Tinzaparin in acute ischaemic stroke: a randomised aspirin ...



Ambulance-delivered transdermal glyceryl trinitrate versus sham for ultra-acute stroke: rationale, design and protocol for the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) trial (ISRCTN26986053)The RIGHT-2 Investigators *Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UKCorrespondence to: Professor Philip M BathStroke, Division of Clinical NeuroscienceUniversity of NottinghamClinical Sciences BuildingCity Hospital campusNottingham NG5 1PB UKTel: +44 115 823 1765?Fax: +44 115 823 1767E-mail: philip.bath@nottingham.ac.ukTwitter: @right2trialUrl: stroke, ambulance, antihypertensive therapy, cerebrovascular disorders, glyceryl trinitrate, nitroglycerin, paramedic, randomised controlled trialWord count 4490AbbreviationsBI: Barthel Index; BP: blood pressure; FAST: face, arm, speech, time; GTN: glyceryl trinitrate; ICH: intracerebral haemorrhage; IS: ischaemic stroke; mRS: modified Rankin scale; NIHSS: National Institutes of Health Stroke Scale ABSTRACTRationale Vascular nitric oxide levels are low in acute stroke and donors such as glyceryl trinitrate (GTN) have shown promise when administered very early after stroke. Potential mechanisms of action include augmentation of cerebral reperfusion, thrombolysis and thrombectomy, lowering blood pressure (BP), and cytoprotection.Aim To test the safety and efficacy of 4 days of transdermal GTN (5 mg/day) versus sham in patients with ultra-acute presumed stroke who are recruited by paramedics prior to hospital presentation.Sample size estimates The sample size of 850 patients will allow a shift in the modified Rankin Scale (mRS) with odds ratio 0.70 (GTN versus sham, ordinal logistic regression) to be detected with 90% power at 5% significance (2-sided).Design The Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) is a multicentre UK prospective randomised sham-controlled outcome-blinded parallel-group trial in 850 patients with ultra-acute (<4 hours of onset) FAST-positive presumed stroke and systolic BP >120 mmHg who present to the ambulance service following a 999 emergency call. Data collection is performed via a secure internet site with real-time data validation. Study outcomes The primary outcome is the mRS measured centrally by telephone at 90 days and masked to treatment. Secondary outcomes include: BP, impairment, recurrence, dysphagia, neuroimaging markers of the acute lesion including vessel patency, discharge disposition, length of stay, death, cognition, quality of life and mood. Neuroimaging and serious adverse events are adjudicated blinded to treatment.Discussion RIGHT-2 has recruited more than 500 participants from 7 UK ambulance services. Status: Trial is ongoing.Funding: British Heart FoundationRegistration: ISRCTN26986053INTRODUCTION AND RATIONALETreatment options for patients with acute stroke are few and may be categorised as those with high efficacy and high or medium cost but of limited utility, such as intravenous thrombolysis, thrombectomy, and hemicraniectomy;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbWJlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

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ADDIN EN.CITE.DATA (1-4) those with intermediate efficacy and very wide utility, specifically stroke unit care; ADDIN EN.CITE <EndNote><Cite><Author>Stroke Unit Trialists&apos; Collaboration</Author><Year>2013</Year><RecNum>7966</RecNum><DisplayText>(5)</DisplayText><record><rec-number>7966</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472810">7966</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stroke Unit Trialists&apos; Collaboration,</author></authors></contributors><titles><title>Organised inpatient (stroke unit) care for stroke</title><secondary-title>Cochrane Database of Systematic Reviews</secondary-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title></periodical><volume>9</volume><number>CD000197</number><edition>September 11 2013</edition><dates><year>2013</year></dates><urls></urls><electronic-resource-num>10.1002/14651858.CD000197.pub3.</electronic-resource-num></record></Cite></EndNote>(5) and those with limited efficacy but wide utility and low cost, e.g. aspirin. ADDIN EN.CITE <EndNote><Cite><Author>Sandercock</Author><Year>2008</Year><RecNum>1643</RecNum><DisplayText>(6)</DisplayText><record><rec-number>1643</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472066">1643</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sandercock, P. A.</author><author>Counsell, C.</author><author>Gubitz, G. J.</author><author>Tseng, M. C.</author></authors></contributors><auth-address>Department of Clinical Neurosciences, University of Edinburgh, Neurosciences Trials Unit, Bramwell Dott Building, Western General Hospital, Crewe Road, Edinburgh, UK, EH4 2XU. peter.sandercock@ed.ac.uk</auth-address><titles><title>Antiplatelet therapy for acute ischaemic stroke</title><secondary-title>Cochrane Database Syst Rev</secondary-title><alt-title>The Cochrane database of systematic reviews</alt-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><alt-periodical><full-title>The Cochrane database of systematic reviews</full-title></alt-periodical><pages>CD000029</pages><number>3</number><edition>2008/07/23</edition><keywords><keyword>Brain Ischemia/drug therapy/prevention &amp; control</keyword><keyword>Humans</keyword><keyword>Platelet Aggregation Inhibitors/ therapeutic use</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Risk</keyword><keyword>Stroke/ drug therapy/prevention &amp; control</keyword></keywords><dates><year>2008</year></dates><isbn>1469-493X (Electronic)&#xD;1361-6137 (Linking)</isbn><accession-num>18646056</accession-num><urls></urls><electronic-resource-num>10.1002/14651858.CD000029.pub2</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(6) There are no definitive drug treatments for patients with spontaneous intracerebral haemorrhage (ICH) although blood pressure (BP) lowering in the hyperacute period may be effective PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+

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ADDIN EN.CITE.DATA (11, 12) NO is a cerebral and systemic vasodilator, modulates vascular and neuronal function, and inhibits apoptosis. Preclinical stroke studies show that NO donors improve regional cerebral blood flow, and reduce stroke lesion size if administered rapidly.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsbW90PC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48

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ADDIN EN.CITE.DATA (13) Five small clinical studies of NO donors have been performed in acute stroke. Intravenous sodium nitroprusside reduced BP without altering cerebral blood flow, and exhibited antiplatelet effects,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXR0ZXJ3b3J0aDwvQXV0aG9yPjxZZWFyPjE5OTg8L1ll

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ADDIN EN.CITE.DATA (14) thereby precluding its use in ICH. Four small trials of transdermal glyceryl trinitrate (GTN, nitroglycerin) found that it lowered peripheral and central BP, 24 hour BP, and pulse pressure.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXRoPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (15-18) GTN had no effect on middle cerebral artery blood flow velocity, cerebral blood flow (hence, no evidence of cerebral steal), intracranial pressure, or platelet activity (so it can be given in ICH).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsbW90PC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48

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ADDIN EN.CITE.DATA (15-18) In the last of these pilot studies (Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial, RIGHT), GTN was administered within 4 hours of stroke onset and significantly, albeit unexpectedly, improved functional outcome in just 41 patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmtvbGVrYXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA (18) The large Efficacy of Nitric Oxide in Stroke trial (ENOS, 4,011 patients recruited from 173 sites in 23 countries) found that GTN was safe to administer but did not modify outcome when given within 48 hours, except in the prespecified subgroup of 273 patients randomised within 6 hours who had an improvement in functional outcome.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXRoPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (18, 21-28) Recently, the large FAST-Mag trial showed that it was feasible to deliver a large phase III trial in the pre-hospital setting, at least in the US emergency care system. ADDIN EN.CITE <EndNote><Cite><Author>Saver</Author><Year>2015</Year><RecNum>7977</RecNum><DisplayText>(29)</DisplayText><record><rec-number>7977</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472811">7977</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saver, J.</author><author>Starkman, S.</author><author>Eckstein, M.</author><author>Stratton, S.</author><author>Pratt, F.</author><author>Hamilton, S.</author><author>Conwit, R.</author><author>Liebeskind, D.</author><author>Sung, G.</author><author>Kramer, I.</author><author>Moreau, G.</author><author>Goldweber, R.</author><author>Sanossian, N.