Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke TARDIS

1
Triple Antiplatelets for Reducing Dependency
after Ischaemic StrokeTARDIS ISRCTN47823388

• TARDIS Team
• Philip Bath, Margaret Adrian
• University of Nottingham

www.tardistrial.org
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Agenda Morning

• Welcome Philip Bath 5
• Aims/objectives/design Philip Bath 45
• Interventions/protocol Marg Adrian 40
• Lunch

3
Agenda Afternoon

• Paperwork, data Marg Adrian 60
• SAEs / SUSARS Philip Bath 30
• Imaging Philip Bath 30
• Tea
• Site responsibilities Marg Adrian 45
• Data Monitoring Cttee Philip Bath 15
• Substudies Philip Bath 20
• Tea

4
TARDIS People

• Patients
• Investigators
• Trial Steering Committee
• Trial Management Committee
• Data Monitoring Committee
• SAE / Events adjudication
• Neuroimaging staff
• Substudy staff

www.tardistrial.org
5
Trial Steering Committee

• Helen Rodgers Newcastle Chair
• Philip Bath Nottingham
• Stan Heptinstall Nottingham
• Hugh Markus London
• Ossie Newell Nottingham Patient
• Tom Robinson Leicester
• Graham Venables Sheffield
• Independent Experts
• Sponsors representative
• Funders representative

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Trial Management Committee

• Philip Bath Chief Investigator
• Margaret Adrian Coordinator
• Tim England Medic
• Chamila Geeganage Medic
• Sandeep Ankolekar Medic
• TBA Statistician
• Wim Clarke Financial

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Other posts

• Niki Sprigg Events adjudicator
• TBA Neuroimaging

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Trial Bodies

• Funding
• The British Heart Foundation
• Sponsor
• University of Nottingham
• Adoption
• Stroke Research Network
• Live Website
• www.tardistrial.org
• Email
• tardis_at_nottingham.ac.uk

9
TARDIS 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 Background

• Philip Bath

www.tardistrial.org
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Atherothrombosis

• Cellular
• Platelets
• White cells
• Endothelial cells

• Soluble
• Fibrinogen
• Thrombin

12
Antiplatelets and Stroke Monotherapy

• Aspirin
• Inhibitor of cyclooxygenase
• Reduces recurrence (RRR) by 17 in patients with
  prior stroke or TIA
• Clopidogrel
• Adenosine diphosphate (ADP) receptor antagonist
• Was slight more efficacious than aspirin in
  CAPRIE
• Dipyridamole
• Inhibits red cell uptake of adenosine
• Reduced recurrence by 16 (vs placebo, ESPS II)

13
Acute ischaemic stroke/TIA

• Stroke
• Aspirin IST, CAST, MAST-I v
• Dual PRoFESS (v)
• Triple ?
• TIA
• Aspirin APT v
• AC FASTER (v)

14
Stroke prevention Antiplatelets

• Strategy RRR () Trial No.
• Aspirin (A) 18 ATT, ESPS II 18270
• Dipyridamole (D) 16 ESPS II 6602
• Clopidogrel (C) vs. A 7 CAPRIE 6431
• AD vs. control 38 ESPS, ESPS II 9102
• AD vs. A 23 ESPS II, ESPRIT 9341
• AC vs. C ( 0) MATCH 7599
• AC vs. A (20) CHARISMA 15603
• AC vs. A (34) FASTER 392
• AD vs. C (- 1) PRoFESS 20332
• ACD vs. A N/A Triple 2 17
• ACD vs. AD ? TARDIS

15
Platelet aggregation In vitro

• In blood from volunteers
• Combined aspirin, AR-C69931 and dipyridamole
  reduce
• Platelet aggregation (figures ADP, PAF)
• Monocyte activation
• Neutrophil activation
• Platelet-monocyte conjugation
• Platelet-neutrophil conjugation
• Platelet p-selectin expression

Zhao et al. Br J Pharm 2001134353-8
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Platelet aggregation Ex vivo

• In volunteers and patients with previous stroke
• Combined aspirin, AR-C69931 and dipyridamole (not
  different from aspirin/clopidogrel) reduce
• Platelet aggregation (figures)
• Monocyte activation
• Neutrophil activation
• Platelet-monocyte conjugation
• Platelet-neutrophil conjugation

Zhao et al. Thromb Haemost 200593527-34
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Triple 2 trial Design

• Randomised controlled trial
• Open label, blinded outcome, blinded adjudication
• 50 patients, 1 centre
• Event ischaemic stroke or TIA lt5 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 n17
• Positive results of ESPRIT (AD gt A)
• Total exposure 282 months
• ISRCTN83673558

Sprigg et al. PLoS 20083(8)e2852
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Triple trial Patient characteristics

• Aspirin ACD
• Number 8 9
• Age (years) 61 63
• Sex, male () 75 67
• Event, stroke () 88 89
• Event ? trial (months) 10 8
• Lacunar syndrome () 63 78
• Hypertension () 63 67
• Diabetes () 13 11

Sprigg et al. PLoS 20083(8)e2852
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Triple trial Discontinuations

• Aspirin ACD 2p
• n8 n9
• Exposure (mo) 144 138
• Discontinuations 0 (0) 4 (44) 0.08
• bruising 1
• GI 2
• non-compliance 1

