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Efficacy of Nitric Oxide in Stroke (ENOS) Trial

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Efficacy of Nitric Oxide in Stroke (ENOS) Trial Training for New Investigators v1.1, 6 October 2010 www.enos.ac.uk/ – PowerPoint PPT presentation

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Title: Efficacy of Nitric Oxide in Stroke (ENOS) Trial


1
Efficacy of Nitric Oxide in Stroke(ENOS) Trial
  • Training for New Investigators
  • v1.1, 6 October 2010

www.enos.ac.uk/
2
Introduction to ENOS
  • Assess if lowering blood pressure improves
    outcome
  • Interventions (for 7 days)
  • Transdermal glyceryl trinitrate patch (5 mg
    daily) or no GTN patch
  • Continue or stop prior antihypertensive therapy
  • Ischaemic or haemorrhagic stroke within 48 hours
  • 5,000 patients
  • Internet Randomisation, data collection, trial
    management
  • Start-up funding by Hypertension Trust, BUPA
    Foundation
  • Main phase funding by MRC, 1 Nov 2006 31 Oct
    2013

3
High blood pressure in acute stroke
  • Common
  • Independently associated with a poor outcome
  • It is unclear whether BP should be altered
  • No completed large trials
  • It is unclear whether and how to alter BP
  • BP is not routinely altered
  • Need more trial data, e.g. ENOS

www.enos.ac.uk/
4
ENOS Aims and interventions
  • Does acute lowering of BP with GTN reduce death
    and dependency?
  • GTN 5mg daily for 7 days or nothing
  • Should prior antihypertensive medication be
    continued or temporarily stopped during the acute
    phase of stroke?
  • Stop/continue prior treatment for 7 days
  • On top of standard evidence-based acute medical
    and nursing care, and secondary prevention

www.enos.ac.uk/
5
ENOS Outcomes
  • Primary (90 days)
  • Modified Rankin Scale
  • Secondary outcomes
  • Efficacy disability, institutionalisation, early
    recurrence, QoL, mood, cognition
  • Safety death, deterioration, CT lesion size
  • Primary outcome in sub-groups
  • Ischaemic, haemorrhagic stroke
  • Systolic BP levels (mmHg) 140-160, gt160
  • Timing of treatment (hours) lt12, 12-48

www.enos.ac.uk/
6
ENOS Interventions
  • No prior antihypertensive therapy (50)
  • GTN
  • No GTN
  • Prior antihypertensive therapy (50)
  • GTN / stop
  • GTN / continue
  • No GTN / stop
  • No GTN / continue

www.enos.ac.uk/
7
ENOS Sub-studies
  • MR substudy (Singapore, ) - funded May 2005
    June 2009
  • GTN on lesion volume, diffusion, perfusion
  • CT substudy
  • GTN on lesion volume, recurrence
  • Pharmacogenetics
  • GTN effects on BP by genotype, e.g. eNOS
  • Surrogate markers of efficacy
  • GTN on serum biomarkers, e.g. NSE S-100

www.enos.ac.uk/
8
Trial Management
  • Sponsor
  • University of Nottingham
  • International Coordinating Centre
  • Nottingham
  • National Coordinating Centres
  • One in each participating country
  • National Coordinator is member of International
    Advisory Committee
  • Supporting Committees
  • Trial Management Committee
  • Trial Steering Committee
  • Data Monitoring Committee

www.enos.ac.uk/
9
National Coordinator Role
  • Promote the trial in their country
  • Recruit centres in country
  • Regulatory and Ethics approval
  • Assist sites with set up (translations)
  • Site monitoring visits (x 3)
  • Perform 90 Day telephone Follow Ups
  • Maintain ICH/GCP standards

www.enos.ac.uk/
10
Role Local Centre
  • Obtain and maintain Ethics approval
  • Ensure adherence to GCP/ICH standards
  • Ensure all staff are trained
  • Ensure staff remain trained
  • Recruit 1-2 ENOS patients per month
  • Complete all patient forms online
  • Fax paperwork to International Coordinating
    Centre
  • Upload CT scans to ENOS website