</author></authors></contributors><titles><title>Prehospital use of magnesium sulfate as neuroprotection in acute stroke</title><secondary-title>The New England Journal of Medicine</secondary-title></titles><periodical><full-title>The New England Journal of Medicine</full-title></periodical><pages>528-36</pages><volume>372</volume><number>6</number><dates><year>2015</year><pub-dates><date>5 February 2015</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1056/NEJMoa1408827</electronic-resource-num></record></Cite></EndNote>(29) While paramedics are uniquely placed to deliver early treatments, their experience of participating in randomised controlled trials (RCTs) to evaluate interventions is limited, in part because pre-hospital research infrastructure is still in development and because the logistics of RCTs are more challenging in this environment. ADDIN EN.CITE <EndNote><Cite><Author>Siriwardena</Author><Year>2010</Year><RecNum>8437</RecNum><DisplayText>(30)</DisplayText><record><rec-number>8437</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472866">8437</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Siriwardena, AN. </author><author>Donohoe, R.</author><author>Stephenson, J.</author><author>Phillips, P.</author></authors></contributors><titles><title>Supporting research and development in ambulance services: research for better health care in prehospital settings.</title><secondary-title>Emergency Medicine Journal</secondary-title></titles><periodical><full-title>Emergency Medicine Journal</full-title></periodical><pages>324-6</pages><volume>27</volume><number>4</number><dates><year>2010</year><pub-dates><date>April 2010</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1136/emj.2009.072363</electronic-resource-num></record></Cite></EndNote>(30)On the basis of apparent positive effects of GTN on outcome in patients treated very early,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmtvbGVrYXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA (18-20) meta-analyses of these data (Figure 1), ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2016</Year><RecNum>8403</RecNum><DisplayText>(31)</DisplayText><record><rec-number>8403</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472862">8403</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, PMW.</author><author>Woodhouse, L.</author><author>Krishnan, K.</author><author>Anderson, C.</author><author>Berge, E.</author><author>Ford, GA.</author><author>Robinson, TG.</author><author>Saver, JL.</author><author>Sprigg, N.</author><author>Wardlaw, JM.</author><author>In Acute Stroke Collaboration Basc GP;</author></authors></contributors><titles><title>Effect of treatment delay, stroke type, and thrombolysis on the effect of glyceryl trinitrate, a nitric oxide donor, on outcome after acute stroke: a systematic review and meta-analysis of individual patient from randomised trials</title><secondary-title>Stroke Research and Treatment</secondary-title></titles><periodical><full-title>Stroke Research and Treatment</full-title></periodical><volume>2016:9706720</volume><edition>17 April 2016</edition><dates><year>2016</year><pub-dates><date>January 2016</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1155/2016/9706720</electronic-resource-num></record></Cite></EndNote>(31) and the apparent feasibility of performing large stroke trials in the pre-hospital ambulance environment, ADDIN EN.CITE <EndNote><Cite><Author>Saver</Author><Year>2015</Year><RecNum>7977</RecNum><DisplayText>(29)</DisplayText><record><rec-number>7977</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472811">7977</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saver, J.</author><author>Starkman, S.</author><author>Eckstein, M.</author><author>Stratton, S.</author><author>Pratt, F.</author><author>Hamilton, S.</author><author>Conwit, R.</author><author>Liebeskind, D.</author><author>Sung, G.</author><author>Kramer, I.</author><author>Moreau, G.</author><author>Goldweber, R.</author><author>Sanossian, N.</author></authors></contributors><titles><title>Prehospital use of magnesium sulfate as neuroprotection in acute stroke</title><secondary-title>The New England Journal of Medicine</secondary-title></titles><periodical><full-title>The New England Journal of Medicine</full-title></periodical><pages>528-36</pages><volume>372</volume><number>6</number><dates><year>2015</year><pub-dates><date>5 February 2015</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1056/NEJMoa1408827</electronic-resource-num></record></Cite></EndNote>(29) the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2, ISRCTN26986053) is testing the safety and efficacy of transdermal GTN in patients with ultra-acute presumed ischaemic or haemorrhagic stroke who are recruited by paramedics, and the feasibility of performing a large prehospital stroke trial in the United Kingdom. We describe here the rationale, design and protocol for RIGHT-2.OBJECTIVESThe RIGHT-2 trial is testing two primary questions in patients with ultra-acute presumed stroke:What is the safety and efficacy of GTN, a nitric oxide donor, when administered within 4 hours of stroke onset?What is the feasibility of performing a multicentre stroke trial where randomisation and treatment is delivered by paramedics in the pre-hospital UK National Health Service ambulance service environment?A further two secondary questions ask:What are the mechanisms by which GTN might work if it shows efficacy in patients with ultra-acute stroke? These include potential effects on reperfusion, accelerated resolution of arterial clot, cytoprotection, facilitation and amplification of thrombolysis and other reperfusion strategies, ambulatory BP, and vascular compliance.Is GTN safe in patients who are found in hospital to have had a mimic rather than stroke or transient ischaemic attack (TIA)?METHODSTrial designRIGHT-2 is a UK-based multicentre prospective randomised sham-controlled outcome-blinded parallel-group trial.Ethics and regulatory approvalsThe study is run according to the principles of the Declaration of Helsinki and Good Clinical Practice. Study approvals have been obtained from: UK Medicines competent authority (MHRA 03057/0064/001-0001, date 1 March 2015; EudraCT 2015-000115-40) and Research Ethics Committee (Nottingham 2, 15/EM/0055, date 24 Feb 2015), and local research & development/innovation departments in each participating Ambulance Service and Hospital (e.g. Nottingham University Hospitals NHS Trust, date 8 Sept 2015). The trial was registered (ISRCTN26986053) and adopted by the National Institute for Health Research Clinical Research Network (date 26 Feb 2015). Trial funding from the British Heart Foundation followed external peer review (grant: CS/14/4/30972, awarded 11 Sept 2014), started on 1 May 2015, and will last three years. The Nottingham Stroke Research Partnership Group (comprising stroke survivors and carers) support the study question, design and delivery plan. Management of personal data adheres to the UK Data Protection Act 1998. The overall flow of patients through the trial, and schedule of procedures and evaluations, are summarised in Figure 2 and Table 1, respectively.Patient populationStudy-trained paramedics consider all patients they attend in the context of an emergency telephone call (999) for ‘stroke’. The inclusion and exclusion criteria are deliberately limited in number to simplify enrolment in a time-limited emergency environment, and to minimise any possible increase in time at scene whilst doing trial-related procedures. Additionally, the criteria attempt to maximise the chances that a participating patient will have a stroke or TIA rather than a mimic, and to minimise recruitment of patients that are already severely dependent before their suspected stroke. No log of excluded patients is kept by either ambulance services or hospitals. Unlike in FAST-Mag, ADDIN EN.CITE <EndNote><Cite><Author>Saver</Author><Year>2015</Year><RecNum>7977</RecNum><DisplayText>(29)</DisplayText><record><rec-number>7977</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472811">7977</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saver, J.</author><author>Starkman, S.</author><author>Eckstein, M.</author><author>Stratton, S.</author><author>Pratt, F.</author><author>Hamilton, S.</author><author>Conwit, R.</author><author>Liebeskind, D.</author><author>Sung, G.</author><author>Kramer, I.</author><author>Moreau, G.</author><author>Goldweber, R.</author><author>Sanossian, N.