Sprigg et al. PLoS 20083(8)e2852
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Triple trial Safety

• Aspirin ACD 2p
• n8 n9
• Death 0 (0) 1 (11) 1.00
• SAEs 0 (0) 3 (33) 0.47
• treatment-related 1
• AEs 2 (25) 7 (77) 0.06
• Bleeding, any 0 (0) 3 (33) 0.21
• Recurrent stroke 0 (0) 1 (11) 1.00

Sprigg et al. PLoS 20083(8)e2852
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Adverse events ordinal

• Plt0.01

Sprigg et al. PLoS 20083(8)e2852
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Triple trial Other measures

• Aspirin ACD 2p
• Hb at end 13.9 13.4 0.76
• Platelet agg. 84 70 0.05
• Monocyte act. 165 96 0.02
• Platelet-monocyte 118 74 0.04
• BP, PP, HR, RPP No effects/differences

Sprigg et al. PLoS 20083(8)e2852
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Triple trial Conclusions

• Trial very underpowered
• Stopped early (17 vs. 50 patients)
• ACD (vs. A)
• Trends to increased discontinuations and AEs
• Reduced platelet aggregation, monocyte
  activation, platelet monocyte conjugates
• Patients at low risk of recurrence
• Long time after stroke, lacunars, young
• Benefit lt hazard?
• Future trials should concentrate on high risk
  patients so benefit gt hazard

Sprigg et al. PLoS 20083(8)e2852
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Triple therapy Case series

• History Prior Rx Length Status
• (months)
• HT/PFO A AD 15 Stopped - PFO closed
• ICAS/HT/HL A AD 20 Continuing
• ICAS/IHD/HT A AD 23 Continuing
• IHD/HT/HL A AD 5 Continuing
• IHD/PE/HL A W WA CD 9 Stopped - further PE
• DM/HL/HT C AC 14 Continuing
• IHD/HL A AD 1 Stopped - haematuria
• DM/HT/HL A AD 7 Continuing
• IHD/ICAS/HT A AD 12 Continuing
• No strokes on ACD

Willmot et al. J Stroke CVD 200413138-40
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Triple therapy (SR) MI
Geeganage et al. Unpublished
26
Triple therapy (SR) Major bleeding
Geeganage et al. Unpublished
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Triple therapy (SR) Absolute effects
Geeganage et al. Unpublished
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Triple therapy (SR) Conclusions

• Short-term triple therapy
• Reduces MI and vascular events
• Increases bleeding and transfusions
• Absolute event - efficacygthazard
• Stroke
• Minimal data on stroke events
• Minimal data on effects in stroke/TIA patients
• Need more data!

Geeganage et al. Unpublished
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Any Questions?
30
TARDIS Aims, objectives

• Philip Bath

www.tardistrial.org
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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
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TARDIS Predications

• Patients at high risk of recurrence
• Acute stroke
• Acute TIA (ABCD2gt4, crescendo TIA)
• Efficacy AD gtgt A bleeding AD A
• Efficacy AC gtgt A bleeding AC gt A
• AD is standard of care in UK (NICE)
• Patients on AD still have strokes (failure)
• Efficacy ACD gtgt AD?
• Bleeding ACD gt AD?
• High risk patients benefit gt hazard

www.tardistrial.org
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TARDIS Design

• Prospective, randomised, open-label, blinded
  endpoint, parallel group controlled trial
• Reduce sources of bias
• Randomised
• Concealment of allocation
• Blinded endpoint assessment
• Controlled
• ACD vs AD (open-label)
• Intention-to-treat

www.tardistrial.org
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TARDIS Design

• Start-up phase of main phase III trial
• 270 patients, 25 SRN centres, 3 years
• Intervention Addition of clopidogrel to standard
  antiplatelet therapy
• ACD vs. AD for one month
• Oral Nasogastric
• Aspirin 75 mg od (150 mg pr alt)
• Dipyridamole 200 mg bd MR 100 mg qds, liq/tab
• Clopidogrel 75 mg od

www.tardistrial.org
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TARDIS Outcomes (start-up)

• Primary outcome (day 30)
• SAEs
• 12 --gt 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
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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?
38
TARDIS Trial interventions, protocol

• Margaret Adrian

www.tardistrial.org
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TARDIS Inclusion criteria

• Adults (aged gt50) 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 (gt1 TIA within 1 week)
• AND/OR Taking dual antiplatelet therapy
  (aspirin/dipyridamole, aspirin/clopidogrel,
  clopidogrel/dipyridamole)
• AND/OR ABCD2 score gt4
• AND Motor weakness/or dysphasia lasting at least
  10 minutes for the randomising event

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ABCD2 score
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Definitions

• Stroke - WHO
• A clinical syndrome characterised by rapidly
  developing clinical symptoms and/or signs of
  focal (and at times global) loss of cerebral
  function with symptoms lasting for more than 24
  hours or leading to death, with no apparent cause
  other than that of vascular origin
• Brain imaging required before trial entry
• TIA
• A sudden focal neurological deficit of the brain
  or eye, presumed to be of vascular origin and
  lasts less than 24 hours
• Brain imaging is not required before trial entry

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TARDIS Exclusion criteria, 1

• Agelt50
• Motor weakness and/or aphasia lasting lt10 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 (mRSgt2)
• No enteral access

