Transcript Stroke - PODCAST

Prevention Of Decline in
Cognition After Stroke Trial
(PODCAST)
www.podcast-trial.org
PODCAST: Agenda, day 1
Welcome
Background
Aims & design overview
Protocol: inclusion/exclusion
Approvals
Interventions: BP/lipid lowering I
Philip Bath, John O’Brien
Philip Bath
Philip Bath
Sandeep Ankolekar
Sheila O’Malley
Philip Bath, Nathalie BaileyFlitter
Tea
Interventions: BP/lipid lowering II Philip Bath, John Reckless
Cognitive outcome measures
Philip Bath, Clive Ballard
Funders’ perspective
Susanne Sorensen
Delegates
Practice data entry (Room A41)
Trial Steering Committee (Room A42)
PODCAST: Agenda, day 2
Serious Adverse Events
Outcomes, dementia & vascular
Electronic data entry I
Philip Bath
Clive Ballard
Philip Bath
Sandeep Ankolekar
Coffee
Electronic data entry II
Imaging: definitions/upload
Site responsibilities
Site monitoring
Data monitoring
Close
Sandeep Ankolekar
Sandeep Ankolekar, Tanya Jones
Sally Utton
Lynn Stokes
Philip Bath
Philip Bath
Lunch
PODCAST: Background to the
trial
Philip Bath
Definitions
Post stroke dementia (PSD):
 Dementia following symptomatic stroke
Vascular dementia (VaD):
 Dementia in presence of cerebrovascular disease
Mixed dementia:
 Coexisting VaD and AD
Post stroke cognitive impairment (PSCI):
 Cognitive impairment following symptomatic stroke
Cognitive impairment/no dementia (CIND)
Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press
Post-stroke dementia

High risk of vascular cognitive impairment
and dementia after stroke
 Dementia
15-30% within 5 years of stroke
Strategic infarcts – rapid
 Lacunar/white matter – insidious
 Attentional/executive dysfunction before memory


Mechanisms
 Stroke

lesion(s): strategic lesions
Cortical, lacunar, white matter disease
 Atherosclerosis

High BP, high cholesterol
 Blood

& risk factors
brain barrier breakdown
Toxic blood components: white matter disease
 Low
blood flow, …
Prevalence of pre-stroke dementia
Pendlebury & Rothwell. Lancet Neurol 2009;8:1006
Prevalence of post-stroke dementia
By 1 year
Pendlebury & Rothwell. Lancet Neurol 2009;8:1006
Incidence of post-stroke dementia
Hospital-based cohorts/any stroke
Community-based cohorts/first stroke
Pendlebury & Rothwell. Lancet Neurol 2009;8:1006
Lessons: Observational data
PSD higher:
 If dementia prevalent at time of stroke
 Self-evident!

After recurrent stroke than first stroke
 Predictable

In hospital series, relative to community
 Predictable

Preventing recurrence may be a key way to
prevent PSD
ENOS: Cognitive decline post stroke
High BP, <48 hours of onset
 Ischaemic stroke, ICH
 5 continents, 16 countries, 105 centres
 RCT of GTN v control; continue v stop
 Blinded telephone outcomes at day 90
 Primary: modified Rankin Scale
 Cognitive: sMMSE (n = 465)
 sMMSE 0-18/18, mean 13.4, SD 4.7

 sMMSE

<14 = 178 (38.3%)
Secondary: Barthel Index, EuroQoL, Zung
www.enos.ac.uk
ENOS: Associations with low sMMSE
+ p<0.001
Age
Female sex
Previous stroke
AF
PICH
TACS
Severe stroke
High SBP
Diabetes
Temperature
Glucose
Univariate
+
+
+
+
+
+
+
+
-
Multivariate
+
+
+
+
+
+
+
Ankolekar et al, for ENOS, UK Stroke Forum 12/2009
ENOS: sMMSE and other outcomes
Measure
Scale
r
Dependency
Disability
QoL
Mood
mRS
-0.368
BI
0.432
EuroQoL 0.314
Zung
-0.135
p
<0.001
<0.001
<0.001
0.004
So, influencing one may alter the others
Ankolekar et al, for ENOS, UK Stroke Forum, 12/2009
ENOS: Implications

Poor cognitive function at day 90 post stroke
 Common,

38%
Associated with:
 Multiple
baseline factors including high BP
 Outcome - poor functional outcome, QoL, mood

Lowering BP acutely is a potential target for
reducing early poor cognition
Ankolekar et al, for ENOS, UK Stroke Forum, 12/2009
PODCAST: Predications

High risk of cognitive decline and dementia
after stroke
 Dementia

Biological rationale and some evidence that
lowering BP reduces cognitive decline and
dementia
 Syst-Eur,

15-30% within 5 years of stroke
PROGRESS
Biological rationale but no good evidence
that lowering lipids reduces cognitive decline
Prevention/treatment of PSCI & PSD
Prevention
VaD AD
CEI
BP
Lipid
Antiplatelet
NSAID
SSRI
Treatment
PSD AD
?+
?+
-
+
?
-
?+
Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press
Dementia: BP lowering trials
Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press
Cognitive decline: BP lowering trials
Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press
Cognitive change: BP lowering trials
Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press
Dementia: BP lowering trials
Trial
Rx
N
OR
Syst-Eur
PROGRESS
SHEP
HYVET
PRoFESS
PROGRESS
SCOPE
CCB
ACE-I+D
Diuretic
Diuretic
ARA
ACE-I
ARA
2418
3544
4736
3336
15049
2561
4886
0.51
0.77
0.84
0.89
1.00
1.08
1.08
ΔSBP LoFU
month
-10.0 24
-12.3 49
*
-11.9 54
-15.0 25
-3.8 30
*
-4.9 49
*
-3.2 45
* Post stroke
Note: no data ALLHAT, ASCOT, PATS
Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press
Prevention: Dementia vs BP
Meta-regression
Log odds ratio vs. SBP
Weighted: inverse of variance
Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press
Cognition: Treatment, Statins
But:
 LEADe:
 No MMSE:
 No data:
Neutral (n=640)
PROSPER, HPS
ASCOT, ALLHAT, SPARCL
Ankolekar, Geeganage, Anderton, Hogg, Bath. JNS 2010;in press
Lessons: Trial data

BP lowering associated with reduction in
dementia/cognitive decline
 Effect

related to magnitude in fall in BP
Potential BP class differences
 But
pattern not clear
Data from mix of hypertension and poststroke trials
 Insufficient data on lipid lowering

 Missed
opportunities
 Must include cognitive measures in non-cognitive
trials
PRoFESS: Dementia over 2.5 years
RCT post ischaemic stroke, n=20,223
Dementia (%)
All
Recurrence
Telmisartan
Placebo
5
5
13
10
Aspirin/dipyridamole
Clopidogrel
5
5
12
11
Diener et al. Lancet 2008;27 Aug
PRoFESS: Recurrent Stroke
Mean follow-up 2.5 yrs
Telmisartan 8.7%
Placebo 9.2%
HR 0.95, 95%CI 0.86-1.04
P=0.23
Cox covariates: age, baseline ACE-inhibitor use, modified Rankin Scale, and baseline diabetes status
Yusuf et al. New Engl J Meds 2008;27 Aug
Analysis of cognition: Suboptimal