</author></authors></contributors><titles><title>Prehospital use of magnesium sulfate as neuroprotection in acute stroke</title><secondary-title>The New England Journal of Medicine</secondary-title></titles><periodical><full-title>The New England Journal of Medicine</full-title></periodical><pages>528-36</pages><volume>372</volume><number>6</number><dates><year>2015</year><pub-dates><date>5 February 2015</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1056/NEJMoa1408827</electronic-resource-num></record></Cite></EndNote>(29) doctors are not involved in recruitment or consent, with paramedics solely responsible for selection, consent and enrolment.Inclusion criteriaPatients presenting to paramedics in context of 999 ambulance call with suspected stroke.Age 18 years or more (with no maximum age). ‘Face Arm Speech Time’ (FAST) score 2 or 3.Time <=4 hours from symptom onset.Systolic BP >=120 mmHg. Informed consent from patient, or proxy consent from a relative/paramedic.Paramedic is from a participating ambulance station and trained in RIGHT-2 procedures, and will take patient to a participating hospital with comprehensive/primary stroke centre.Exclusion criteriaPatient at a Nursing Home.Glucose (BM stix) <2.5 mmol/l.Glasgow Coma Scale <8.Witnessed seizure/fit at presentation. Known life expectancy <6 months.Known to have taken a phosphodiesterase-5 inhibitor, such as sildenafil, within 24 hours of randomisation.Known sensitivity to Transiderm Nitro patch.Known sensitivity to DuoDERM hydrocolloid dressing.Known previous enrolment into RIGHT-2.If it becomes apparent at a later point that the participant did not have a stroke, they continue in the trial and are followed-up as per protocol. Patients already taking a nitrate such as glyceryl trinitrate may be recruited into the trial.A comparison of the inclusion/exclusion criteria with the Face Arm Speech and Time test, and modified Los Angeles Prehospital Stroke Screen (mLAPSS, as used in FAST-MAG) is given in Table 2. Overall, the RIGHT-2 inclusion/exclusion criteria lead to a similar population of patients being recruited to those identified by mLAPSS.ConsentConsent or proxy consent is obtained at the stroke scene or in the ambulance; if patients lack capacity initially, then further consent or proxy consent is obtained at hospital. The algorithm for consent is shown in Figure 3 and comprises three stages:At scene/in ambulance, with supervision by paramedic, in all patients, for: Ambulance activities; four days of GTN/sham administration; day 2 repeat brain scan (for research purposes); assessment of primary and secondary outcomes at days 90 and 365 by telephone or mail; and access to the participant’s data (for trial purposes). Patient capacity is assessed using structured questions – see below. ADDIN EN.CITE <EndNote><Cite><Author>Ankolekar</Author><Year>2012</Year><RecNum>965</RecNum><DisplayText>(27)</DisplayText><record><rec-number>965</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472003">965</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ankolekar, S.</author><author>Sare, G.</author><author>Geeganage, C.</author><author>Fuller, M.</author><author>Stokes, L.</author><author>Sprigg, N.</author><author>Parry, R.</author><author>Siriwardena, A. N.</author><author>Bath, P. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Stroke, University of Nottingham, City Hospital Campus, Hucknall Road, Nottingham NG5 1PB, UK.</auth-address><titles><title>Determining the Feasibility of Ambulance-Based Randomised Controlled Trials in Patients with Ultra-Acute Stroke: Study Protocol for the &quot;Rapid Intervention with GTN in Hypertensive Stroke Trial&quot; (RIGHT, ISRCTN66434824)</title><secondary-title>Stroke Res Treat</secondary-title></titles><periodical><full-title>Stroke Res Treat</full-title></periodical><pages>385753</pages><volume>2012</volume><edition>2012/11/06</edition><dates><year>2012</year></dates><isbn>2042-0056 (Electronic)</isbn><accession-num>23125943</accession-num><urls></urls><custom2>3480012</custom2><electronic-resource-num>10.1155/2012/385753 [doi]</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>(27) Patients with capacity give written or witnessed oral consent to the paramedic otherwise proxy consent is obtained from a relative/carer/friend, or by the paramedic as witnessed by another person.In hospital at any time, with supervision by research team (research nurse/coordinator/doctor), in patients who lacked capacity in the ambulance, for: Follow-up procedures in hospital. Patients with capacity (assessed as above) give written or witnessed oral consent to the research team member otherwise proxy consent is obtained from a relative/carer/friend. Patients who regain capacity will be re-consented for these procedures.In hospital prior to additional research, with supervision by research team for: Additional research, including one or more of blood and genetic biomarkers, transcranial Doppler, pulse wave analysis, and/or ambulatory blood pressure monitoring. Patients with capacity (assessed as above) give written or witnessed oral consent to the research team member otherwise proxy consent is obtained from a relative/carer/friend.Brief assessment of capacity by the paramedic is performed in the ambulance by explaining to the patient that they have had a suspected stroke, their BP may need lowering, and that a patch will be applied that might lower their BP. ADDIN EN.CITE <EndNote><Cite><Author>Ankolekar</Author><Year>2012</Year><RecNum>965</RecNum><DisplayText>(27)</DisplayText><record><rec-number>965</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472003">965</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ankolekar, S.</author><author>Sare, G.</author><author>Geeganage, C.</author><author>Fuller, M.</author><author>Stokes, L.</author><author>Sprigg, N.</author><author>Parry, R.</author><author>Siriwardena, A. N.</author><author>Bath, P. M.</author></authors></contributors><auth-address>Stroke Trials Unit, Division of Stroke, University of Nottingham, City Hospital Campus, Hucknall Road, Nottingham NG5 1PB, UK.</auth-address><titles><title>Determining the Feasibility of Ambulance-Based Randomised Controlled Trials in Patients with Ultra-Acute Stroke: Study Protocol for the &quot;Rapid Intervention with GTN in Hypertensive Stroke Trial&quot; (RIGHT, ISRCTN66434824)</title><secondary-title>Stroke Res Treat</secondary-title></titles><periodical><full-title>Stroke Res Treat</full-title></periodical><pages>385753</pages><volume>2012</volume><edition>2012/11/06</edition><dates><year>2012</year></dates><isbn>2042-0056 (Electronic)</isbn><accession-num>23125943</accession-num><urls></urls><custom2>3480012</custom2><electronic-resource-num>10.1155/2012/385753 [doi]</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>(27) They are then asked what the suspected diagnosis is (‘stroke’), what might need to be done to their BP (‘lower’), and how this will be done (‘patch’). Lack of capacity is assumed if one or more answers are missing or incorrect, and is likely to reflect that the patient is semi-conscious, dysphasic or confused.This overall consent approach builds on processes used in the PIL-FAST and RIGHT pilot stroke ambulance trials.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGF3PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (18, 26-28) It is designed to reflect that stroke is a severe and often fatal or disabling condition; that the treatment has to be given very early (and ideally in the diamond half-hour or golden hour ADDIN EN.CITE <EndNote><Cite><Author>Saver</Author><Year>2010</Year><RecNum>8309</RecNum><DisplayText>(32)</DisplayText><record><rec-number>8309</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472851">8309</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saver, J.</author><author>Smith, E.</author><author>Fonarow, G.</author><author>Reeves, M.</author><author>Zhao, X.</author><author>Olson, D.</author><author>Schwamm, L.</author></authors></contributors><titles><title>The &quot;Golden Hour&quot; and Acute Brain Ischemia; Presenting Features and LYtic Therapy in &gt;30000 Patients Arriving Within 60 Minutes of Stroke Onset</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1431-9</pages><volume>41</volume><number>7</number><edition>3 June 2010</edition><dates><year>2010</year><pub-dates><date>July 2010</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1161/STROKEAHA.110.583815.</electronic-resource-num></record></Cite></EndNote>(32)) in view of the apparent time-dependency of GTN;PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmtvbGVrYXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA (18)) so that waiver of consent would be inappropriate. ADDIN EN.CITE <EndNote><Cite><Author>Dickert</Author><Year>2015</Year><RecNum>8106</RecNum><DisplayText>(33)</DisplayText><record><rec-number>8106</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472832">8106</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dickert, NW.</author><author>Miller, FG.