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TARDIS Exclusion criteria, 2

• TIA not fulfilling inclusion criteria
• Definite need for full dose oral (e.g. warfarin)
  or parenteral (e.g. heparin, GP IIb/IIIa
  inhibitor) anti-coagulation
• AF, recent MI
• Low dose heparin for DVT prophylaxis is allowed
• Thrombolysis within last 30 hours
• Severe high BP (BPgt185/110 mmHg)
• Bleeding within 1 year (e.g. peptic ulcer,
  intracerebral haemorrhage)

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TARDIS Exclusion criteria, 3

• Parenchymal haemorrhagic transformation (PH
  I/II), subarachnoid haemorrhage
• Other non ischaemic cause for weakness
• Known haemoglobin lt10g/dL
• Known platelet count lt100 x 1E9/L
• Known white cell count lt3.5 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, 4

• Stroke secondary to a procedure
• e.g. carotid or coronary intervention
• Coma (GCSlt8)
• Non-stroke life expectancylt6 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
  breastfeeding

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TARDIS Interventions / Trial Flow
Stroke or
TIA (lt48)
Dual Therapy
Triple Therapy
(AD) for 1 month
(ACD) for 1 month
(
Randomised
11)
Assessment at days 7 and 35 for
safety, efficacy, and tolerability
90 day central blinded telephone
follow up and end of the trial
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TARDIS Trial Flow
FBC Form
Brain Imaging Form
SAE / Outcome Form
Hospital Events Form
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TARDIS Aspirin

• Dose
• Loading dose 300mg (whether or not already on
  aspirin)
• Maintenance dose 25mg bd to 75mg od
• Protocol violation maintained on 300mg aspirin
• Route
• Enteral (including via nasogastric tube)
  dispersible or crushed tablets
• Rectal 150mg suppository alternate days
• Alternative if necessary
• All authorised UK brands may be used

www.tardistrial.org
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TARDIS Dipyridamole

• Dose
• Oral 200mg modified release (MR) bd
• Nasogastric tube (e.g. dysphagia) Dipyridamole
  suspension 75mg tds - 100mg qds
• Headache from dipyridamole Wean up from daily MR
  200mg or standard release 75mg od to MR 200mg bd
• Fixed combinations of A and D may be used
• E.g. Asasantin Retard (aspirin 25mg, dipyridamole
  200mg MR bd)
• All authorised UK brands may be used

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TARDIS IMP - Clopidogrel

• Dose
• Loading dose 300mg (day 0)
• Maintenance dose 75mg od (days 1 to 30)
• Route Enteral (including via nasogastric tube
  tablets may be crushed)
• The IMP is defined by active substance only, so
  all authorised UK brands may be used

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TARDIS Discontinuation of IMP

• Should the participant discontinue any trial
  medication, they should remain in the study and
  take the remaining medications until the end of
  the trial at day 90, as completeness of follow-up
  is essential
• However, should they wish to do so, any
  participant is free to withdraw from the trial at
  any time and without giving reason
• Please notify the Trial Office 0115 823 0210

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TARDIS Investigators 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. AD as recommended by NICE

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TARDIS 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 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 TIMELINE
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TARDIS Trial status

• Stroke Research Network trial adopted
• First patient randomized 7 April 2009
• Site visits 16 centres
• Actively recruiting centres 3
• Patients recruited 13
• 10 stroke / 3 TIA
• Sites obtaining local RD approval gt60

www.tardistrial.org
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TARDIS New sites welcome!

• Scotland (9)
• Aberdeen Royal Infirmary
• Dundee Ninewells
• Fife Victoria Hospital
• Glasgow Royal Infirmary
• Glasgow Western Infirm.
• Inverness Raigmore Hosp.
• Lanarkshire Monklands Hosp
• Melrose Borders General Hosp
• Stirling Stirling Royal Infirm

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Any questions?
59
TARDIS Forms and data entry

• Margaret Adrian

www.tardistrial.org
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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 Details

• 1-page form
• Fax to Nottingham Co-ordinating Centre
• with consent form/s

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TARDIS http//www.tardistrial.org
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TARDIS Database Entry
www.tardistrial.org
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TARDIS Add a new patient
www.tardistrial.org
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TARDIS Check inclusion/exclusion
www.tardistrial.org
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TARDIS Baseline form completion

• Details of Patient and qualifying event
  (Stroke/TIA)
• Risk Factors and Past Medical History
• Current Medications
• Antithrombotic
• Antihypertensives
• Lipid Lowering
• Anti Gastric Acid medication
• Premorbid mRS
• Current Feeding ability
• Baseline BP x 2, ECG, BM, Temp, Weight
• GCS, NIHSS
• Baseline CT/MRI head result
• TCD
• Bloods (FBC result)
• Whether taking bloods for sub-studies

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TARDIS Baseline help
1
www.tardistrial.org
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TARDIS Baseline validations
TIA - weakness and/or dysphasia for minimum of
10mins
STROKE - weakness and/or dysphasia must still be
present
Duration of symptoms
AF?
ECG result
MI within last 12 mos
Alteplase treatment within 30hrs
Serious Bleed within last 12 mos
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TARDIS Error messages
70
TARDIS Baseline completion
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TARDIS Randomisation Result
72
TARDIS Additional Clinical Brain Imaging
www.tardistrial.org
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TARDIS Hospital Events
74
TARDIS SAE / Outcome
75
TARDIS SAE/Outcome
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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