Ignore baseline



Ignore continuous nature of data





Comparison of on-treatment means
Comparison of on-treatment medians
Comparison of proportions of cognitive impairment
Comparison of proportions of cognitive decline
Ignore ordinal nature of cognition/dementia
Ignore death
Poor methods for dealing with missing data


Imputation of missing data
Last value carried forward
OAST-Cog: Analysis of cognition
Optimising analysis:
 Binary vs ordinal vs continuous
 Proportions vs Shift in scores vs Gradient
(repeated measures) vs ANCOVA vs …
 Include death – part of cognitive continuum
 Deal with missing data – multiple measures
Advantages: Ordinal vs Binary
More powerful statistically:
 Smaller p-value / confidence intervals [1]
 Smaller sample size
[2]
 Smaller NNT (i.e. more favourable)
[3]

Also worth including co-variates
[4]
1. OAST. Stroke 2007;38:1911-5
2. OAST. Int J Stroke 2008;3:78-84
3. OAST. To be submitted
4. OAST. Stroke 2009;40:888-94
ECASS III: Modified Rankin Scale
mRS 0,1 vs 2-6: 52.4% vs. 45.2%; ARR 7.2%
Odds ratio 1.34 (95% CI 1.02-1.76, P = 0.04)
Hacke et al. New Engl J Med 2008;359:1317-29
Ordered categorical outcomes
Such ordered categorical outcomes could be more powerful statistically,
reduce sample size, reduce numbers-needed to treat, and improve
health economic arguments
Bath et al. Stroke 2008
Stroke, 4 levels: NASCET
No Endarterectomy Yes
‘p’ 2 level 0.002, 3 level 0.001, 4 level 0.0009
0%
100%
Number of patients (log)
No stroke
Mild
Severe
Fatal
Geeganage, Bath, Gray, Collier, Pocock. British Hypertension Society 2006
PROGRESS: Cognition (severity)
Binary, dementia: p=0.22 NNT 129 (49-∞)
Ordinal ‘shift’:
p=0.021 NNT 47 (28-138)
Ankolekar, Geeganage, Bath. In preparation
OAST-Cog: Relevant trials
Vascular:
 BP: HOPE, HYVET, ONTARGET, PROGRESS,
PRoFESS, SCOPE, Syst-Eur, TRANSCEND, …
 Lipid: HPS, LEADe, PROSPER, …
Cholinesterase inhibitors:
Antiplatelets:
 PRoFESS, …
NSAIDs:
[email protected]
Lessons: Trial design

Interventions: Limited
 Cholinesterase
inhibitors, lipid/BP lowering, …
 Prevention vs. treatment
Risk factor difference: often small (BP, lipid)
 Follow-up: usually too short (months)
 Size: usually too small
 Analysis: often suboptimal
 Outcomes: varying, some non-ideal

 MMSE,

TICS, …
Cognition: secondary/tertiary outcome
SPS3
Secondary Prevention of Small Subcortical Stroke trial
N=2,500 with MR+ve lacunar stroke/TIA (<6/12), age 40+
US, Canada, Mexico, Latin America, Spain
Interventions (for mean 3 years) – factorial design:
 Aspirin + clopidogrel vs. aspirin + placebo
 SBP lowering: <130mmHg vs. <150 mmHg
Primary outcomes:
 Ischaemic stroke recurrence
 Haemorrhagic stroke (PICH, SAH)
Secondary outcome:
 Rate of cognitive decline (for AC vs. A)
www.sps3.org/
NCT00059306
PODCAST: Addressing lessons


Cognition (inc. dementia) is primary outcome
Intensive vs guideline BP lowering



Factor in lipid lowering (ischaemic stroke)
Recruit 3-7/12 post stroke





Force big difference, A(B)/CD rule
Cognition stable, exclude prevalent dementia/early PSD
Recruit from hospital
Long follow-up (years)
Large sample size (1,000s)
Optimise statistical analysis
www.podcast-trial.org/
IRCTN85562386
PODCAST: Background
Any questions?
PODCAST: Trial aims & overview
Philip Bath
PODCAST

Prevention of Dementia & Cognitive decline
After Stroke trial

Randomised controlled partial factorial trial
 Open

label, blinded outcome, blinded adjudication
Phases:
 Start-up:
600 patients, 40 SRN centres, 3 years
 Main: ~3,500 patients over 5 years

100+ centres – UK, France? Singapore? …
PODCAST: Interventions

All stroke
 Intensive


<125 mmHg vs. <140 mmHg
Ischaemic stroke only
 Intensive

vs. guideline lipid lowering
<4/2 mmol/l vs. <5/3 mmol/l
 (Statins

vs. guideline BP lowering
associated with increased bleeding)
Trial of management trial, not specific drugs
PODCAST: Sample size per group
Assumes ~90% of patients are ischaemic
ICH
No lipid
BP int
30
BP guide 30
Ischaemic stroke
Lipid
Total
Lip int
Lip guide
135
135
300
135
135
300
Total
270
60
270
600
PODCAST: Primary outcome

Comparison of cognition using the
standardised ’Addenbrooke’s Cognitive
Examination’ between treatment groups
 Proportion
with reduction in ACE at end of trial; or
 Shift in ordinal cognition/dementia
Method of analysis subject to results of
OAST-Cog and other studies
 ACE includes ‘Mini-Mental State Examination’
(MMSE)

PODCAST: Secondary outcomes
Individual cognitive domains:
 Global
TICS, MOCA
 Attention
Trail making A/B
 Attention/executive
Stroop
 Memory
MMSE
 Informant
IQCODE
Vascular:
 Stroke recurrence, MI
Function
 mRS, QoL, mood
PODCAST: Safety
Death
 Falls (leading to fracture or hospitalisation)
 Postural hypotension
 Myositis, rhabdomyolysis
 SAEs

Notes:
 AEs will not be collected since drugs are
licensed
 Outcomes and SAEs will be entered using a
common form to facilitate data collection
PODCAST: Other aims
CT/MR scanning:
 Index event


Characterise patients at baseline
On-treatment clinical scan (dementia, vascular)

Characterise clinical event
Health economics
 Costs of dementia/cognitive impairment


Costs of excess treatment



Carer, institutionalisation
BP drugs, lipid drugs
Cost/event (cognitive decline) prevented
Cost/QALY
PODCAST: Recruiting centres
Start-up phase:
 Recruitment over 2 years
 40+
sites x 1 patient/site/month = ~400 pa
Follow-up over 1-2.5 years
 Recruitment:

 SRN

hospital sites
Follow-up:
 Primary
care (guideline management, blood tests)
 SRN hospitals (DeNDRoN)
PODCAST: Status
Approvals:
 Eudract, MHRA, MREC, SSI
 ISRCTN 85562386
 SRN adoption (with DeNDRoN, PCRN)
 User/consumer support
 AS QRD, TSA, Nottingham Forum
Documents:
 Protocol, PIS/RIS
http://www.podcast-trial.org/
 Data forms, database, algorithms
https://www.nottingham.ac.uk/~nszwww/podcas
t/podcasttrialdb/demo/podcast_login.php
PODCAST: Time lines, start-up
Start-up
-6-0
Protocol
Approvals
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Site id
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Funding
Recruit
patients
Review
main phase?
0-2
3-6
7-18
19-24 25-30 31-36
=
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PODCAST: Promotion