</author></authors></contributors><titles><title>Involving patients in enrolment decisions for acute myocardial infarction trials</title><secondary-title>The British Medical Journal</secondary-title></titles><periodical><full-title>The British Medical Journal</full-title></periodical><volume>351</volume><number>h3791</number><dates><year>2015</year><pub-dates><date>29 July 2015</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1136/bmj.h3791</electronic-resource-num></record></Cite></EndNote>(33)RandomisationPatients are randomised (1:1) to receive either GTN patches or sham patches. A randomisation sequence was generated by the trial programmer at the Nottingham Stroke Trials Unit (STU) using random-permuted fixed-size blocks stratified by ambulance station. Identical looking numbered treatment packs are sent in blocks (four treatment packs per block) to each ambulance station. Trial-trained paramedics only carry one treatment pack at any time. In order to minimise selection bias, a participant must be enrolled in the study before the treatment pack is opened. Patients and outcome assessors are masked to treatment allocation.InterventionsThe investigational medicinal product is transdermal GTN (5mg daily for 4 days, given as Transiderm Nitro ‘5’, Novartis Pharmaceuticals Ltd UK). Although there is no matching placebo patch, patients randomised to the control group receive a sham patch of similar size to the GTN patch (DuoDERM – a hydrocolloid dressing of size 4.4cm x 3.8cm, ConvaTec Ltd UK). The Nottingham University Hospitals NHS Trust pharmacy prepare opaque sealed sachets containing either a GTN or sham patch, and a gauze dressing. Four of these sachets are contained within a larger plastic box (treatment pack) containing a Patient Information Sheet, Consent Form and ambulance Case Report Form. Although not identical in appearance, both the GTN and DuoDERM patches are unmarked.The GTN/sham patches are placed on the participant’s shoulders or back and the position rotated daily for four days; on days 2 to 4, patches are placed between 08.00 and 09.00 hours in hospital. The doses of patches are not adjusted during treatment. Patches are covered with a gauze dressing to further mask the patient to treatment.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmtvbGVrYXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA (17-19) In order to minimise bias that could be introduced through knowledge of what the participant has received, the number of unmasked staff is kept to a minimum (paramedic and nursing staff administering the patch) and they are asked not to reveal the treatment to colleagues.If there is an emergency situation where further treatment of the participant is dependent on knowledge of the administered treatment, unblinding can be performed by review of the patch on the participant’s shoulder or back. Study agents are stopped if an alternative diagnosis to stroke is made (e.g. TIA or mimic), the patient withdraws consent, for safety reasons, or if unacceptable adverse events develop. New prescriptions of non-trial nitrates are avoided, where possible, during the treatment period.Background careTreatment is given on top of standard best medical care, including management in an acute stroke unit, and treatment with thrombolysis, mechanical thrombectomy, hemicraniectomy or other necessary surgery, intensive care, any other licensed treatment for acute stroke, and aspirin, as relevant. Clinicians are encouraged to comply with national guidelines and actively lower raised BP in hospital within the first 6 hours of ICH. ADDIN EN.CITE <EndNote><Cite><Author>Royal College of Physicians</Author><Year>2016</Year><RecNum>8782</RecNum><DisplayText>(10)</DisplayText><record><rec-number>8782</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472907">8782</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><authors><author>Royal College of Physicians,</author></authors></contributors><titles><title>National clinical guideline for stroke. Prepared by the Intercollegiate Stroke Working Party</title></titles><edition>Fifth</edition><dates><year>2016</year></dates><publisher>Royal College of Physicians</publisher><urls></urls></record></Cite></EndNote>(10) In addition, pre-stroke anti-hypertensive medication is re-started at the discretion of the treating doctor, e.g. once the patient is medically stable and can swallow safely or has enteral access. Systematic use of long-term oral antithrombotic and lipid lowering agents are recommended for secondary prevention in patients with ischaemic stroke, and antihypertensive therapy is encouraged, where appropriate, once the 4-day treatment period is over.Data collection and follow-upAll patients are followed-up daily during the four days of treatment, and then at discharge from hospital, and days 90 and 365, unless death occurs earlier (Table 1, Figure 1). Patients who are unable to complete the four days of treatment as per the protocol are still followed at days 90 and 365. Baseline details are collected by the recruiting paramedic using data recorded as part of routine clinical care; these include information on demography (age, sex), stroke (onset date/time), and physiology (blood pressure, heart rate, oxygen saturation, glucose).On arrival at hospital, further routine clinical details are collected, including stroke syndrome,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW1mb3JkPC9BdXRob3I+PFllYXI+MTk5MTwvWWVhcj48

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ADDIN EN.CITE.DATA (34), stroke severity (National Institutes of Health Stroke Scale, NIHSS ADDIN EN.CITE <EndNote><Cite><Author>Adams</Author><Year>1999</Year><RecNum>7828</RecNum><DisplayText>(35)</DisplayText><record><rec-number>7828</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472790">7828</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Adams, H. P.</author><author>Davis, P. H.</author><author>Leira, E. C.</author><author>Chang, K. C.</author><author>Bendixen, B. H.</author><author>Clarke, W. R.</author><author>Woolson, R. F.</author><author>Hansen, M. D.</author></authors></contributors><auth-address>Dr harold P Adams, department of neurology, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242; e-mail harold-adams@uiowa.edu</auth-address><titles><title>Baseline NIH Stroke Scale score strongly predicts outcome after stroke. A report of the trial of Org 10172 in Acute Stroke Treatment (TOAST)</title><secondary-title>Neurology</secondary-title></titles><periodical><full-title>Neurology</full-title><abbr-1>Neurology</abbr-1></periodical><pages>126-131</pages><volume>53</volume><dates><year>1999</year></dates><label>3685</label><urls></urls></record></Cite></EndNote>(35)), haemodynamics (blood pressure, heart rate). Neuroimaging (plain CT or MR scanning, ideally with CT or MR angiography) is performed on admission to diagnose stroke type (ischaemic, ICH) or non-stroke lesions. CT angiography (if performed as part of routine practice) is used to determine if GTN improves collateral blood supply and influences reperfusion. Importantly, these hospital admission measures are made on treatment following application of the first GTN/sham patch at the stroke scene; hence, it is possible that treatment will have altered the diagnosis (e.g. conversion of mild stroke to TIA), stroke syndrome and severity, and neuroimaging findings, in hospital.Blood pressure and heart rate are collected daily, one hour after placement of the second, third and fourth treatment patches. A research plain CT (or MR) scan is performed on day 2 to allow assessment of the evolution of the infarct and symptomatic artery, or haematoma. Intermediate outcome data (e.g. NIHSS, adverse events such as headache, hypotension) are collected at day 4 by hospital research staff, and the final diagnosis is made at discharge from hospital. The primary outcome, modified Rankin Scale (mRS), is determined at day 90 with central telephone follow-up by trained staff blinded to treatment assignment; additional measures of disability, cognition, mood and quality of life are similarly recorded. The same measures are also recorded at day 365 to ensure that any findings are maintained long term.Routine carotid ultrasound examination is performed to identify severe carotid stenosis and need for early carotid endarterectomy; such scanning may be performed at any time during the hospital admission and is not necessary prior to randomisation. Blood pressure is measured using calibrated standard semiautomatic equipment available in ambulances and hospitals.All information is entered online over a secure encrypted password/PIN protected internet connection (HTTPS) with data validated in real-time. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>8157</RecNum><DisplayText>(19)</DisplayText><record><rec-number>8157</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472837">8157</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, PMW.</author><author>Woodhouse, L.</author><author>Scutt, P.</author><author>Krishnan, K.</author><author>Wardlaw, JM.</author><author>Bereczki, D.</author><author>Sprigg, N.</author><author>Berge, E.</author><author>Beridze, M.</author><author>Caso, V.</author><author>Chen, C.</author><author>Christensen, H.</author><author>Collins, R.</author><author>Etribi, A.</author><author>Laska, A.</author><author>Lees, KR.</author><author>Ozturk, S.</author><author>Phillips, S.</author><author>Pocock, S.</author><author>DeSilva, A.</author><author>Szatmari, S.</author><author>Utton, S.</author></authors></contributors><titles><title>Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial.</title><secondary-title>The Lancet</secondary-title></titles><periodical><full-title>The Lancet</full-title></periodical><pages>617-28</pages><volume>385</volume><number>9968</number><edition>22 October 2014</edition><dates><year>2015</year><pub-dates><date>13 February 2015</date></pub-dates></dates><urls></urls><electronic-resource-num>(14)61121-1</electronic-resource-num></record></Cite></EndNote>(19) Neuroimaging (CT or MR) are interpreted by the local investigator, and then centrally over the internet by independent assessors blinded to treatment and using a validated structured classification system.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MTk5NDwvWWVhcj48

