
Triple 2 trial: LogisticsTriple 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 reviewTriple 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 reviewTriple 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 - RCTsTriple therapy (SR): Results - RCTs
T N E OR CI
EfficacyMI 10 9795 783 0.71 0.56-0.90Ischaemic stroke 3 3684 6 3.02 0.60-15.23Vascular 9 9595 852 0.73 0.58-0.92
SafetyDeath 9 9595 103 0.87 0.59-1.29Bleed major 10 9820 156 1.24 0.90-1.73Bleed minor 8 8864 242 1.52 1.17-1.97Transfusion 6 8874 192 1.52 1.13-2.05Thrombocytopen. 5 6541 25 9.45 2.53-33.34
Geeganage et al. Unpublished
Triple therapy (SR): Results - OSsTriple therapy (SR): Results - OSs
T N E OR CI
EfficacyMI 4 8240 327 0.46 0.25-0.85Ischaemic stroke 0Vascular 4 8240 430 0.44 0.25-0.79
SafetyDeath 6 11923 71 0.34 0.18-0.64Bleed major 7 20004 316 1.57 1.11-2.22Bleed minor 3 5477 191 1.08 0.63-1.88Transfusion 1 4809 61 1.44 0.45-4.62Thrombocytopen. 2 3311 12 0.79 0.21-3.01
Geeganage et al. Unpublished