77
TARDIS Day 35

• SAEs Day 7 to D35 (or death)
• Ask for empty blister pack to be returned for
  clopidogrel
• Other medications
• Two BP readings
• NIHSS, feeding ability
• Whether TCD undertaken at baseline and day 2
• FBC for Day 35

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TARDIS Day 90

• This will be undertaken by Nottingham
  Coordinating Centre - by telephone
• Assessor blinded to treatment
• Need full contact details of patient to enable
  follow-up

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TARDIS Site responsibility (delegation) log
80
TARDIS Patient Details
81
TARDIS Full Blood Count (FBC)
www.tardistrial.org
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TARDIS FBC results
83
TARDIS FBC results
84
TARDIS Blood sample freezer log
85
TARDIS Drug accountability log
Add drug accountability form
86
TARDIS Screening Log
Consecutive
31350 08093
87
TARDIS Data Query / Correction

88
TARDIS Fax cover sheet
89
TARDIS Other information

• Within TARDIS Website
• Frequently Asked Questions (FAQs)
• Demo Website (demoinv1 / nottingham / 8888)
• Data Entry Forms
• Contact list
• Working Practice Documents (WPDs)
• Telephone [phone] (plus answerphone)

www.tardistrial.org
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Any questions?
91
TARDIS Outcome events, Serious Adverse Events,
and pharmacovigilance

• Philip Bath

www.tardistrial.org
92
TARDIS Outcome events / SAEs

• All Events and SAEs within final follow-up (90
  /- 10 days of enrollment) will be collected
• Events and SAEs will be collected using same
  online form to avoid confusion
• Data will be adjudicated by blinded observer
• Insufficient information ? follow-up questions
• Events
• Vascular stroke, TIA, MI, angina, death
• Bleeding
• SAEs

www.tardistrial.org
93
TARDIS SAE / Event form
www.tardistrial.org
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TARDIS Stroke/TIA information

• Stroke
• Clinical symptoms, signs, outcome
• Imaging - CT and/or MR (send images)
• TIA
• Clinical symptoms, signs (nil new), length, not
  a mimic

www.tardistrial.org
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TARDIS Stroke event
www.tardistrial.org
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TARDIS MI/angina information

• Myocardial infarction
• Clinical chest pain, tachycardia, pale, sweaty,
  nausea, duration,
• Biochemistry enzyme levels (troponin, CK)
• ECG new q waves, ST elevation, (fax it)
• Angina, unstable / stable
• Clinical symptoms
• Biochemistry enzyme levels
• ECG no new q wave, ST depression

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97
Definitions Acute Coronary Syndromes
Acute cardiac chest pain
No ST segment elevation
ST segment elevation
Elevated cardiac enzymes
Elevated cardiac enzymes
Cardiac enzymes not elevated
NSTEMI Non-ST elevation myocardial infarction
UNSTABLE ANGINA (including new onset angina,
angina at rest and increasing angina)
STEMI ST elevation myocardial infarction
98
TARDIS Bleeding, definition 1

• Major bleed
• Fatal bleeding and/or
• Symptomatic bleeding in a critical area or organ,
  such as intracranial, intraspinal, intraocular,
  retroperitoneal, intraarticular or pericardial,
  or intramuscular with compartment syndrome
  and/or
• Bleeding causing fall in Hb gt2 g/l (1.24 mmol/l)
  or more, or leading to transfusion of gt2 units of
  whole blood or red cells
• All major bleeds are an SAE

www.tardistrial.org
99
TARDIS Bleeding, definition 2

• Moderate bleed
• Not major and
• Bleeding causing fall in Hb lt2 g/l (1.24 mmol/l),
  and leading to no transfusion, or transfusion of
  only 1 unit of whole blood or red cells
• Moderate bleeds may or may not be a SAE depending
  on other criteria, e.g. hospitalisation,
  disabling
• The CC will sort this out

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100
TARDIS Bleeding, definition 3

• Mild bleed
• Not major or moderate and
• Comprising bruising, ecchymoses, gingival bleed
  or similar other type bleeding
• Mild bleeds cannot constitute a serious adverse
  event

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101
TARDIS 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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102
Pharmacovigilance Question

• What is it?
• The science and activities to monitor drug
  interactions
• The science and activities to detect, assess,
  understand and prevent adverse drug effects

103
Pharmacovigilance Answer

• What is it?
• The science and activities to monitor drug
  interactions
• The science and activities to detect, assess,
  understand and prevent adverse drug effects

104
TARDIS Adverse events

• We will not collect AEs
• Clopidogrel is already licensed
• Considerable information is already known about
  it
• CAPRIE, CURE, CREDA, CHARISMA,

105
(S)AE Recording - Question

• What should be recorded?
• Any untoward medical occurrence to a patient
  after (s)he has signed the informed consent
• Operations/procedures occurring during the trial,
  but scheduled prior to trial enrolment
• Illnesses recorded at screening visit
• Significant laboratory abnormalities