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ADDIN EN.CITE.DATA (19, 36, 37) Similarly, serious adverse events (SAEs) are adjudicated centrally over the internet by independent assessors blinded to treatment. ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2015</Year><RecNum>8157</RecNum><DisplayText>(19)</DisplayText><record><rec-number>8157</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472837">8157</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, PMW.</author><author>Woodhouse, L.</author><author>Scutt, P.</author><author>Krishnan, K.</author><author>Wardlaw, JM.</author><author>Bereczki, D.</author><author>Sprigg, N.</author><author>Berge, E.</author><author>Beridze, M.</author><author>Caso, V.</author><author>Chen, C.</author><author>Christensen, H.</author><author>Collins, R.</author><author>Etribi, A.</author><author>Laska, A.</author><author>Lees, KR.</author><author>Ozturk, S.</author><author>Phillips, S.</author><author>Pocock, S.</author><author>DeSilva, A.</author><author>Szatmari, S.</author><author>Utton, S.</author></authors></contributors><titles><title>Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial.</title><secondary-title>The Lancet</secondary-title></titles><periodical><full-title>The Lancet</full-title></periodical><pages>617-28</pages><volume>385</volume><number>9968</number><edition>22 October 2014</edition><dates><year>2015</year><pub-dates><date>13 February 2015</date></pub-dates></dates><urls></urls><electronic-resource-num>(14)61121-1</electronic-resource-num></record></Cite></EndNote>(19)Primary OutcomeThe primary outcome is the modified Rankin Scale (mRS).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXRoPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (19, 38-40) mRS is determined centrally by telephone by a trained assessor at day 90 (+7 days) according to an algorithm. ADDIN EN.CITE <EndNote><Cite><Author>Bruno</Author><Year>2011</Year><RecNum>8308</RecNum><DisplayText>(41)</DisplayText><record><rec-number>8308</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472851">8308</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bruno, A.</author><author>Shah, N.</author><author>Lin, C.</author><author>Close, B.</author><author>Hess, D.</author><author>Davis, K.</author><author>Baute, V.</author><author>Switzer, J.</author><author>Waller, J.</author><author>Nichols, F.</author></authors></contributors><titles><title>Improving Modified Rankin Scale Assessment With a Simplified Questionnaire</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1048-50</pages><volume>41</volume><number>5</number><edition>11 March 2011</edition><dates><year>2011</year><pub-dates><date>May 2010</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1161/STROKEAHA.109.571562.</electronic-resource-num></record></Cite></EndNote>(41) Assessors are masked to treatment assignment and baseline clinical characteristics. The primary analysis will compare GTN versus sham using ordinal logistic regression, both overall and in pre-specified sub-groups.Secondary outcomesOutcomes are assessed at hospital admission; during the four days of intervention; then at day 4, discharge from hospital, and days 90 and 365.Hospital admission:Neurological impairment (NIHSS, /42)Systolic and diastolic blood pressure (mmHg)Systolic blood pressure <185 mmHg, ischaemic stroke (%)Systolic blood pressure <140 mmHg, ICH (%)Heart rate (bpm)Stroke lesion (infarct or haemorrhage) extent on brain scan (CT or MR)Stroke lesion (infarct or haemorrhage) mass effect and swellingPresence of intravascular thrombus (hyperattenuated artery on CT or absent flow void/high signal on FLAIR MR) and cerebral arterial patency (CT or MR angiography) on relevant brain scanningUse and timing of hyperacute and acute treatments in hospital:Open-label blood pressure lowering (%)Intravenous thrombolysis (%)Intra-arterial therapy / mechanical thrombectomy (%)Hemicraniectomy (%)Surgery for ICH (%)Admission to intensive/critical care unit (%)Required artificial ventilation (%)At day 2-4:Systolic and diastolic blood pressure, heart rateNeuroimaging: Infarct/haematoma extent, presence of hyper-attenuated artery sign (CT) or absent flow void (MR), infarct swelling, secondary haemorrhagic transformation of infarct, haematoma expansionAt day 4 (or discharge if sooner):Stroke recurrence (%)Neurological impairment – NIHSS (/42)Neurological deterioration from baseline (NIHSS >=4 points, or >=2 point increase in any domain) (%)Infection (pneumonia/chest, urinary tract, other) (%)Feeding status, non-oral (%)Required physiotherapy (%)Required occupational therapy (%)Required speech & language therapy (%)At discharge/death:Length of stay in hospital (days)Patient disposition (died, institution/in hospital, home)At days 90 and 365 by telephone (or post):Dependency – mRS >2 (%)Disability/Activities of Daily Living - Barthel Index (BI, /100)Quality of life - Health Utility Status (HUS, derived from EuroQoL-5D, /1) ADDIN EN.CITE <EndNote><Cite><Author>Dorman</Author><Year>1997</Year><RecNum>5090</RecNum><DisplayText>(42)</DisplayText><record><rec-number>5090</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472485">5090</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dorman,P.J.</author><author>Slattery,J.</author><author>Farrell,B.</author><author>Dennis,M.S.</author><author>Sandercock,P.A.G.</author><author>United Kingdom Collaborators in the International Stroke Trial,</author></authors></contributors><titles><title>A randomised comparison of the EuroQol and short form-36 after stroke</title><secondary-title>Br.Med.J.</secondary-title></titles><periodical><full-title>Br.Med.J.</full-title></periodical><pages>461</pages><volume>315</volume><keywords><keyword>Randomised</keyword><keyword>stroke</keyword><keyword>EuroQol</keyword><keyword>SF-36</keyword></keywords><dates><year>1997</year></dates><label>967</label><urls></urls></record></Cite></EndNote>(42)Quality of life - EQ-Visual Analogue Scale (EQ-VAS) (/100)Cognition - telephone-MMSE (/22)Cognition - Telephone Interview Cognition Scale (TICS, /39)Cognition – verbal fluency (animal naming) (∞)Mood - Zung Depression Scale (ZDS, /102.5) ADDIN EN.CITE <EndNote><Cite><Author>Zung</Author><Year>1965</Year><RecNum>3186</RecNum><DisplayText>(43)</DisplayText><record><database name="STROKEGR-Converted.enl" path="/Users/pbath/Documents/EndNote/STROKEGR-Converted.enl">STROKEGR-Converted.enl</database><source-app name="EndNote" version="8.0">EndNote</source-app><rec-number>3186</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Zung, W.W.K.</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">A self-rating depression scale</style></title><secondary-title><style face="normal" font="default" size="100%">Archives of general psychiatry</style></secondary-title></titles><pages><style face="normal" font="default" size="100%">63-70</style></pages><volume><style face="normal" font="default" size="100%">12</style></volume><dates><year><style face="normal" font="default" size="100%">1965</style></year></dates><label><style face="normal" font="default" size="100%">198</style></label><urls></urls></record></Cite></EndNote>(43)Patient disposition (died, institution/in hospital, home)Stroke recurrence (%)Safety outcomesDeath (%)Serious adverse events, by day 4 (%)Serious adverse events, by day 4 (fatal, non-fatal, none)Headache, by day 4 (%)Infection (pneumonia, chest, urinary tract, other) by day 4 (%)Hypotension, requiring clinical intervention, by day 4 (%)Hypertension, requiring clinical intervention, by day 4 (%)Investigator-reported serious adverse events are grouped by time of onset (during or after treatment), and validated and categorised blindly by independent adjudicators. 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ADDIN EN.CITE.DATA (19, 44)Explanatory and mechanistic additional researchRIGHT-2 aims to study potential mechanisms by which GTN versus sham might be beneficial if the primary analysis is statistically positive. These comprise:Hospital admission (day 1)Plain CT brain – at all sites:Identify stroke type (IS, ICH, non-stroke).Location/length of hyperattenuated artery (CT) or absent flow void/increased signal on FLAIR MRI, and visibility and extent of acute ischaemic change or haematoma.Pre-stroke brain health assessed by presence of leukoaraiosis, brain atrophy, prior infarct or haemorrhage CT angiography – at some sites:IS – collateral status, and location, length, luminal reduction of any occlusion.ICH – active bleeding (spot sign, larger haematoma).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGF0cmk8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (49, 50)Genetic blood biomarkers.Hydration status - On BP response: calculated osmolarity (2Na+2K+glucose+urea); urea : creatinine ratio; packed cell volume. ADDIN EN.CITE <EndNote><Cite><Author>Rowat</Author><Year>2012</Year><RecNum>887</RecNum><DisplayText>(51, 52)</DisplayText><record><rec-number>887</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491471995">887</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rowat, A.</author><author>Graham, C.</author><author>Dennis, M.