UK Investigator meeting


Stroke Res. Network Annual meeting


2010, May 2011 (Hamburg)
Other meetings


2009, Dec 2010 (Glasgow)
European Stroke Conference


Thames, West Midlands, …
UK Stroke Forum


2009, 2010, …
SRN Local Research Networks


Sept 2010, …
Int Geriatrics Society (Sept 2010), …
Trial protocol publication
PODCAST: Funding

Start-up phase (n=600), joint equal funding
 Alzheimer’s
Society
 The Stroke Association

Main phase
 To
be submitted for funding when feasibility data
from start-up available
PODCAST: Trial Steering Committee
Independent Chair
 Grant applicants
 Independent experts

 Stroke
 Vascular/cardiology

Ahamad Hassan (Leeds)
Stephen Ball (Leeds)
Patient reps
 Alzheimer’S
 The
Society
Stroke Association
Funder rep
 Sponsor rep

John O’Brien
x9
Andrew Pepper, Dave
Hanbury
John Murray
Susanne Sorensen
Angela Shone
PODCAST: Grant applicants
Clive Ballard
 Philip Bath
 Alistair Burns
 Gary Ford
 Jonathan Mant
 Peter Passmore
 John Reckless
 Rob Stewart
 Joanna Wardlaw

London
Nottingham
Manchester
Newcastle
Cambridge
Belfast
Bath
London
Edinburgh
PODCAST: Adjudication Committees
Cognition/dementia:
 Alistair Burns (Manchester)
 Clive Ballard (London)
 Gary Ford (Newcastle)
Vascular:
 Peter Passmore (Belfast)
 Amit Mistri (Leicester)
 Bob Wilcox (Nottingham)
PODCAST: Staff

Trial administrator (nurse)
 Lynn

Stokes
Outcome assessor (blinded, nurse)
 TBA

Statistician (Ms C Hogg)
3

years, 0.1 wte
Programmer (Ms E Walker)
1
year, 1.0 wte
Trial aims & overview
Any questions?
PODCAST: Protocol, inclusions &
exclusions
Sandeep Ankolekar
PODCAST: Inclusion criteria, 1

Age/cognition:
 Age>70
& t-MMSE>16/22
 Age 60-69 & MMSE 17-20/22
Functionally independent (mRS 0-2)
 Stroke:

 Ischaemic
- any OCSP/TOAST type
 Primary intracerebral haemorrhage – cortical or
basal ganglia

3-7 months post-event
PODCAST: Inclusion criteria, 2

Systolic BP:
 125-170

mmHg
Total cholesterol:
 3-8
mmol/l
Presence of an informant (partner, sibling,
child, friend)
 Capacity and willingness to give consent

PODCAST: Exclusion criteria, 1
Patients not meeting inclusion criteria
 Subarachnoid haemorrhage
 Secondary intracranial haemorrhage

 Trauma,
AVM, cavernoma
No CT/MR during index stroke
 Inability to give consent or do study
measures

 e.g.
severe dysphasia, weakness of dominant arm
Definite need for intensive BP control
 Definite need for potent statin or ezetimibe

PODCAST: Exclusion criteria, 2








Need for a cholinesterase inhibitor
Familial stroke associated with dementia, e.g.
CADASIL
Chronic renal failure: eGFR<45 (,37 African/AfroCaribbean)
Chronic liver disease: ALT>60
Ongoing participation in trials in drug and/or devices
(screening allowed if the other trial completes prior
to PODCAST randomisation)
Any serious comorbidity (life expectancy <24
months)
Clinically unstable at the time of enrolment
Dementia
PODCAST: Randomisation


Randomisation and data collection/validation to be
performed in real-time over a secure internet site
Blinding


Stratification



Both participants and investigators are unblinded
Stroke type (ischaemic/ICH)
Country
Minimisation on prognostic baseline factors






Age (<70/>70 yrs)
MMSE (>28/<28)
SBP (<140/>140 mmHg)
No. of BP drugs (0-1/>1)
Time from stroke (>4/<4 m)
Region (subcortex/cortex)
Sex (female/male)
TC (<5.0/>5.0 mM)
Statin (no/yes)
Dysphasia (no/yes)
Leukoaraiosis (no/yes)
Selection of Participants

Initial approach
 Hospital
based stroke services
 General pre-screen
 Approach patient/PIS
Screening Consent (Form)
 Collect GP/Patient/Informant contact details
(Form)
 Screening telephone call
 GP letter and Practice Briefing Sheet (Form)
 PIS (Form), Lipid test form (IS only)
 Arrange baseline visit (minimum 2 weeks
after screening telephone call)

Trial Flow Chart, 1
Informed Consent
All patients must have capacity
 Screening consent

 PIS
(Form)
 Participant Screening Consent (Form)

Baseline consent
 Pre
consent questions
What is the trial aiming to achieve ?
 What are the two groups of intervention ?
 How long will treatment continue ?

 Form

Informant
 Informant
PIS (Form)
 Informant Consent (Form)
Trial Flow Chart, 2
Post Randomisation
Genetic blood tests
 GP letter
 Intensive groups

 UE
form for the next visit (BP arm)
 Lipid form for the 3 month visit (lipid arm)

Guideline groups
 Refer
back to GP
 Next visit at 6 months
PODCAST Substudies
Pharmacogenetics substudy
 24 hour ambulatory blood pressure
monitoring substudy
 Neuroimaging sub study

Separate information sheet and consent
forms: single form for all three sub
studies(Form)
 Only genetic sub study: currently active for
all centres
 Centres will be contacted regarding other sub
studies

Genetics Substudy

Aim
 Study
effect of interventions on blood biomarkers
 Pharmacogenetics: why different individuals have
different response to drugs?
Baseline or second clinic visit
 Adequate local centrifuge/freezer facilities
 4 ml EDTA (purple top)- frozen directly
 8 ml serum (red [preferred] or gold top:
centrifuge at 5000 rpm for 10 minutes prior
to freezing
 Freezing: -20°Celsius or lower
 Transfer: Arranged by PODCAST ICC

Neuroimaging Substudy

Aim
 Can
imaging characteristics be used as surrogate
markers for cognitive impairment?
 Can treatment modify these characteristics?

What does it involve?
 An
additional brain scan at the end of 3 years
 MRI preferred (or CT scan)
Await funding
 No sites currently active

Ambulatory BP monitoring Substudy

Aim
 Does
24 BP monitoring help in better
management of patients BP?