106
(S)AE Recording - Answer

• What should be recorded?
• Any untoward medical occurrence to a patient
  after (s)he has signed the informed consent
• Operations/procedures occurring during the trial,
  but scheduled prior to trial enrolment
• Illnesses recorded at screening visit
• Significant laboratory abnormalities

107
Adverse event Definition

• Any untoward medical occurrence in a study
  subject administered an intervention and which
  does not necessarily have a causal relationship
  with this treatment
• Reporting an adverse event is NOT limited to NOR
  implies a causal relationship
• A medical or surgical procedure is not an AE, the
  reason for the procedure is!
• Abnormal laboritory values are AEs if clinically
  significant, lead to treatment change, are a
  SAE, or are a safety risk

108
SAE Components - Question

• Any untoward medical occurrence that?
• Results in death
• Is life-threatening
• Requires inpatient hospitalisation or
  prolongation of existing hospitalisation
• Is an adverse event assessed as severe
• Results in persistent or significant
  disability/incapacity
• Is a congenital anomaly/birth defect
• Is medically important

109
SAE Components - Answer

• Any untoward medical occurrence that?
• Results in death
• Is life-threatening
• Requires inpatient hospitalisation or
  prolongation of existing hospitalisation
• Is an adverse event assessed as severe
• Results in persistent or significant
  disability/incapacity
• Is a congenital anomaly/birth defect
• Is medically important

110
SAE Life-threatening

• Refers to an event in which the patient was at
  risk of death at the time of the event
• Does not refer to an event which hypothetically
  might have caused death if it had been more severe

111
SAE Medically important

• Serious adverse events that may jeopardise the
  patient or may require medical or surgical
  intervention to prevent one of the other serious
  outcomes
• Examples
• Allergic bronchospasm requiring intensive
  treatment in AE
• Convulsion not resulting in in-patient
  hospitalisation
• An abnormal lab value which needs active
  out-patient management

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SAE Required information Quest.

1. Causality
2. Prognosis
3. Patients address
4. Intensity
5. Outcome
6. Hospital cost
7. Action taken

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SAE Required information - Answer

1. Causality
2. Prognosis
3. Patients address
4. Intensity
5. Outcome
6. Hospital cost
7. Action taken

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SAE Causality to intervention

• Temporal Re-challenge Other
• relationship aetiology
• Definitely v. strong v. strong none
• Probably strong strong unlikely
• Possibly suggestive N/A equally likely
• Unlikely weak N/A likely
• Not related none N/A v. likely

115
SAE Intensity

• Severe
• Incapacitating
• Prevents daily activities
• Not a measure of seriousness
• Moderate
• Uncomfortable
• Impairs daily activities
• Mild
• Minimal discomfort
• Non-intefering with daily activities

116
SAE Serious or Severe

• Severe
• A medical judgement used to describe intensity
  (severity) of a specific event (as in mild,
  moderate, or severe myocardial infarction)
• The event itself, however, may be of relatively
  minor medical significance (e.g. severe
  headache). So severity does not mean serious
• Serious
• Based on event outcome or action criteria usually
  associated with events that pose a threat to a
  patient's life or functioning
• Serves as a guide for defining regulatory
  reporting obligations

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SAE Outcome

• Recovered
• Not yet recovered
• Used for chronic conditions
• Died

118
SAE Outcome - Question

• What is important when recording a SAE with fatal
  outcome?
• Death should be the primary SAE event
• Death is an outcome
• Provide a clinicial summary describing the
  symptoms/events preceding death
• Provide the autopsy report when available

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SAE Outcome - Answer

• What is important when recording a SAE with fatal
  outcome?
• Death should be the primary SAE event
• Death is an outcome
• Provide a clinicial summary describing the
  symptoms/events preceding death
• Provide the autopsy report when available
• So, death is an outcome, not an event!

120
SAE Action taken

• Treatment
• None, i.e. continued
• Interrupted
• Discontinued

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SUSAR, 1

• Suspected Unexpected Serious Adverse Reaction
• Unexpected
• Unlikely in context of antiplatelet agents
• Serious needs to meet criteria for serious
• Fatal
• Life threatening
• Disabling
• Hospitalisation (admission or prolongation)
• Teratogenic
• Medically important

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SUSAR, 2

• Reaction
• Suspected drug reaction
• Not just a consequence or complication of stroke
• Requires notification to Trial Office lt24 hours
• TARDIS should generate very few, if any, SUSARs

123
SAE Example - Question

• A patient experiences myocardial infarction with
  chest pain, dyspnoea, diaphoresis, ECG changes,
  enzyme changes, and jaundice. What SAE(s) should
  be recorded?
• Record all diagnoses and symptoms as SAEs
• Only record the overall diagnosis of MI as an SAE
• Record MI and jaundice as SAEs

124
SAE Example - Answer

• A patient experiences myocardial infarction with
  chest pain, dyspnoea, diaphoresis, ECG changes,
  enzyme changes, and jaundice. What SAE(s) should
  be recorded?
• Record all diagnoses and symptoms as SAEs
• Only record the overall diagnosis of MI as an SAE
• Record MI and jaundice as SAEs

125
SAE Coding

• Example
• Investigator term Headache, head pain
• Verbatim, raw term cephalgia
• Standard term Headache
• Please look for standard term in available list

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TARDIS SAE questions, 1

• When did it start? Before / during / after
• Fatal? Y/N
• Life-threatening? Y/N
• Hospitalisation? Y/N
• Disabling? Y/N
• Birth defect? Y/N
• Medically important? Y/N
• Category? Stroke / MI / Bleed / SAE
• Describe?