</author></authors></contributors><titles><title>Dehydration in Hospital-Admitted Stroke Patients</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>857-859</pages><volume>43</volume><edition>11 October 2011</edition><dates><year>2012</year></dates><urls></urls><electronic-resource-num>10.1161/STROKEAHA.111.640821</electronic-resource-num></record></Cite><Cite><Author>Kelly</Author><Year>2004</Year><RecNum>2801</RecNum><record><rec-number>2801</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472197">2801</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kelly, J.</author><author>Huntm BJ.</author><author>Lewis, RR.</author><author>Swaminathan, R.</author><author>Moody, A.</author><author>Seed, PT.</author><author>Rudd, A.</author></authors></contributors><titles><title>Dehydration and venous thromboembolism after acute stroke</title><secondary-title>QJM</secondary-title></titles><periodical><full-title>QJM</full-title></periodical><pages>293-296</pages><volume>97</volume><dates><year>2004</year><pub-dates><date>February 2004</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1093/qjmed/hch050</electronic-resource-num></record></Cite></EndNote>(51, 52)Images are curated and adjudicated using a derivative of the MRC IST-3/ENOS system, part of the Systematic Image Review System (SIRS-2) web-based imaging system from University of Edinburgh (Wardlaw, neuroimage.co.uk/sirs).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJkbGF3PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

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ADDIN EN.CITE.DATA (19, 53, 54)Data Monitoring CommitteeThe DMC review unblinded data twice yearly in respect of safety and efficacy, and consider the study in the context of other trials of altering BP in stroke. Stopping rules are based on the Haybittle-Peto rule as a guide for proof beyond reasonable doubt for:HazardPoor outcome (mRS >2) is less frequent in the sham/control group, P<0.01 (nominal, 2-sided); ORDeath is less frequent in the sham/control group, P<0.01 (nominal, 2-sided)EfficacyPoor outcome (mRS >2) is less frequent in the GTN/active group, P<0.01 (nominal, 2-sided); ANDDeath is less frequent in the GTN/active group, P<0.01 (nominal, 2-sided); ANDPoor outcome (mRS >2) is less frequent in the GTN/active group in ischaemic stroke, P<0.01 (nominal, 2-sided); ANDPoor outcome (mRS >2) is less frequent in the GTN/active group in intracerebral haemorrhage, P<0.05 (nominal, 2-sided).The stopping rules for efficacy are designed to persuade practitioners that such a simple and inexpensive treatment can significantly reduce poor functional outcome, including separately in patients with ischaemic stoke and ICH, and reduce death.The DMC also monitor SAEs and neurological deterioration, and outcomes in particular subgroups of patients including those with severe stroke (TACS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW1mb3JkPC9BdXRob3I+PFllYXI+MTk5MTwvWWVhcj48

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ADDIN EN.CITE.DATA (18) and reduction for baseline co-variate adjustment of 20%. ADDIN EN.CITE <EndNote><Cite><Author>Gray</Author><Year>2009</Year><RecNum>1502</RecNum><DisplayText>(57)</DisplayText><record><rec-number>1502</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472056">1502</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gray, L. J.</author><author>Bath, P. M.</author><author>Collier, T.</author></authors></contributors><auth-address>Stroke Trials Unit, University of Nottingham, UK.</auth-address><titles><title>Should stroke trials adjust functional outcome for baseline prognostic factors?</title><secondary-title>Stroke</secondary-title><alt-title>Stroke; a journal of cerebral circulation</alt-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>888-94</pages><volume>40</volume><number>3</number><edition>2009/01/24</edition><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Computer Simulation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Models, Statistical</keyword><keyword>Prognosis</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Research Design</keyword><keyword>Sample Size</keyword><keyword>Sex Factors</keyword><keyword>Stroke/ epidemiology</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1524-4628 (Electronic)&#xD;0039-2499 (Linking)</isbn><accession-num>19164798</accession-num><urls></urls><electronic-resource-num>10.1161/strokeaha.108.519207</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(57) If only 650 participants are recruited, there will be 82% power to detect this odds ratio using the same assumptions above. Whilst one formal interim analysis is planned, no adjustment has been made to the sample size given the pre-specified high level of significance required to stop the trial.Analysis populationsRIGHT-2 will follow the intention-to-treat principle, i.e. analysis is based on the initial treatment assignment and not on the treatment received. Additionally, the primary efficacy analysis will be performed in patients with a stroke, or a stroke and TIA, since there is no expectation that GTN will alter outcomes in patients presenting with a mimic. Finally, a per protocol analysis may be performed for hypothesis-generation if the primary analysis shows a significant treatment effect.Statistical analysesThe distribution of mRS at day 90 between GTN and sham groups will be analysed using ordinal logistic regression with adjustment for age, sex, pre-morbid mRS, FAST, pre-treatment systolic BP, index event (ICH, ischaemic stroke, TIA, mimic) and time to treatment. The effect of GTN on mRS will be studied in pre-specified subgroups comprising those based on premorbid or ambulance/pre-randomisation data, and on post-treatment data collected at admission to hospital. This distinction is necessary since GTN may alter information collected at admission to hospital such as diagnosis (e.g. stroke to TIA), stroke syndrome and severity, and neuroimaging findings.Other outcomes will be analysed using binary logistic regression for dichotomised measures (e.g. serious adverse events), Cox proportional hazards regression (e.g. time to death), or multiple linear regression (e.g. NIHSS, MMSE, HUS, ZDS), with presentation of 95% confidence intervals and two-sided p-values.Study organisation and fundingRIGHT-2 is an independent academic trial performed by a UK collaborative group. The study is supervised by a Trial Steering Committee and receives advice from an International Advisory Committee. The trial is run day-to-day by a Trial Management Committee based at the Coordinating Centre in Nottingham. Approximately 7 ambulance services across the UK will recruit, initiate treatment and then transport patients to ~40 acute hospitals with a stroke service. The image data are managed by researchers at the University of Edinburgh, via databases for image management and transfer of results of image reads linked to the University of Nottingham. Independent and blinded Adjudicators classify serious adverse events for a separate and independent Data Monitoring Committee. The trial is funded by the British Heart Foundation; the University of Nottingham is the sponsor.Publication and data sharingIn addition to this description of the RIGHT-2 protocol, subsequent publications will report the statistical analysis plan (prior to data-lock at trial conclusion), a complete description of baseline data, and the main results. This approach follows that used in the ENOS trial.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGUgRU5PUyBUcmlhbCBJbnZlc3RpZ2F0b3JzPC9BdXRo

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ADDIN EN.CITE.DATA (58-60) Subsequent publications will focus on the effect of GTN on potential mechanisms of action, and factors involved in delivering a large multicentre paramedic-delivered ambulance-based ultra-acute stroke trial.In the future, data from RIGHT-2 will be added to the Cochrane Collaboration review of NO donors in stroke, ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2017</Year><RecNum>17563</RecNum><DisplayText>(61)</DisplayText><record><rec-number>17563</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1493036763">17563</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, P. M.</author><author>Krishnan, K.</author><author>Appleton, J. P.</author></authors></contributors><auth-address>Stroke, Division of Clinical Neuroscience, University of Nottingham, City Hospital Campus, Nottingham, UK, NG5 1PB.</auth-address><titles><title>Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD000398</pages><volume>4</volume><dates><year>2017</year><pub-dates><date>Apr 21</date></pub-dates></dates><isbn>1469-493X (Electronic)&#xD;1361-6137 (Linking)</isbn><accession-num>28429459</accession-num><urls><related-urls><url>;(61) and integrated into individual patient data meta-analyses of nitric oxide donors, ADDIN EN.CITE <EndNote><Cite><Author>Bath</Author><Year>2016</Year><RecNum>8403</RecNum><DisplayText>(31)</DisplayText><record><rec-number>8403</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472862">8403</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bath, PMW.</author><author>Woodhouse, L.</author><author>Krishnan, K.</author><author>Anderson, C.</author><author>Berge, E.</author><author>Ford, GA.</author><author>Robinson, TG.</author><author>Saver, JL.</author><author>Sprigg, N.