triple antiplatelets for reducing dependency after ischaemic stroke tardis – isrctn47823388

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

www.tardistrial.org

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

www.tardistrial.org

Other postsOther posts

Niki Sprigg Events adjudicator

TBA Neuroimaging

www.tardistrial.org

Trial BodiesTrial Bodies

Funding The British Heart Foundation

Sponsor University of Nottingham

Adoption Stroke Research Network

Live Website www.tardistrial.org

Email tardis@nottingham.ac.uk

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

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

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

Adverse events: ordinalAdverse events: ordinal

P<0.01

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

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

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

Triple therapy (SR): Absolute effectsTriple therapy (SR): Absolute effects

Vascular event

Major bleedTransfusion

ControlTriple

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!

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

www.tardistrial.org

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 =

www.tardistrial.org

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

www.tardistrial.org

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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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

www.tardistrial.org

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

www.tardistrial.org

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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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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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

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

www.tardistrial.org

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

www.tardistrial.org

TARDIS: Add a new patientTARDIS: Add a new patient

www.tardistrial.org

TARDIS: Check inclusion/exclusionTARDIS: Check inclusion/exclusion

www.tardistrial.org

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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TARDIS: Baseline helpTARDIS: Baseline help

www.tardistrial.org

MI within last 12 mos

Alteplase treatment within 30hrs

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

www.tardistrial.org

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)

www.tardistrial.org

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)

www.tardistrial.org

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

www.tardistrial.org

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

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

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?

www.tardistrial.org

Date/time began?Nature? Single / MultipleIntensity? Mild / Moderate / SevereRelationship? Definitely not / … /

definiteAction? Continue/Missed/StoppedOutcome? Recovered / … / Died

www.tardistrial.org

Diagnostic evidence *As much info. as possible

PathologyRadiologyECGBacteriologyBiochemistryHaematologyClinicalComment

www.tardistrial.org

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/?

www.tardistrial.org

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

www.tardistrial.org

Bleed Minor / Moderate / Major / N/ABlood transfusion 0/ 1/ 2/ 3/ 4/ 5/ 6/ >6 unitsWhereCNS RespiratoryCV RetroperitonealGI SkinGU OtherMSOcular

www.tardistrial.org

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

SUSAR Y/N

If fatal, cause IS, IHD, PAD, VTE, other vasc, non vasc, major

bleed date

www.tardistrial.org

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

TARDIS: ImagingTARDIS: Imaging

Philip Bath

www.tardistrial.org

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

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

www.tardistrial.org

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.

www.tardistrial.org

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.

www.tardistrial.org

TARDIS: Baseline formTARDIS: Baseline form

www.tardistrial.org

TARDIS: Baseline formTARDIS: Baseline form

www.tardistrial.org

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

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

TARDIS: Day 7 Form - ImagingTARDIS: Day 7 Form - ImagingBASELINE CT/MRI SCAN (performed prior to randomisation)

YES NO

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

www.tardistrial.org

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.

www.tardistrial.org

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

YES NO

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!

www.tardistrial.org

TARDIS: Mass effectTARDIS: Mass effectBASELINE CT/MRI SCAN (performed prior to randomisation)

YES NO

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

www.tardistrial.org

Mass effect v hydrocephalusMass effect v hydrocephalus

TARDIS: Cerebral AtrophyTARDIS: Cerebral AtrophyBASELINE CT/MRI SCAN (performed prior to randomisation)

YES NO

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

www.tardistrial.org

TARDIS: LeukoariosisTARDIS: LeukoariosisBASELINE CT/MRI SCAN (performed prior to randomisation)

YES NO

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.

www.tardistrial.org

YES NO

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.

www.tardistrial.org

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

www.tardistrial.org

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)

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

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.

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

YES NO

www.tardistrial.org

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

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 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 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

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

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

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

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

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

Trials status: Timelines Recruitment

Patients, centres, patients/centre Data completeness, quality

Patients: Baseline features

Balance by treatment groups Outcomes

Data: Modified Rankin Scale Stroke (ischaemic and haemorrhage) Bleeding: major SICH (<2%) Death SAEs

www.tardistrial.org

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

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

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

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

triple antiplatelets for reducing dependency after ischaemic stroke tardis – isrctn47823388

esps ii18270dipyridamole

volunteerscombined aspirin

tardisplatelet aggregation

prior stroke

mrec ref

08h1102112sponsor ref

c 1profess20332acd

clopidogrel c

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