3 recordings
 Baseline,
12 mths and 24 mths
 One day -24 hours
Currently not active any center
 Centres with facilities will be contacted

Follow up
Protocol Violations and Deviations

Violations
 Failure
to adhere to the inclusion and exclusion
criteria
 Participant doesn’t receive intensive BP or lipid
lowering when randomised to do so.
 Failure to complete SAEs where appropriate
 Annual clinic/telephone assessments are not
performed

Deviations
 Assessments
done outside the specified time by
more than 30 days
 Participant not fully compliant with randomised
treatment
Withdrawal of participants
Withdrawal of consent
 Clinical indication
 Failure of participant to adhere to protocol
requirements

Protocol: Reference Document
List and definitions of SAEs
 Appendix: Cognitive and other assessments
 Definitions
 Ethical and regulatory aspects
 Trial Management
 Trial treatment, algorithms

Protocol, inclusions & exclusions
Any questions?
PODCAST: Approval of sites
Sheila O’Malley
Manager, Trent Comprehensive
Local Research network
Approval of sites
Any questions?
PODCAST: Interventions
Philip Bath
John Reckless
Nathalie Bailey-Flitter
PODCAST: Interventions by type
Assumes ~90% of patients are ischaemic
ICH
No lipid
BP int
30
BP guide 30
Ischaemic stroke
Lipid
Total
Lip int
Lip guide
135
135
300
135
135
300
Total
270
60
270
600
PODCAST: Interventions
Management site
Hospital
GP
BP lowering
Lipid lowering
Intensive
Intensive
Guideline
Guideline
Intensity:
 BP lowering - number of drugs
 Lipid lowering - type & numbers of drugs
PODCAST: Hospital Research Clinic

Pre-screen:


Screening telephone call:


During acute/sub acute phase
MMSE, mRS
Baseline visit:


Consent, history, exam
Intensive BP group

Management: Initiate/escalate lifestyle and drugs
 Target systolic BP <125 mmHg

Intensive lipid group

Management: Initiate/escalate lifestyle and drugs
 Target LDL-cholesterol <2 mmol/l (TC <4 mmol/l)

Guideline BP group


Management: No action (patient should see GP if SBP>160)
Guideline lipid group

Management: No action (patient should see GP if TC>7)
PODCAST: Hospital Research Clinic

Intensive BP group visits (1, 2, 3 months)


Intensive lipid group visits (3 months)


Initiate/escalate BP management
Initiate/escalate lipid management
Follow-up visits (6, 18, 30, … months):


Cog exam, identify vascular events and AEs
Intensive BP group

Management: Initiate/escalate lifestyle and drugs
 Target systolic BP <125 mmHg

Intensive lipid group

Management: Initiate/escalate lifestyle and drugs
 Target LDL-cholesterol <2 mmol/l (TC <4 mmol/l)

Guideline BP group


Management: No action (patient should see GP if SBP>160)
Guideline lipid group

Management: No action (patient should see GP if TC>7)
PODCAST: General practice, 1
PCTs likely to have ~20 participants
 Each GP likely to have <2 participants

On treatment:
 All groups
 Blood
tests - U&E, fasting TC/TG/HDL
LDL-c is calculated by lab
 ~2 weeks before next hospital research clinic

 Address

any AEs
Refer back to hospital research clinic (or telephone) if
necessary
PODCAST: General practice, 2

Guideline BP group
 Management:
Usual practice/NICE BP guideline
A(B)/CD rule
 Likely to be on 0-2 drugs
 Target systolic BP <140 mmHg


Guideline lipid group
 Management:
Usual practice/NICE lipid guideline
Likely to be on nothing or simvastatin, pravastatin, …
 Target LDL-cholesterol <3 mmol/l (TC<5 mmol/l)

PODCAST: General practice, 3
Role in intensive groups:
 Intensive BP group
 Management:


Continue hospital prescription
(Patient should see hospital early if SBP>140 mmHg)
Intensive lipid group
 Management:

Continue hospital prescription
(Patient should see hospital early if TC>5 mmol/l)
PODCAST: General practice, 4
Lipid management:
 To follow NICE and local guidelines
 Where considered that lipid Rx is appropriate
likely targets are:
 Total

cholesterol <5 mmol/l, LDL-C <3 mmol/l
Use a generic statin:
 Simvastatin

or pravastatin 40mg daily
Lower targets, a different statin or use of
another agent are not normally
recommended unless patient is at very high
risk for another reason
PODCAST: Intensive - BP group, 1




Participants: All
Aim: maintain SBP>10 mmHg difference between
groups
Target SBP<125 mmHg
Specific advice on diet

Salt restriction







No added salt in cooking or at table
Avoid/reduce processed food (packets, cans)
Fruit & vegetables
Drug dose/numbers will be escalated monthly at
hospital research clinic using an algorithm until the
target is reached or 3 visits completed
Wean up drugs if target not reached
Wean down drugs if symptomatic hypotension
Months 1, 2, 3, 6, 18, 30, …
PODCAST: Intensive - BP group, 2

Drugs chosen using NICE/BHS ‘A(B)/CD’ rule:
 A = ACE-inhibitor (e.g. perindopril), ARB (e.g. losartan)

Renin inhibitor (e.g. aliskiren)
B = ß-blocker (e.g. atenolol)
 C = calcium channel blocker (e.g. amlodipine)
 D = diuretic (e.g. bendroflumethiazide)
 α-blocker (e.g. doxazosin)
 Potassium sparing diuretic (e.g. spironolactone)
 Central acting (e.g. moxonidine)
Management decisions up to prescriber



Computer algorithm will act as aide memoir

Composition of agents will vary
 Other indications, e.g. 'A'/'B' post MI
 Contraindications, e.g. avoid 'A' in bilateral RAS, ‘B’ in asthma

GP will support with re-prescribing
PODCAST: Intensive - BP group, 3
Algorithm (general):
 Follow NICE/BHS AB/C(D) rule
 Choose true once daily drugs (to improve compliance)
 Use drugs at medium dose where possible (to reduce AE)
 Add a new drug in preference to maximising the dose of an
existing drug (to reduce AE)
 Avoid drug classes if >2 drugs in that class have an AE when
used at max dose
 Record AEs by dose: none, at high / medium / low dose
 Avoid drug if it has an AE at high dose, i.e. only use it at
low/moderate dose
 Avoid a drug if one from the same super-class is being used
(eg ACE-I on top of an ARB)
 Do not use a drug if another from the same class is being used
 Allow up to 7 (super-)drug classes
 Hard code the algorithm - address every potential combination
 Avoid combinations (proprietary, high cost)
PODCAST: Intensive - BP group, 4
ACEI:
 Super-class: ACEI, ARB, RI
 Use ARB (or RI) if ACEI cough
 Rank high in suggestions
 Rank low if already on an potassium-sparing diuretic and not
on a non-loop or loop diuretic
 If on, preferentially add a CCB or diuretic
 Avoid if RAS, high potassium
 Useful if previous MI, CCF
ß-Blockers:
 Rank low
 If on, preferentially add a CCB, diuretic, a-blocker
 Avoid if asthma, PAD or heart-block
 Useful if previous MI, AF
PODCAST: Intensive - BP group, 5
CCB:
 Super-class: dihydropyridine, phenylalkamine and
benzothiazepines
 Rank high in suggestions
 If on, add a ACE-I (or beta-blocker if not on verapamil)
 Avoid Verapamil if on a beta-blocker
Diuretics:
 Super-class: non-loop and loop diuretics
 Use loop (rather than non-loop) if low GFR
 If on, add an ACE-I, beta-blocker or potassium-sparing diuretic
 Avoid if potassium low
 Avoid if sodium low
PODCAST: Intensive BP Group, 6
Alpha-blockers:
 Rank medium in suggestions
 If on, add a beta-blocker
 Avoid as a first-line agent
Potassium-sparing diuretics:
 Rank high is already on 3 drugs
 Rank lower in suggestions if already on ACE-I
 Rank low if already on an ACE-I and not on a diuretic
 If on, add a diuretic
 Avoid as a first-line agent
 Avoid if potassium high
 Avoid if GFR low
PODCAST: Intensive BP Group, 7
Centrally acting drugs:
 Rank low in suggestions
 If on, add anything
 Avoid if heart block present
 Avoid if GFR low
 Wean off if stopping (wean-off beta-blocker first if
also being stopped)
PODCAST: Intensive BP Group, 8
Adverse effects:
 Generic:
 Symptomatic
hypotension
 Falls