</author><author>Wardlaw, JM.</author><author>In Acute Stroke Collaboration Basc GP;</author></authors></contributors><titles><title>Effect of treatment delay, stroke type, and thrombolysis on the effect of glyceryl trinitrate, a nitric oxide donor, on outcome after acute stroke: a systematic review and meta-analysis of individual patient from randomised trials</title><secondary-title>Stroke Research and Treatment</secondary-title></titles><periodical><full-title>Stroke Research and Treatment</full-title></periodical><volume>2016:9706720</volume><edition>17 April 2016</edition><dates><year>2016</year><pub-dates><date>January 2016</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1155/2016/9706720</electronic-resource-num></record></Cite></EndNote>(31) and blood pressure lowering, for acute stroke (the latter through the ‘Blood pressure in Acute Stroke Collaboration’, BASC), and the ‘Virtual International Stroke Trials Archive’ (VISTA). ADDIN EN.CITE <EndNote><Cite><Author>Ali</Author><Year>2007</Year><RecNum>2036</RecNum><DisplayText>(62)</DisplayText><record><rec-number>2036</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472132">2036</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ali, M.</author><author>Bath, P.M.B</author><author>Davis, S.M.</author><author>Diener, H-C.</author><author>Donnan, G.A.</author><author>Fisher, M.</author><author>Grotta, J.</author><author>Hacke, W.</author><author>Hennerici, M.G.</author><author>Hommel, M.</author><author>Kaste, M.</author><author>Lyden, P.</author><author>Sacco, R.L.</author><author>Wahlgren, N.G.</author><author>Warach, S.</author><author>Weir, C.J.</author><author>Lees, K.R.</author></authors></contributors><auth-address>Dr K Lees, Division of Cardiovascular and Medical Sciences, University Dept of Medicine and Therapeutics, Gardiner Institute, 44 Church St, Glasgow, G11 6NT</auth-address><titles><title>The virtual international stroke trials archive (VISTA)</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1905-1910</pages><volume>38</volume><keywords><keyword>clinical trials</keyword><keyword>trial design</keyword><keyword>natural history</keyword><keyword>database</keyword><keyword>modified rankin scale</keyword><keyword>national institute of health stroke scale</keyword></keywords><dates><year>2007</year></dates><label>5213</label><urls></urls><electronic-resource-num>10.1161.STROKEAHA.106.473579</electronic-resource-num></record></Cite></EndNote>(62) Ultimately, a subset of the data will be made available over the web, as with the International Stroke Trial. ADDIN EN.CITE <EndNote><Cite><Author>Sandercock</Author><Year>2011</Year><RecNum>1029</RecNum><DisplayText>(63)</DisplayText><record><rec-number>1029</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472018">1029</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sandercock, P. A.</author><author>Niewada, M.</author><author>Czlonkowska, A.</author></authors></contributors><auth-address>Department of Clinical Neurosciences, University of Edinburgh, Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK. Peter.Sandercock@ed.ac.uk.</auth-address><titles><title>The International Stroke Trial database</title><secondary-title>Trials</secondary-title></titles><periodical><full-title>Trials</full-title></periodical><pages>101</pages><volume>12</volume><number>1</number><dates><year>2011</year></dates><isbn>1745-6215 (Electronic)&#xD;1745-6215 (Linking)</isbn><accession-num>21510853</accession-num><label>16988</label><urls></urls><language>Eng</language></record></Cite></EndNote>(63) Similarly, anonymised neuroimaging data will be published. ADDIN EN.CITE <EndNote><Cite><Author>Wardlaw</Author><Year>2007</Year><RecNum>1809</RecNum><DisplayText>(54)</DisplayText><record><rec-number>1809</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472107">1809</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wardlaw, J.</author><author>Bath, P.</author><author>Sandercock, P.</author><author>Perry, D.</author><author>Palmer, J.</author><author>Watson, G.</author><author>Lloyd, S.</author><author>Geddes, J.</author><author>Farrall, A.</author></authors></contributors><auth-address>J M Wardlaw, Division of Clinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU</auth-address><titles><title>The NeuroGrid stroke examplar clinical trial protocol</title><secondary-title>International Journal of Stroke</secondary-title></titles><periodical><full-title>International Journal of Stroke</full-title></periodical><pages>63-9</pages><volume>2</volume><keywords><keyword>clinical trials</keyword><keyword>CT</keyword><keyword>eScience</keyword><keyword>stroke</keyword></keywords><dates><year>2007</year></dates><label>5346</label><urls></urls></record></Cite></EndNote>(54)Summary and conclusionsRIGHT-2 is addressing the safety and efficacy of ultra-acute administration of GTN in patients with stroke. 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ADDIN EN.CITE.DATA (64)) means that a moderate-high clinical effect can be detectable with high statistical power (90%). A positive trial could be implemented easily because of the pragmatic inclusion criteria and collection of safety data from non-stroke participants. As such, transdermal GTN could be introduced rapidly into pre-hospital clinical practice around the world since it is readily available, easy to administer, and inexpensive (?2 per patient, equivalent to €2.5/$3). Successful delivery of the trial, whatever the result for GTN, would also support FAST-Mag ADDIN EN.CITE <EndNote><Cite><Author>Saver</Author><Year>2015</Year><RecNum>7977</RecNum><DisplayText>(29)</DisplayText><record><rec-number>7977</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472811">7977</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saver, J.</author><author>Starkman, S.</author><author>Eckstein, M.</author><author>Stratton, S.</author><author>Pratt, F.</author><author>Hamilton, S.</author><author>Conwit, R.</author><author>Liebeskind, D.</author><author>Sung, G.</author><author>Kramer, I.</author><author>Moreau, G.</author><author>Goldweber, R.</author><author>Sanossian, N.</author></authors></contributors><titles><title>Prehospital use of magnesium sulfate as neuroprotection in acute stroke</title><secondary-title>The New England Journal of Medicine</secondary-title></titles><periodical><full-title>The New England Journal of Medicine</full-title></periodical><pages>528-36</pages><volume>372</volume><number>6</number><dates><year>2015</year><pub-dates><date>5 February 2015</date></pub-dates></dates><urls></urls><electronic-resource-num>10.1056/NEJMoa1408827</electronic-resource-num></record></Cite></EndNote>(29) in demonstrating that large multicentre pre-hospital based trials are feasible in ultra-acute stroke.ACKNOWLEDGEMENTSJPA, PS, LH, DH are funded in part by the trial (British Heart Foundation); MD, HH are funded by the trial; LW is funded in part by NIHR HTA. PMB is Stroke Association Professor of Stroke Medicine and is a NIHR Senior Investigator. Imaging adjudication system developed with funding from MRC, Chest Heart Stroke Scotland, Stroke Association, The Health Foundation, and the Chief Scientist Office (JMW).RIGHT-2 INVESTIGATORSWriting CommitteeJ P Appleton,1 P Scutt, 1 M Dixon, 1 H Howard, 1 L Haywood, 1 D Havard, 1 T Hepburn,2 T England,3 N Sprigg,1 L J Woodhouse,1 J M Wardlaw,4 A A Montgomery,2 S Pocock,5 P M Bath.11 Stroke Trials Unit, University of Nottingham, Nottingham NG5 1PB UK2 Nottingham Clinical Trials Unit, University of Nottingham, Nottingham NG7 2UH UK3 Division of Medical Sciences, University of Nottingham, Derby DE22 3DT UK4 Neuroimaging Sciences, University of Edinburgh, Edinburgh EH16 4SB UK5 Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London WC1E 7HT UKTrial Steering CommitteeIndependent: G Venables (Chair/Neurologist; Sheffield), Pierre Amarenco (Neurologist; Paris), M Jarvis (Participant Representative; Nottingham), K Muir (Neurologist; Glasgow).Grant applicants: P M Bath (Chief Investigator/Stroke Physician; Nottingham), T England (Stroke Physician; Derby), A A Montgomery (Statistician; Nottingham), J Potter (Stroke Physician; Norwich), S Pocock (Statistician; London), C Price (Stroke Physician; Newcastle), T Robinson (Stroke Physician; Leicester), C Roffe (Stroke Physician; Stoke-on-Trent), N Siriwardena (Pre-Hospital Healthcare; Lincoln), N Sprigg (Stroke Physician; Nottingham), J M Wardlaw (Neuroradiologist; Edinburgh).Representatives: S Amoils (Funder; London), A Shone (Sponsor; Nottingham).International Advisory CommitteeC Anderson (Sydney, Australia), E Berge (Oslo, Norway), S Phillips (Halifax, Canada), P Rothwell (Oxford, UK), E Sandset (Oslo, Norway), N Sanossian (Los Angeles, USA), J Saver (Los Angeles, USA).Data Monitoring CommitteeP A G Sandercock (Chairman, Edinburgh), K Asplund (Ume?), C Baigent (Oxford).Trial Management Committee (Nottingham)P M Bath (Chief Investigator), D Havard (Chair, Senior Trial Manager), H Foster (Trial Manager), J P Appleton (Medic), W Clarke (Finance), M Dixon (National Paramedic), L Haywood (Programming), D Hazle (Data Administration), T Hepburn (Protocol Author), H Howard (Trial Coordinator), P Robinson (Secretary), M Sampson (Data Administration), P Scutt (Statistician), H Gregory (Outcome Coordinator).Neuroimaging (Edinburgh)J M Wardlaw (Chair), D Buchanan (Programming), J Palmer (Programming), E Sakka (Manager), A Hutchison (Programming)Adjudication: J M Wardlaw (Chair), G Mair, L CalaSerious Adverse Event AdjudicationS Ankolekar (Birmingham).Funding agencyBritish Heart Foundation (grant CS/14/4/30972).SponsorUniversity of NottinghamREFERENCES ADDIN EN.REFLIST 1.Emberson J, Lees K, Lyden P, et al. 