www.enos.ac.uk/
11
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12
ENOS Inclusion criteria
  • Adult (age gt 18 years)
  • Clinical stroke syndrome with limb weakness
    lasting gt1 hour
  • So not likely to be a transient ischaemic attack
  • Residual limb weakness at the time of enrolment
  • Onset lt 48 hours. If the time of onset is
    unknown, apply the time when the patient was last
    known to be well
  • Conscious (Glasgow Coma Scale gt 8)
  • Systolic blood pressure 140-220 mmHg inclusive
  • In at least one of the three pre-randomisation
    measures
  • Independent prior to stroke
  • Pre-morbid modified Rankin Scale 2
  • Meaningful consent
  • Or proxy consent from a relative or carer, or
    proxy consent from an independent physician if
    patient unable to give meaningful consent
  • E.g. If dysphasia, confusion, or reduced
    conscious level

www.enos.ac.uk/
13
ENOS Exclusion criteria
  • Need for nitrate
  • Myocardial infarction, unstable angina, heart
    failure
  • Contraindication to nitrate
  • Dehydration/hypovolaemia, HOCM, sildenafil
  • Need for prior antihypertensive therapy
  • Definite need for new antihypertensive
  • Usual antihypertensive taken post stroke
  • New antihypertensive commenced post stroke
  • Expected to need for surgery
  • Known intracranial pathology other than stroke
  • Pregnant females
  • Not available for follow-up

www.enos.ac.uk/
14
BP measurement
  • Baseline if exclusion BP (lt140, gt220)
  • Consider repeating within 48 hours of stroke
    onset
  • Only one measurement needs to be within the range
  • Baseline BPs should be recorded shortly before
    randomisation
  • Unaffected arm
  • Correct cuff size
  • Supine/sitting
  • Consistency between measurements
  • BP should be recorded 1-2 hours post-patch (GTN
    or gauze)
  • Non-reading automatic versus 170/200/240

www.enos.ac.uk/
15
Omron machines
  • 2 per centre
  • For trial use only
  • Keep secure
  • Battery and paper
  • Paper printout mounted on sheet
  • Ensure time and date is set correctly before use

www.enos.ac.uk/
16
Treatment GTN/control (1)
  • All patients need a gauze dressing
  • Control patients place over chest, shoulder
  • GTN patients place over patch
  • Apply over healthy skin
  • Avoid discussing with patient
  • Enter date/time of gauze dressing (with or
    without GTN) on day 7 form
  • Nurses may prescribe/place first patch if they
    have local approval from LREC (needs Dr
    countersignature)

www.enos.ac.uk/
17
Treatment GTN/control (2)
  • First gauze dressing /- GTN patch to be applied
    immediately after randomisation
  • BP measured 90 minutes after application
  • Days 2-7
  • Apply gauze dressing /- GTN patch 09.00
    (irrespective of when application on day 1)
  • BP measured 90 minutes later, 10.30

www.enos.ac.uk/
18
Day 7
  • Complete Day 7 form online
  • Fax
  • Consent form
  • Patient/relative contact details
  • BP measurements
  • Drug chart (relative part)
  • CT reports
  • Carotid doppler!
  • Ideally we administer at least 4 days of
    treatment (i.e. do not enroll patients expected
    to be in hospital lt4-7 days)

www.enos.ac.uk/
19
90 Day Follow Up
  • All patient details need to be received at least
    1 month prior to follow up due date.
  • Ensure that the patient details form is complete,
    accurate and updated as there is only a 7 day
    window at Day 90 to complete the follow up
  • Ensure that the patient can be contacted at day
    90 by telephone
  • Avoid randomizing patients that are on holiday,
    immigrants or those who cannot be contacted at
    day 90,or refuse to take part in the day 90
    assessment
  • All SAEs requested at day 90 need to completed in
    a timely manner