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TARDIS SAE questions, 2

• Date/time began?
• Nature? Single / Multiple
• Intensity? Mild / Moderate / Severe
• Relationship? Definitely not / / definite
• Action? Continue/Missed/Stopped
• Outcome? Recovered / / Died

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TARDIS SAE questions, 3

• Diagnostic evidence As much info. as possible
• Pathology
• Radiology
• ECG
• Bacteriology
• Biochemistry
• Haematology
• Clinical
• Comment

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TARDIS SAE questions, 4

• Event Stroke / TIA / N/A
• Limb weakness Y/N
• Speech disturbance Y/N
• Sensory disturbance Y/N
• Visual field loss Y/N
• Posterior circulation Y/N
• Other Describe
• Length of symptoms ABCD2 bands
• Severity ABCD2 / NIHSS score / ?
• Brain imaging
• Type IS/HTI/ICH/?

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TARDIS SAE questions, 5

• Event UA / NSTEMI / STEMI / N/A
• Chest pain Y/N
• SOB Y/N
• Sweating Y/N
• Nausea/vomit Y/N
• ECG date
• ECG changes Ts inv / ST el / ST dep / Q wave
• Enzyme date
• Enzymes Trop I/Trop T/CK/CKMB/ND

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TARDIS SAE questions, 6

• Bleed Minor / Moderate / Major / N/A
• Blood transfusion
• 0/ 1/ 2/ 3/ 4/ 5/ 6/ gt6 units
• Where
• CNS Respiratory
• CV Retroperitoneal
• GI Skin
• GU Other
• MS
• Ocular

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TARDIS 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

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TARDIS 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 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 gt48 hours of knowledge
• SUSAR gt24 hours of knowledge
• If uncertain, ask TARDIS CC

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Any questions?
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TARDIS Imaging

• Philip Bath

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Introduction

• Importance of CT in classification of stroke
• Classification of stroke type
• Type of stroke
• Compatibility with presenting stroke
• Mass effect
• Cerebral atrophy
• White matter disease
• Previous stroke
• Quiz

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CT scans

• Usually dont 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

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TARIS Baseline form
Stroke - head scan required before
randomisation TIA - no scan required
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Haemorrhagic Transformation of Infarction (HTI)
ISCHAEMIC STROKE MINOR BLOOD Haemorrhagic Infarct (HI) petechial infarction without space occupying effect. HI1 - small petechiae HI2 - more confluent petechiae ISCHAEMIC STROKE MAJOR BLOOD Parenchymal Haemorrhage (PH) haemorrhage with mass effect. PH1 - lt30 of the infarcted area with mild space occupying effect PH2 - gt30 of the infarcted area with significant space occupying effect.
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Haemorrhagic Transformation of Infarction (HTI)
ISCHAEMIC STROKE MINOR BLOOD Haemorrhagic Infarct (HI) petechial infarction without space occupying effect. HI1 - small petechiae HI2 - more confluent petechiae ISCHAEMIC STROKE MAJOR BLOOD Parenchymal Haemorrhage (PH) haemorrhage with mass effect PH1 - lt30 of the infarcted area with mild space occupying effect PH2 - gt30 of the infarcted area with significant space occupying effect.
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TARDIS Baseline form
v
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TARDIS Baseline form
v
?
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CT scans - Ischaemic stroke
145
CT scans - Haemorrhagic stroke
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TARDIS Day 7 Form - Imaging
Report available
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TARDIS Day 7 Form - Imaging
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TARDIS CT scan - lesion

• Choose normal if
• Normal scan
• Normal for age
• no intracranial abnormalities
• Choose no lesion explaining symptoms
• lesion on the wrong side
• or if only old strokes, atrophy and white matter
  change mentioned

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TARDIS 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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TARDIS CT scan - lesion

• Choose OTHER if
• Most commonly tumour
• If there is something mentioned in the scan that
  you dont understand or you are not sure if it
  explains the presentation, ask
• If they mention a stroke AND another lesion, ask

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TARDIS CT scan - compatible with presentation?
152
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 effect
154
Mass effect
155
TARDIS CT scan - mass effect

• Chose yes if
• mass effect, midline shift, ventricular
  effacement
• If it says these are not present or there is no
  mention of them, chose no
• Please note that hydrocephalus is NOT mass effect

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Mass effect v hydrocephalus
157
TARDIS Cerebral Atrophy
158
Atrophy
159
TARDIS CT scans - atrophy

• Answer yes if
• Atrophy or involutional change
• If no mention or age appropriate and the
  patient is under 60, say no

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TARDIS Leukoariosis
161
CT scan - periventricular white matter lucency
162
TARDIS CT scan - periventricular white matter
lucency

• Choose yes if
• periventricular white matter lucency,
  leukoaraiosis, white matter disease, white
  matter change, small vessel disease, small
  vessel ischaemia.
• If the report says these are absent or not
  mentioned, say no.

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TARDIS CT scan - previous strokes
164
TARDIS CT scan - previous strokes

• Choose yes if
• old, or mature infarcts
• If they are not mentioned, or are noted to be
  absent absent, say no.

