Transcript Limited choices for stroke prevention in patients with AF?

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