Specific to Class
 ACE-I:
 Beta-blockers:
 CBBs:
verapamil  Diuretics:
 Alpha-blockers:
 K-sparing diuretics:
 Central acting:
cough, fist dose low BP
bradycardia
bradycardia
low sodium/potassium
high potassium
PODCAST: Intensive Lipid Group, 1



Participants: Ischaemic stroke only
Aim: TC>1 mmol/l difference between groups
Target LDL-cholesterol <2 mmol/l




Measure fasting, not random, lipids
Lifestyle advice





Or Total Cholesterol <4 mmol/l if no LDL-c
So prioritise on LDL-c, not TC
Reduce weight
Moderate alcohol
Low saturated fat diet
Cholesterol lowering spreads (ProActiv, Benechol)
Use potent statin

E.g. atorvastatin 80 mg, rosuvastatin
PODCAST: Intensive Lipid Group, 2

If LDL-c above target (>2 mmol/l) at 3/12 or
later
 Increase
statin dose if not already at maximum
 Add ezetimibe 10 mg (NICE TA 132)

Other interventions if needed
 Other
statins - simvastatin
 Fibrates
 Resin
 Nicotinic acid derivative

Actual drug up to prescriber
 Computer
algorithm will act as aide memoir
PODCAST: Intensive Lipid Group, 3




There is no evidence that LDL-c ~ 1 mmol/l are
inappropriate
Data from cardiovascular RCTs suggest that best
prevention achieved with LDL-c < 1.8 mmol/l
If LDL-c < 1.8mmol/l, maintain treatment if well
tolerated
If only TC available, aim for <3.5 mmol/l



Approximates to LDL-c < 2mmol/l
If LDL-c < 2 mmol/l with simvastatin (or
pravastatin) 40 mg then OK, but atorvastatin or
rosuvastatin more likely to be successful
Rosuvastatin (20mg, increased after 1 month to
40mg daily) is an alternative to atorvastatin
PODCAST: Intensive Lipid Group, 4

If LDL-c > 2 mmol/l on statin (at maximum
tolerated dose)
 Add

ezetimibe 10 mg
If LDL-c > 2 mmol/l on statin and ezetimibe
 Add
nicotinic acid as 3rd agent
 Use Tredaptive (nicotinic acid + laropiprant) so
less flushing side-effect

If LDL-c > 2 mmol on statin, ezetimibe and
nicotinic acid
 Add
resin
PODCAST: Intensive Lipid Group, 5
Adverse events:
 Class specific
 Statins:
 Nicotinic
acid:
myositis, rhabdomyositis
flushing
 Fibrates:
 Resins:
GI upset
PODCAST: Intensive Lipid Group, 6

Have a (pre-)baseline ALT and CK
 No
need to monitor these on treatment unless
liver or muscle symptoms

Significant myositis is rare.
 Localised
muscle symptoms, cramps and joint
pains are not statin-related
 Generalised muscle pain, discomfort, tenderness
or weakness lasting more than 2 days should be
investigated (participant --> GP --> Clinic)
PODCAST: Monitoring interventions

Coordinating centre nurse
 Monitor
computer guided algorithms and
individual patient BP and lipids (unblinded)
 Will contact centre if participant badly missing
target

Trial Management Group
 Monitor
BP and lipid levels, and crossovers, by
treatment group (unblinded)

TMG will report to TSC 6 monthly
Interventions: Practicalities, 1
Roles:
 Research nurse
 Obtain

current prescriptions
Patients should bring tables in for each clinic
 Obtain
BP and latest fasting lipids
 Obtain AEs, SAEs
 Give form for fasting lipid - to do 2/52 before next
research clinic

Medic
 Prescribe
 Address
AEs, SAEs
Interventions: Practicalities, 2
Use drugs you are familiar with
 Look up doses, adverse events, interactions
 Discuss common adverse events with
participants - this will help reduce them!

Interventions: Algorithms
Computerised aide memoir
 Uses data entered at time of visit

 Demographic:
age, race-ethnicity
 BP,
lipid levels
 Drugs, doses
 Adverse events, contraindications

Will suggest possible management changes
 Several
solutions (in most cases)
 An aide memoir, not to be followed ‘blindly’
 The final decision rests with the prescribing medic

Requires live access to internet
Interventions
Any questions?
PODCAST: Cognitive outcome
meaures
Philip Bath
Clive Ballard
Cognitive assessments
Cognition:
 Primary outcome of trial
 Addenbrooke’s

Cognitive Examination
Key secondary outcomes
 IQCODE
 Stroop
 Trail

making A & B
Telephone assessments (blinded)
 MMSE
 TICS
(Telephone Interview of Cognition Screen)
ACE
Aim:
 Cognitive screen
 Primary outcome in
PODCAST
Components:
 Orientation
 Attention
 Memory
 Verbal Fluency
 Language
 Visuospatial
Includes:
 Mini-Mental State Exam
 We have extended it to
include a modified
version of the Montreal
Cognitive Assessment
http://www.podcasttrial.org/jevpybki.htm
PodTrainAce.wmv
IQCODE
Aim:
 Cognitive screen done
by third party



Scores:
 Average score over 26
situations: 3 (/5)
Relative, close friend
Secondary outcome in
PODCAST
Assesses change from
10 years previously


Dementia >3.3-4.0
Total core: 26-130
http://www.podcasttrial.org/jevpybki.htm
PodTrainIQCodeInterview.
mov
Stroop
Aim:
 Assessment of
Executive function
Measure of:
 Reaction time
 Selective attention
Increased interference
with:
 Dementia
 Brain damage
 Depression
 Addictions
 Schizophrenia, …
http://www.podcasttrial.org/jevpybki.htm
QuickTime™ and a
decompressor
are needed to see this picture.
Trail making A


Download pdf file
and print out, and
provide pencil
Draw lines between
points 1 to 25 in
order as quickly as
possible and
without lifting penpencil up, i.e.



1-2-3-4-5-6-7- …
Correct any errors
as they happen
Time procedure

Should take <90
seconds
QuickTime™ and a
decompressor
are needed to see this picture.
Trail making B


Download pdf file and
print out, and provide
pencil
Draw lines between
points 1 to 13 and A to
L in order as quickly as
possible and without
lifting pen-pencil up, i.e.