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TARDIS Most important of all

• If you dont 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 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.

167
Case 1 - answers
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Case 1 - answers
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Case 1 - answers
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Case 1 - answers
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Case 1 - answers
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Case 1 - answers
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Case 1 - answers
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Test number 2

• 70 year old patient with sudden onset right sided
  weakness.
• CT report
• There is evidence of multiple well-established
  old infarction in both cerebral hemispheres.
  There is an area of hypodensity in the region of
  the left internal capsule which may represent
  more recent ischaemia. There is extensive
  leukoaraiosis and atrophy.

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Case 2 - answers
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Case 2 - answers
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Case 2 - answers
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Case 2 - answers
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Case 2 - answers
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Case 2 - answers
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Case 2 - answers
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Any questions?
183
TARDIS Site responsibilities and trial files

• Margaret Adrian

www.tardistrial.org
184
Record Keeping

• Documents individually and collectively permit
  the evaluation of the trial and the quality of
  the data produced.
• Documents serve to demonstrate the compliance of
  the investigator, sponsor and monitor with the
  standards of GCP and all applicable regulatory
  requirements
• ICH GCP 8.1

185
What do we mean by records?

• Site file
• Case record form
• Medical notes

186
Site File

• Contact List / Investigator Site Personnel
• Study Documentation
• Regulatory Approved Documents
• Signed Agreement
• Study Medication/Laboratory
• Recruitment
• Screening log/signed consent forms
• SAE/SUSAR Report
• Monitoring Reports
• Miscellaneous

187
Case Record Form (CRF)

• Accurate and legible
• Changes
• Consistent with source documents
• Document all visits/tests
• Document and explain all deviations

188
Patient medical notes

• Stickers
• Copy of PIS/consent
• GP letter
• Trial medication
• Serious Adverse Events

189
Storage of records

• Confidential
• Archiving
• TARDIS is sponsored by The University of
  Nottingham

190
Conclusion

• A simple and accurate paper trial is essential to
  demonstrate the validity and integrity of study
  conduct

191
Any Questions?
192
TARDIS Trial monitoring

• Margaret Adrian

www.tardistrial.org
193
Purpose of monitoring

• To verify that
• The rights and well being of human subjects are
  protected
• The reported trial data are accurate, complete,
  and verifiable from source documents
• The conduct of the trial is in compliance with
  the protocol, GCP and regulatory requirements

194
Types of monitoring in clinical trials

• Approaches to trial monitoring should be
  appropriate to the trial and should be
  proportionate to its
• Size
• Complexity
• Risks, both to the participants and the results

195
Trial Oversight Committees

• The funding body or sponsor may specify
  particular oversight arrangements, but even if
  they do not, some form of oversight is strongly
  recommended for all trials, although the
  appropriate structures will vary according to the
  size, complexity and risks associated with the
  trial
• Commonly employed oversight committees
• Trial Steering Committee (TSC)
• Trial Management Committee (TMC)
• Data Monitoring Committee (DMC)

196
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

197
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

198
Coordinating centre monitoring

• Day-to-day monitoring should be carried out by
  those responsible for running a trial
• Typically includes following checks
• Data consistent with adherence to protocol
• CRFs 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

199
Central monitoring

• Central monitoring is defined as
• Centralised procedures for quality control of
  trial data
• These may include
• Statistical checks over time and across different
  data items to identify unusual data patterns
  within and across centers
• External validation of selected data items

200
Central monitoring

• Central collection of copies of radiographs,
  scans, or pathology reports which permit the
  study coordinators to verify independently key
  criteria for eligibility or outcome
• With the participants consent, national vital
  statistics services may be used for the
  corroboration of the existence of the subject or
  the verification of mortality outcomes

201
Central monitoring

• Using stroke registers to confirm information on
  eligibility or outcomes
• Central monitoring of data using statistical
  techniques for identification of unusual patterns
  of data
• Can be used to identify sites or contributors
  that may be deviating from the protocol
• Participant consent may be confirmed by the
  collection of a copy of the consent form at the
  coordinating centre, with measures to ensure
  confidentiality

202
On-site monitoring, 1

• On-site visits provide the opportunity to
• Educate staff about the trial
• Understand the protocol and trial procedures
• Verify that site staff have access to the
  necessary documents to conduct the trial
• Confirm that required pharmacy and laboratory
  resources are in place

203
On-site monitoring, 2

• On-site visits provide the opportunity to
  (continued)
• Check adherence to the protocol and GCP
• Verify selected data and SAEs recorded in CRFs as
  compared with data in clinical records to
  identify errors of omission as well as
  inaccuracies
• Confirm that written consent was obtained
• If copies of the form are not held in the
  coordinating centre

204
Source documentation

• All electronic data should be supported by source
  documentation
• Source documentation is any form of documentation
  on which the initial information is written,
  regardless of what it has been written on
• All forms of source documentation will need to be
  filed and retained
• Minimum information Centre No, Recruit ID,
  Recruit Initials

205
Source documentation

• The following are all considered forms of source
  documentation
• Medical records
• Nursing records
• Drug chart
• Paper CRFs
• CT/MRI reports
• Diagnostic investigational reports