www.enos.ac.uk/
20
ENOS Sample form
www.enos.ac.uk/
21
ENOS Sample form
www.enos.ac.uk/
22
Data errors
  • Data validation on-line when submitting data
  • Post-entry errors let ENOS Office know
  • Direct database correction
  • enos_at_nottingham.ac.uk
  • Email incorrrect data/correct data by centre,
    number initials
  • Do not randomise patients twice

www.enos.ac.uk/
23
ENOS Time and severity
  • Recruitment is often late, most patients
    recruited gt24 hours
  • Only 10 lt12 hours
  • Later patients tend to be milder
  • ENOS needs
  • Early patients if it is to answer the question of
    how to manage hyperacute BP
  • More severe patients, since milder ones tend to
    do better irrespective of treatment

www.enos.ac.uk/
24
ENOS Repatriation
  • UK and other countries stroke services are
    evolving into hub-spoke models
  • Admission to comprehensive/acute centres
  • Rehabilitation at these or at local centres
  • Repatriation
  • If you repatriate, please ensure all local
    centres are part of ENOS and let us know
  • Models
  • Same Trust - acute local centres, and near
  • Same Trust - acute local centres, but far
  • Different Trusts - acute local centres

www.enos.ac.uk/
25
ENOS Web-site www.enos.ac.uk Documents link
http//www.nottingham.ac.uk/nszwww/enos//jevpybki
.htm

www.enos.ac.uk/
26
ENOS Newsletters
  • Issued every other month
  • Sent to Investigators and uploaded to website
  • Check for current issues, new forms,
    Tips of the Month

www.enos.ac.uk/
27
Data Quality - Site Monitoring Visits
  • It is vital that the information that is
    collected on patients in the ENOS trial is
    correct
  • Sites will be monitored at least once during the
    trial period
  • UK will be monitored by Nottingham and
    international sites by the National Coordinator
  • We will check whether the information provided by
    the investigators is confirmed by source
    documentation
  • We will check that sites are maintaining trial
    files according to their legal and GCP
    obligations
  • Poor sites will be subjected to further
    inspections and could be closed down

www.enos.ac.uk/
28
Data Quality - Common ENOS Mistakes
  • Version Control - are you using the most up to
    date version?
  • Training
  • All staff should be GCP trained
  • MRS and SSS training
  • Site Files
  • Need to be kept in good order
  • Up to date and signed CVs every 2 years
  • Randomisation when web site down
  • Remember telephone randomisation

www.enos.ac.uk/
29
Frequently Asked Questions
  • http//www.nottingham.ac.uk/nszwww/enos//EnosFaqV
    22.pdf

www.enos.ac.uk/
30
ENOS Summary of Key Points
  • Melds with other trials hyperacute, high-tech
  • Wide time-window, 1-48 hours
  • Ischaemic and haemorrhagic stroke
  • Any clinical syndrome, pathophysiology
  • Can be given with rt-PA (nitrates in NINDS!)
  • Easy intervention transdermal / dysphagia
  • Can be led by nurses
  • Modest data collection days 0, 7, 90 (SAE)
  • Internet randomisation / data registration
  • ASTN, CSC, UKSRN approved
  • This trial needs you!

www.enos.ac.uk/
31
ENOS Staff
Philip Bath Chief Investigator
ENOS Investigators. Int J Stroke 20061245-9
32
ENOS Contacts
ENOS Trial Office Contacts B56 Clinical Sciences
Building Nottingham University Hospital NHS
Trust Hucknall Road, Nottingham NG5
1PB enos_at_nottingham.ac.uk www.enos.ac.uk General
enquiries Tel 44 (0) 115 823 1770 Medical
enquiries Tel 44 (0) 115 823 1769 Fax 44
(0) 115 823 1771
www.enos.ac.uk/
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