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Trials 2011;12(1):101.64.Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. New England Journal of Medicine 2008;359(13):1317-29.65.Kidwell CS, Starkman S, Eckstein M, Weems K, Saver JL. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000;31:71-6.66.Mohd Nor A, McAllister C, Louw SJ, et al. Agreement between ambulance paramedic and physician recorded neurological sings with face arm sppech test (FAST) in acute stroke patients. Stroke 2004;35:1355-9.TABLE 1. Schedule of procedures and evaluationsTimingBaselineDay 1+15minDay1Day2Day3Day4±1DischargeDay90±7Day365±7EnvironmentAmbAmbHospHospHospHospHospTel/postTel/postParamedic: Consent/proxy-consent for main trialEnrolmentBaseline assessment: FAST, BP/HR, ECGAdminister GTN/sham + gauze dressingBlood pressure & heart rate ***Paramedic-hospital handoverConsent if patient lacks capacity in ambulance ~<===>Impairment / deterioration (NIHSS/GCS)CT brain, plain ?CT angiography - if routine ?Haematology/chemistry/ECG - routineAll SAEs including fatal SAEs**Fatal SAEsRecurrent strokeTolerability/side effectsPlain CT scan - routine if post rt-PA ?Additional clinical neuroimagingConsent for additional research (where appropriate)24 hour ambulatory blood pressure monitoring ?<=>Blood biomarkers (e.g. S-100, NOx, P-selectin) ?<=>Genetics: EDTA sample ?<=>Pulse wave analysis ?<=*>Transcranial Doppler ?<=*>Consent if patient regains capacity<===>Disposition (home/institution/home)Dependency: modified Rankin ScaleDisability: Barthel IndexCognition: MMSE, TICSQuality of Life: EQ-5D, EQ-VASMood: Zung Depression Scale*1-2 hours after administration of GTN/sham patch; **If discharge before Day 4; Routine care in italics. Amb: Ambulance; BP: Blood pressure; FAST: Face, Arm, Speech, Time test; GCS: Glasgow Coma Scale; Hosp: Hospital; HR: heart rate; IMP: Investigational Medicinal Product; MMSE: Mini-Mental State Examination; NIHSS: National Institutes of Health Stroke Scale; Tel: Telephone (done by central telephone questionnaire masked to treatment assignment); TICS: Telephone Interview of Cognition Status. ? Imaging sent as ‘volume data’? Separate consent to be obtained in-hospital. 08.00 Time (+/- 2 hour) for patch administration or measurement ~Only for participants whose baseline consent was by proxy (can be anytime during hospital stay).TABLE 2. Comparison and contrast of inclusion and exclusion criteria for RIGHT-2 (uses Face, Arm, Speech, Time test, FAST) versus FAST-MAG (used modified Los Angeles Prehospital Stroke Screen, mLAPSS)CriteriaRIGHT-2mLAPSS/FAST-MAG PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWR3ZWxsPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48

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ADDIN EN.CITE.DATA (29, 65)Age18-40-95History of seizure absentWitnessed at/after strokeEverSymptom duration<4 hours<2 hoursDisability/dependencyNot in nursing homeNot wheelchair bound or bedriddenBlood glucose (mmol/L)2.5-3.3-22.2Face weak/droopYesYesArm weak/driftYesYesSpeechYes-FAST ?2 or 3-Grip weak/none-YesGlasgow coma scale8-15-? FAST ADDIN EN.CITE <EndNote><Cite><Author>Mohd Nor</Author><Year>2004</Year><RecNum>2753</RecNum><DisplayText>(66)</DisplayText><record><rec-number>2753</rec-number><foreign-keys><key app="EN" db-id="x25warrpv92fpreve0mxz507z9rwete9ftpt" timestamp="1491472193">2753</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mohd Nor, A.</author><author>McAllister, C.</author><author>Louw, S.J.</author><author>Dyker, A.G.</author><author>Davis, M.</author><author>Jenkinson, D.</author><author>Ford, G.A.</author></authors></contributors><auth-address>Prof G.A. Ford, Wolfson Unit of Clinical Pharmacology, Claremont Place, University of Newcastle upon Tune, NE2 4HH</auth-address><titles><title>Agreement between ambulance paramedic and physician recorded neurological sings with face arm sppech test (FAST) in acute stroke patients</title><secondary-title>Stroke</secondary-title></titles><periodical><full-title>Stroke</full-title></periodical><pages>1355-1359</pages><volume>35</volume><keywords><keyword>stroke</keyword><keyword>emergency medical services</keyword></keywords><dates><year>2004</year></dates><label>4904</label><urls></urls></record></Cite></EndNote>(66) = facial weakness + arm weakness + speech abnormalityTABLE 3. Distribution of modified Rankin Scale (mRS) in pre-hospital stroke trials with aggregation of rates across treatment groups. The sample size calculation for RIGHT-2 assumes the mRS distribution seen in the RIGHT pilot trial (highlighted in bold).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmtvbGVrYXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA (18-20)FIGURE 2. Flow of patients through trial.999 call for strokeFAST>1SBP>=120mmHgConsentEnrolmentTreatment package openedGTN patchBP and HR at 15 minsSham patchBP and HR at 15 minsHandover from ambulance to hospitalParamedic informs trial co-ordinating centre of recruitmentCT/CTA/MRI/MRA (according to local practice)CT/CTA/MRI/MRA (according to local practice)Sham patchCT/CTA (or MRI/MRA if clinically needed)Sham patchTelephone/postal assessmentSham patchTelephone/postal assessmentGTN patchCT/CTA (or MRI/MRA if clinically needed)GTN patchGTN patchTelephone/postal assessmentTelephone/postal assessmentHOME or AMBULANCE?HOSPITAL?HOSPITAL or HOME?DAY 1?DAY 2?DAY 3DAY 4DAY 90?DAY 365?999 call for strokeFAST>1SBP>=120mmHgConsentEnrolmentTreatment package openedGTN patchBP and HR at 15 minsSham patchBP and HR at 15 minsHandover from ambulance to hospitalParamedic informs trial co-ordinating centre of recruitmentCT/CTA/MRI/MRA (according to local practice)CT/CTA/MRI/MRA (according to local practice)Sham patchCT/CTA (or MRI/MRA if clinically needed)Sham patchTelephone/postal assessmentSham patchTelephone/postal assessmentGTN patchCT/CTA (or MRI/MRA if clinically needed)GTN patchGTN patchTelephone/postal assessmentTelephone/postal assessmentHOME or AMBULANCE?HOSPITAL?HOSPITAL or HOME?DAY 1?DAY 2?DAY 3DAY 4DAY 90?DAY 365?FIGURE 3. Consent algorithmPotential participantMeets eligibility criteriaParamedic assesses patient for capacityPatient has capacityPatient lacks capacityHOME or AMBULANCE?Paramedic explains trial*and asks for written informed consentRelative/ friend presentNo relative/friend presentParamedic explains trial* and asks for proxy consentParamedic provides proxy consent witnessed by another ambulance crew memberHandover from ambulance to hospitalResearcher assesses participant for capacityParticipant has capacityParticipant lacks capacityResearcher further explains trial and answers any further questions.Where appropriate, researcher asks for written informed consent for additional research.Researcher further explains trial **to relatives, answers any further questions and obtains proxy consent for continuation in study.Where appropriate, researcher asks for written informed consent for additional research from relative/ friend. If not present, the participant cannot take part in additional research.HOSPITAL?DAY 90?ENROLMENT AND TREATMENTConsent reconfirmed verbally***Researcher further explains trial**, answers any questions and obtains written consent for continuation in study.Where appropriate, researcher asks for written informed consent for additional research.Potential participantMeets eligibility criteriaParamedic assesses patient for capacityPatient has capacityPatient lacks capacityHOME or AMBULANCE?Paramedic explains trial*and asks for written informed consentRelative/ friend presentNo relative/friend presentParamedic explains trial* and asks for proxy consentParamedic provides proxy consent witnessed by another ambulance crew memberHandover from ambulance to hospitalResearcher assesses participant for capacityParticipant has capacityParticipant lacks capacityResearcher further explains trial and answers any further questions.Where appropriate, researcher asks for written informed consent for additional research.Researcher further explains trial **to relatives, answers any further questions and obtains proxy consent for continuation in study.Where appropriate, researcher asks for written informed consent for additional research from relative/ friend. If not present, the participant cannot take part in additional research.HOSPITAL?DAY 90?ENROLMENT AND TREATMENTConsent reconfirmed verbally***Researcher further explains trial**, answers any questions and obtains written consent for continuation in study.Where appropriate, researcher asks for written informed consent for additional research.* Using short information sheet/consent form** Using long information sheet and consent to continue form*** If participant contacted by post, return of questionnaires will represent consent to continue participation in the study ................
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