206
Findings from site monitoring visits

• Document Control - Version Numbers
• Stroke onset time not clearly documented in
  medical records
• Absence of documents
• Lack of Delegation of responsibilities
• Site files non-existent/not up to date
• Inconsistent dates and times
• Limited written entries in medical records
• Failure to report SAEs
• Each page of a CRF must have unique trial
  identifier and the dated and signed by
  investigator

207
Any Questions?
208
TARDIS Data Monitoring

• Philip Bath

www.tardistrial.org
209
TARDIS 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

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TARDIS Data Monitoring, 2

• Roles
• Safeguard interests of participants
• Assess safety and efficacy
• Monitor trial conduct
• Respond to any investigator concerns
• Consider requests for release of data
• Advice potential funder(s) of main phase
• Perform extra interim analyses as needed
• Consider results of any other studies/trials
• Recommend continuation, change or stop

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TARDIS Data Monitoring, 3

• Modus operandi
• 6 monthly assessments of data
• Data tables prepared by trial statistician
• Teleconference (or meeting)
• Open then closed session
• Minuted
• Report to Chair of TSC (Helen Rodgers), cc CI
  (PB)
• Closed session confidential

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TARDIS Data Monitoring, 4

• Roles
• Review accruing unblinded trial data
• Assess whether there are any safety issues that
  participants should be informed of
• Assess whether trial should continue or not
• Be independent of investigators, funder sponsor
• Make recommendations to the TSC

213
TARDIS Data Monitoring, 4

• Trials status
• Timelines
• Recruitment
• Patients, centres, patients/centre
• Data completeness, quality
• Patients
• Baseline features
• Balance by treatment groups
• Outcomes

214
TARDIS Data Monitoring, 5

• Data
• Modified Rankin Scale
• Stroke (ischaemic and haemorrhage)
• Bleeding major
• SICH (lt2)
• Death
• SAEs

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Any Questions?
216
TARDIS Sub-studies

• Philip Bath

www.tardistrial.org
217
TARDIS Sub-studies

• Transcranial Doppler
• Centres with TCD machines and staff already
  trained in their use
• MCA monitoring of emboli
• P-Selectin
• Aspirin / clopidogrel resistance
• Pharmacogenetics
• Antiplatelet effects/resistance by genotype
• Serum Plasma samples
• For future testing

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Any Questions?And many thanks for attending
219
(No Transcript)
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TARDIS Inclusion criteria

• Adults at high risk of recurrent ischaemic
  stroke
• Acute non-cardioembolic ischaemic stroke (lt48
  hours of onset)
• Acute TIA (lt48 hours of onset) with an ABCD2
  score gt5 (stroke rate at 13 weeksgt10).
• (All TIAs and strokes must have motor weakness
  lasting at least 10 minutes)

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TARDIS Exclusion criteria

• Agelt50
• Motor weakness lasting lt10 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 (mRSgt3)
• No enteral access
• Parenchymal haemorrhage (PH I/II)
• TIA not fulfilling inclusion criteria
• AF/cardioembolic stroke
• BPgt185/110 mmHg
• Recent PU, ICH
• Planned surgery within 3 months

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TARDIS Substudies - biomarkers

• TCD emboli (baseline, day 2)?
• As in CARESS
• At Leicester Nottingham
• LAD but limited power (or do as pilot)
• Platelet function (baseline, day 7)
• All centres
• P-selectin (fixed blood)
• Central assay Nottingham
• Also VerifyNow (PoC) at Nottingham
• Pharmacogenetics
• Antiplatelet efefcts, resistance

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TARDIS Trial status

• MREC approval
• MHRA approval
• Local SSI/RD ongoing
• UKSRN Adoption ongoing
• UK investigator meeting 23-24/03/09
• Start April 2009

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Resistant stroke/TIA

• Non-cardioembolic stroke/TIA with recurrence
• On mono antiplatelet therapy
• Add another antiplatelet (A-gtAD, C-gt?)
• 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

225
Triple 2 trial Logistics

• TSA grant
• Trial manager
• Trent LRN Research Nurses
• Identify, recruit patients perform measurements
• Trent LRN TCD equipment?
• NHS Treatment Costs Clopidogrel
• NHS Indirect Costs Blood counts

226
Triple therapy Systematic review

• Aim
• Safety and efficacy of triple vs. conventional
  antiplatelet therapy in the prevention of
  vascular events
• Methods
• Electronic searches
• Cochrane Review Manager

Geeganage et al. Unpublished
227
Triple therapy Systematic review

• RCTs
• Trials 12 patients 10,538
• ACS/PCI 11 stroke/TIA 1
• Observational studies
• Studies 7 patients 20,167
• Treatment
• Start
• Length

Geeganage et al. Unpublished
228
Triple therapy (SR) Results - RCTs

• T N E OR CI
• Efficacy
• MI 10 9795 783 0.71 0.56-0.90
• Ischaemic stroke 3 3684 6 3.02 0.60-15.23
• Vascular 9 9595 852 0.73 0.58-0.92
• Safety
• Death 9 9595 103 0.87 0.59-1.29
• Bleed major 10 9820 156 1.24 0.90-1.73
• Bleed minor 8 8864 242 1.52 1.17-1.97
• Transfusion 6 8874 192 1.52 1.13-2.05
• Thrombocytopen. 5 6541