Correct any errors as
they happen
Time procedure


1-A-2-B-3-C-4-D- …
Should take <180
seconds
Discontinue when total
for tests A & B exceeds
5 minutes
QuickTime™ and a
decompressor
are needed to see this picture.
Dementia
Dementia is component of primary outcome
 Detection

 By
participant, informant, research staff
 Results of PODCAST cognition testing (low scores)
 Demegraph: integrates MMSE and IQCODE

Needs formal diagnostic Assessment
 By

expert in research clinic, memory clinic, …
Complete dementia outcome form
 Include

‘vignette’
Free text, letter from memory clinic, …
 Adjudication
committee
Dementia: Free Text Vignette
What practical cognitive impairments are
there in every day life?
 Has the severity of practical cognitive
impairments in every day life progressed?
 To what degree is the level of functional
impairment explained by stroke &
cerebrovascular events?
 Has the level of functional impairments
progressed in the absence of further strokes?
 What examples are there of changes in other
domains such as social functioning,
personality?

Cognition: Timings of testing
Pre-screen on wards: Informal --> ‘normal’
Screening telephone call (2-6/12 post stroke)
 MMSE, mRS
Baseline clinic (3-7/12 post stroke)
 ACE (MMSE, MOCA), Stroop, Trail making, TICS,
IQCODE (informant)
[Telephone (central, 12, 24, 36, …/12)
 tMMSE, TICS, mRS]
Clinic (6, 18, 30, …/12)
 ACE (MMSE, MOCA), Stroop, Trail, TCS, IQCODE
Cognition: Practicalities
Need:
 Quiet room
 Adequate time with participant and informant
 Consistent approach - same nurse
 Print outs of Trail Making Tests A & B
 Access to internet - direct entry of data
including Stroop
 May need a break mid-way
 Cognition testing can be done by research
nurses or medic
 Training and practice (on each other)
Cognitive outcome measures
Any questions?
Funders’ perspectives: AS/TSA
Susanne Sorensen
Funders’ perspectives: AS/TSA
Any questions?
End of day 1
Thanks
Enjoy the evening
See you at 09.00 tomorrow!
PODCAST: Agenda, day 2
Serious Adverse Events
Outcomes, dementia & vascular
Electronic data entry I
Philip Bath
Clive Ballard
Philip Bath
Sandeep Ankolekar
Coffee
Electronic data entry II
Imaging: definitions/upload
Site responsibilities
Site monitoring
Data monitoring
Close
Sandeep Ankolekar
Sandeep Ankolekar, Tanya Jones
Sally Utton
Lynn Stokes
Philip Bath
Philip Bath
Lunch
PODCAST: Serious Adverse
Event reporting
including pharmacovigilance
Philip Bath
PODCAST: Outcomes/SAEs
All Events and SAEs within final follow-up
(end-of-trial) will be collected
 Events and SAEs will be collected using same
online form to avoid confusion
 Forms will be adjudicated by blinded
observers - dementia, vascular, SAE

 Insufficient
information  follow-up questions
Events:
 Dementia
 Vascular: stroke, TIA, MI, angina, death
 SAEs
www.podcast-trial.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
PODCAST: Adverse events
Only collect ARs:
 These will influence future drug treatment
Do not collect all AEs:
 Trial of management startegies
 Lifestyle
 All drug BP and lipid interventions are
already licensed and in routine clinical use
 Considerable information is already known
for each
(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 laboratory 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
PODCAST: Outcome/SAE questions
When did it start?
after
Before / during /
Fatal?
Life-threatening?
Hospitalisation?
Disabling?
Birth defect?
Medically important?
Category?
Describe?
Y/N
Y/N
Y/N
Y/N
Y/N
Y/N
SAE
www.podcast-trial.org
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
PODCAST: Outcome/SAE questions
Date/time began?
Nature?
Intensity?
Relationship?
Action?
Outcome?
Single / Multiple
Mild / Moderate / Severe
Definitely not / … / definite
Continue/Missed/Stopped
Recovered / … / Died
www.podcast-trial.org
SAE: Intensity

Severe
 Incapacitating
 Prevents
daily activities
 Not a measure of seriousness

Moderate
 Uncomfortable
 Impairs

daily activities
Mild
 Minimal
discomfort
 Does not interfere 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: Relationship / causality
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: Action taken
Treatment:

None, i.e. continued

Interrupted

Discontinued
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 clinical 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: Diagnostic evidence
Give as much information as possible:
Pathology
Radiology
ECG
Bacteriology
Biochemistry
Haematology
Clinical
Comment
PM, …
CT, MR, Carotid, …
AF, MI, LVH, …
LFTs, CRP, …
FBC, ESR, …
NIHSS, …
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
 PODCAST should generate very few, if any,
SUSARs
 But not CTIMP trial!

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
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 Coordinating Centre
Serious Adverse Events
Any questions?
PODCAST: Outcomes, cognition
& dementia, vascular
Clive Ballard
Philip Bath
PODCAST: Secondary outcomes, 1

Dementia





Total - ICD-10
AD - NINCDS/ADRDA
VaD - NINDS-AIREN
With/without recurrent stroke
Cognition:







Global – tMMSE, TICS-m
Semantic - animal naming (part of ACE)
Association – trail making A/B
Cognitive decline with/without recurrent stroke
Ordinal cognition (MMSE>28/23-28/10-22/<10/dementia/dead)
Informant (IQCODE)
Stroop
PODCAST: Secondary outcomes, 2





Quality of life – EuroQoL, informant (DEMQoL)
Depression (Zung)
Dependency (mRS)
Disability (BI)
Ordinal vascular events








Stroke: fatal/severe non-fatal/mild/TIA/none
MI: fatal/non-fatal/angina/none
Vascular: fatal/non-fatal/none
New diabetes
New AF
Residence (home, institution); care package, family
BP (SBP, DBP, PP, RPP)
Lipids (TC, TG, HDL, calculated LDL)
PODCAST: Dementia adjudication
Baseline:
 Age, sex, race, education
 HT, HL, DM, smoking, …
 Stroke: type (IS/ICH, cortical, subcortical)
During trial:
 New vascular event: stroke (type, site), MI
 Non BP/lipid medications
 Diagnosis of dementia: third party/at clinic
 Vignette (free text)
www.podcast-trial.org
PODCAST: Dementia adjudication
S
+
tMMSE
ACE
subscales
MMSE
TICS
mRS
+
Stroop
Trail making
IQCODE
B
+
+
+
+
+
+
+
6
+
+
+
+
+
+
+
+
+
12
+
+
+
18
+
+
+
+
+
+
+
+
24
+
+
+
30
+
+
+
+
+
+
+
…
+
www.podcast-trial.org
Dementia: Free Text Vignette


Give as much information as possible
Supply memory clinic letter
Important information:
 Is the severity of functional impairments/level of
dependency sufficient to interfere with daily life
 If so, to what degree does cognitive impairment add
to stroke related functional impairment
 Do any cognitive impairments identified by the
participant or informant interfere with daily life
 What impairments are there in other domains such
as social functioning, changes in personality
PODCAST: 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.podcast-trial.org
PODCAST: Stroke questions
Event
Stroke / TIA / N/A
Limb weakness
Speech disturbance
Sensory disturbance
Visual field loss
Posterior circulation
Other
Length of symptoms
Severity
Brain imaging
Type
Y/N
Y/N
Y/N
Y/N
Y/N
Describe
ABCD2 bands
ABCD2 / NIHSS score / ?
IS/HTI/ICH/?
www.podcast-trial.org
PODCAST: 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.podcast-trial.org
Definitions: Myocardial Infarction
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
www.podcast-trial.org
PODCAST: MI questions
Event
UA / NSTEMI / STEMI
Chest pain
SOB
Sweating
Nausea/vomit
ECG date
ECG changes
Enzyme date
Enzymes
Y/N
Y/N
Y/N
Y/N
Ts inv / ST el / ST dep / Q wave
Trop I/Trop T/CK/CKMB/ND
www.podcast-trial.org
PODCAST: Outcome/SAE questions
SAE preferred term:
 Cardiovascular
 CNS
 Cutaneous
 Gastrointestinal
 Genito-urinary
 Haematological
 Immunological
 Musculoskeletal
 Respiratory
 Other
AF/ bradycardis/…
Agitation/ anxiety/…
Bullous/ eczema/…
Abdo pain/ colitis/…
Sex dys./ incont./…
Anaemia/ agran/…
Anaphylactic/…
Arthritis/…
Bronchospasm/…
www.podcast-trial.org
PODCAST: Outcome/SAE questions

SUSAR

If fatal, cause
Y/N
 IS,
IHD, PAD, VTE, other vasc, non vasc, major
bleed
 date
www.podcast-trial.org
Adjudication, cognition &
dementia
Any questions?
ECRF and data entry
Sandeep Ankolekar
How many forms?


Patient Details
Participant







Telephone screening
Baseline (randomisation)
1,2,3 month follow-up (intensive groups only)
Clinic follow up: 6, 18,30 months
Telephone follow up: 12,24,36
Serious Adverse Event/Outcome
Informant



Baseline
Clinic follow up- 6,18,30 months
Telephone follow up - 12,24,36 months
ISRCTN47823388
Patient Details Form
Patient Details
ISRCTN47823388
http://www.podcast-trial.org/
ISRCTN47823388
PODCAST Database Entry
ISRCTN47823388
Data Entry

Drop Down Lists





Buttons





Yes/No Answers
Score: 1-7
Age calculator
Dates


Medications
Rankin Scale
CT scan results
Dates (date, month and year)
Drop down list
Numerical values entry (will have background
validation)
Free text entry
Screening
ISRCTN47823388
Screening
ISRCTN47823388
Screening
ISRCTN47823388
Vascular territory
Orange : Anterior (ACA and MCA)
Blue: Posterior (PCA, Basilar, Vertebral)
CT Reports

Anterior circulation
 Territories:
MCA (Middle cerebral artery), ACA
 Regions: Frontal lobe, basal ganglia

Posterior circulation
 Territories:
PCA (Posterior cerebral artery),
Basilar artery, vertebral artery
 Regions: Occipital lobe, cerebellum, brainstem,
medulla, pons, midbrain, thalamus

If in doubt: Ask
Screening
Screening: modified Rankin Scale
No symptoms at all.
0
No significant disability despite symptoms;
able to carry out all usual duties and activities.
1
Slight disability; unable to carry out all
previous activities, but able to look after own
affairs without assistance.
2
Moderate disability; requiring some help, but
able to walk without assistance.
3
Moderately severe disability; unable to walk
without assistance and unable to attend to
own bodily needs without assistance.
4
Severe disability; bedridden, incontinent and
requiring constant nursing care and attention.
5
Screening: Cognition
Screening: Cognition
PODCAST: Check your answers!
Failed screening
Successful screening
Baseline Form
Baseline Form
ISRCTN47823388
Baseline Form
Patient Details
 Risk Factors/Past Medical History
 Index Stroke Presentation
 Post screening lipid profile
 NIHSS
 Cognitive Assessments

 Addenbrooke’s
cognitive examination
 Trail making Test
 Stroop Test
 TICS-M

Other functional assesments (mood, rankin,
EUROQOL)
Baseline Form
Baseline form: Drug & doses
Baseline form: Submission
1 / 2 / 3 month clinic forms
1 / 2 / 3 month clinic forms
Medications history
 If there is a change in medications since last
review
 Post review medications

Participant Clinic follow ups
6, 18, 30, … months:
 Similar to baseline form
 In addition will ask if the patient has had any
outcome/serious adverse events
Participant Telephone follow ups:
 12, 24, 36, … months
 Telephone instrument for cognitive status
 Functional status questions
 In addition will ask for outcome events/SAEs
Informant Baseline/Clinic follow ups
Baseline, 6, 18, 30, … months:
 Outcome events/ SAEs for the patient
 Disposition of the patient
 IQCODE
Informant telephone follow ups:
 12, 24, 36, … months
 IQCODE
 SAE/Outcome events for the participant
Help with filling the forms

ISRCTN47823388
Within PODCAST Website:
 Videos

ACE-R, IQCODE
 Practice

Stroop
 Frequently
Asked Questions (FAQs)
 Demo Website (demoinv1 nottingham 8888)
 Paper Forms
 Contact list
 Working Practice Documents (WPDs)

Telephone: +44 (0) 115 823 1671 (plus
answerphone)
ECRF and date entry
Any questions?
PODCAST: Imaging definition &
upload
Sandeep Ankolekar
Tanya Jones
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
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
Neuroimaging within 10 days of index stroke
(inclusion criteria)
Neuroimaging details
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
CT scan- lesion

Choose ‘normal’ if…
 ‘Normal
scan’
 ‘Normal for age’
 ‘no intracranial abnormalities’

Choose ‘old/other lesions not explaining
symptoms’
 lesion
on the wrong side
 or if only old strokes, atrophy and white matter
change mentioned
Neuroimaging details
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
CT scan: Ischaemic stroke, HT
Neuroimaging details
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
CT scan: Ischaemic stroke, no HT
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.
Neuroimaging details
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
CT scans: PICH
Neuroimaging details
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
CT scan: Brain metastasis
CT scan: Abscess
CT reports: The result of the scan?

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.
CT reports - the result of the scan?

Choose ‘OTHER’ if…
 Tumour
(most common), abscess, cysts etc
 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…
Is the lesion compatible with
presentation?
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
Is it compatible with the
presentation?

Remember
 Left
sided lesions cause right sided symptoms and
vice versa

Bear 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!
Mass Effect
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
CT scan: Mass effect
Lateral
ventricle
shifted
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.
CT scan: Mass effect vs
hydrocephalus
Cerebral Atrophy
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
CT scans: Cerebral Atrophy
CT scans: Atrophy
Answer yes if…

“Atrophy” or “involutional change”

If no mention or ‘age appropriate’ and the
patient is under 60 say no
Periventricular ischaemia
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
CT scan: Periventricular white
matter lucency
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 answer no.
CT scan: Previous strokes
Choose yes if…


“old”, or “mature” infarcts
If they are not mentioned, or are noted to be
absent absent, answer no.
Previous strokes
Date of first head scan after index stroke.
Type of scan?
Please complete with regards to the index
stroke head scan using radiology report.
/
/
CT
MRI
Normal
Other/old lesions not
explaining Symptoms
Ischaemic Stroke with HT
Ischaemic Stroke without HT
Primary Intracerebral
Haemorrhage
Other (e.g. Tumour, Abscess)
Is the lesion compatible with the presenting
stroke?
Is there evidence of mass effect?
Yes
No
Yes
No
Is there evidence of cerebral atrophy?
Yes
No
Is there evidence of periventricular or white
matter lucency?
Is there evidence of previous stroke?
Yes
No
Yes
No
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 you
more you will get used to the terminology
Imaging Upload
PODCAST – CT Scans
Upload Methods
Transfer System for Scans
Acceptable methods:
 CD – to upload or send
 Film
No facility for:
 Uploading directly from PACS
 Using the N3 highway (National Database
Spine)
PACS team/Radiology Request

Dicom format plain CT or MRI scans only
No:
 Localizers
 Scouts
 Protocols
 Dose reports
 Viewing Software
Methods Of Transfer
Uploading to Podcast Website at your centre.
 Posting an encrypted CD.
 Posting an anonymised CD.
 Posting hard copy film.

Uploading to Podcast Website
Two methods:
 Using JAVA applet – drag folder containing
the scans into the upload box.
o
o
▲
o
Maximum images per folder approx 50
Process can be repeated
Not Using JAVA applet – the screen will
show a Browse button to select each image
individually
Screen upload can be repeated for however many images
need uploading.
Investigator Screen
Upload Files Screen
Upload images Files using Java Applet
Drag Dicom folder from CD
Confirmation of upload
Upload Files Screen – showing Files uploaded
Upload Files – Not using Java Applet
Upload - Not using Java Applet
Browse and Select Files
Upload – maximum of 25 files but repeatable
Upload confirmation
Posting Scans

All posting methods must use a secure courier where
a signature is required upon receipt.

Send an encrypted CD. Password needs to be
communicated separately.
Send in an anonymised CD. We will need email or
written confirmation that this method is consistent
with your Trust’s policy of sending electronic data.
If none of the above methods are available, we can
accept hard copy film. Please use a hard sided
envelope.


Web Security
To ensure that the CT upload is for the correct patient
the upload process requires most fields to remain in
the dicom header. (Name /ID is not one of the
required fields)
The upload process will encrypt the data and
anonymise the following fields in the dicom header:
 Patient data:
Name, ID, Address, and Date of Birth.
 Hospital data:
Hospital name and address, Physician
name and address
Success!

If your images have uploaded successfully
from your centre then you will receive an
email to confirm this.
(You will have already seen confirmation messages
on the Upload screen)

An email will confirm that any CDs/Films sent
to the Podcast office have arrived safely.
Imaging definitions & upload
Any questions?
PODCAST: Site responsibilities
and trial files
Sally Utton
The local centre’s role /responsiblities
Obtain and maintain local approvals
 Ensure adherence to GCP/ICH standards
 Ensure all staff are trained & remain trained
 Ensure that site files are current
 Recruit patients: 1-2 per month
 Complete all patient forms online within the
time line

What makes a good Local Centre
Commitment to trial (PI, time, staff, hospital)
 Access to team

 Research
Coordinators
Experience in doing trials
 Commitment to recruit consistently
 Fax/record and complete data in a timely
manner
 Be prepared for monitor visits to check
records

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
What do we mean by records?
Site file
 Case record form
 Patient trial files
 Logs
 Medical notes

Site File
Contact List
 Study Documentation
 Regulatory Approved Documents
 Signed Agreement
 Study Medication/Laboratory
 SAE/SUSAR Report
 Monitoring Reports
 Miscellaneous

Case Record Form
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
 Adverse/serious events

PATIENT NUMBER:
This patient has been participating
in the ENOS study.
MREC/01/4/046.
Please retain these notes until
31/12/2021
Storage of records
Confidential
 Archiving
 PODCAST is sponsored by The University of
Nottingham

MHRA Inspection

The Clinical Trials Directive 2001 provides
the framework for inspection requirements
 Audit
 Inspection
Visit
 Outcome

Note: PODCAST is not a CTIMP and should
not come under MHRA scrutiny. But GCP still
applies and we should practice many of the
CTIMP practices
MHRA findings:

Delegation/signature logs
 What
is delegated
Evidence that staff have been trained
 Evidence that staff have read sponsor SOPs
and trial WPDs
 Version control for consent form and PIS
…

Conclusion

A simple and accurate paper trial is essential
to demonstrate the validity and integrity of
study conduct
Site responsibilities
Any questions?
PODCAST: Site monitoring
Lynn Stokes
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 the:
 Size
 Complexity
 Risks
associated with the trial
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.
 Commonly employed oversight committees:


Trial Steering Committee (TSC)

Trial Management Committee (TMC)

Data Monitoring Committee (DMC)
Trial Steering Committee (TSC)
Provide overall supervision of the trial
 Ensure that trial is being conducted
according to GCP and the relevant
regulations
 Agrees the trial protocol and any protocol
amendments
 Provides 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

Data Monitoring Committee (DMC)
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
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 data are missing
 Data appear to be valid (range, consistency)
 Review of recruitment rates, withdrawals and
losses to follow-up overall and by site
Central monitoring, 1
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 centres
 External validation of selected data items
Central monitoring, 2

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, 3

Using stroke registers to confirm information
on eligibility or outcomes.

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
On-site visits provide the opportunity to:
 Educate staff about the trial






Understand the protocol and trial procedures
Verify that the staff at the site have access to the necessary
documents to conduct the trial
Confirm that required pharmacy and laboratory resources are
in place
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, 1

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.
Source documentation, 2

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, SUSARs

Site Monitoring
Any questions?
PODCAST: Data Monitoring
Philip Bath
PODCAST: Data Monitoring, 1
Composition:
 TBA (Chair)
 Prof Jan Staessen (Leuven)
 Hypertension

Dr Chris Weir (Edinburgh)
 Statistician
Supported by:
 Ms Cheryl Hogg (Nottingham)
 PODCAST
statistician
PODCAST: 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
PODCAST: Data Monitoring, 3
Modus operandi:
 6 monthly assessments of data
 Data tables prepared by trial statistician
 Teleconference (or meeting)
 Open
then closed session
 Minuted
 Closed session confidential

Report to Chair of TSC (John O’Brien)
 cc

CI (PB)
Have a Charter and hold a contract with
sponsor
PODCAST: Data Monitoring, 4
Trials status:
 Timelines
 Recruitment
 Patients,

centres, patients/centre
Data completeness, quality
Patients:
 Baseline features
 Balance

by treatment groups
Outcomes
PODCAST: Data Monitoring, 5
Data:
 Dementia
 Cignitive impairment
 Vascular events
 Stroke
(ischaemic and haemorrhage), MI,
vascular death
Death
 SAEs

Data Monitoring
Any questions?
PODCAST: UK Investigator
meeting - Close
Philip Bath
Many thanks for attending
 An important and interesting, if not
challenging, trial
 If you are ready to start

 Lynn

If you have submitted SSIs etc
 Keep

will arrange a start-up visit
Lynn up to date with progress
If you and your PCTs are interested in joining
 Please
submit SSI
Close, many thanks again
Good luck and have a safe
journey home