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    linical trials inlinical trials introke an overviewtroke an overviewr Melvin George

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    IntroductionIntroduction

    v Stroke remains a leading cause of death.and disability worldwide

    v Recombinant tissue plasminogen activator( ) -rtPA in acute ischemic stroke has

    improved the clinical outcome ofpatients who present early after onset

    .of symptoms

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    linical trials inlinical trials instroketroke Acute ischemic stroke trials

    Acute hemorragic stroke trials

    Stroke Prevention trials

    Stroke rehabilitation trials

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    Acute ischemic stroke trialsAcute ischemic stroke trials

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    A randomized controlled trialof antiplatelet therapy in

    -combination with rt PA :thrombolysis in ischemic stroke

    rationale and design of the

    -ARTIS Trial

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    Hypotheses:Hypotheses:

    Immeditate addition of antiplateletImmeditate addition of antiplatelettherapy to rt-PA in acute ischemictherapy to rt-PA in acute ischemic

    stroke improves outcome by enhancingstroke improves outcome by enhancingclot lysis and preventing re-occlusionclot lysis and preventing re-occlusionafter initial recanalisation.after initial recanalisation.

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    Primary objectivePrimary objective

    To investigate whether theaddition of aspirin to standard

    -rt PA thrombolysis reduces poor

    outcome in acute ischemic.stroke

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    v o o r o u t c o m e i s d e f i n e d a s d e a t ho o r o u t c o m e i s d e f i n e d a s d e a t hr d e p e n d e n c y a s s e s s e d b y t h er d e p e n d e n c y a s s e s s e d b y t h e( ,o d i f i e d R a n k i n S c a l e m R S s c o r e( ,o d i f i e d R a n k i n S c a l e m R S s c o r e- ) - .6 a t 3 m o n t h s f o l l o w u p) - .6 a t 3 m o n t h s f o l l o w u p

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    ankin scoreankin scorev Most widely used clinical outcome

    .measure for stroke clinical trialsvv It was originally introduced in 1957 by

    Rankin

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    Modified Rankin ScoreModified Rankin Score(mRS)(mRS)

    corecore escriptionescription0 o symptoms at allo symptoms at all1 ;o significant disability despite symptoms able;o significant disability despite symptoms ableo carry out all usual duties and activitieso carry out all usual duties and activities2 ;light disability unable to carry out all;light disability unable to carry out all,revious activities but able to look after own,revious activities but able to look after ownffairs without assistanceffairs without assistance3 ; ,oderate disability requiring some help but able; ,oderate disability requiring some help but ableo walk without assistanceo walk without assistance4 ;oderately severe disability unable to walk;oderately severe disability unable to walkithout assistance and unable to attend to ownithout assistance and unable to attend to ownodily needs without assistanceodily needs without assistance5 ; ,evere disability bedridden incontinent and; ,evere disability bedridden incontinent andequiring constant nursing care and attentionequiring constant nursing care and attention6 Deadead

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    Inclusion criteriaInclusion criteria

    . -ge 18 80 years. atients with acute ischemic stroke3.Exclusion crit eriaExclusion crit eria

    1. nown antiplatelet therapy in the previous(days in

    ase of uncertainty the patient may be);ncluded

    . nown thrombocytopenia

    . -nown contra indications to acetylsalicylic;cid treatment

    . nown anticogualant therapy in the previous 5

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    Recommendations forRecommendations forrtPArtPA

    q Diagnosis of ischemic stroke causingmeasurable neurological deficit

    q Neurological signs should not beclearing spontaneously

    q Neurological signs should not be minorand isolated

    q Symptoms not suggestive of intracerebralhaemorrhage

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    Recommendations forRecommendations forrtPArtPA

    q

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    Recommendations forRecommendations forrtPArtPA

    q No evidence of active bleedingq Not taking anticoagulantq ,If on heparin aPTT must be in normal

    range

    q > /Blood glucose 50 mg dlq >Platelet count 100 000 mm3

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    Recommendations forRecommendations forrtPArtPA

    q CT does not show multilobar infarction(hypodensity greater than one third of

    )cerebral hemisphere

    q No seizure with residual neurologic deficitq ( >Blood pressure not elevated systolic 185

    > )mm Hg and diastolic 110 mm Hgq The patient or family members understand

    the potential risks and benefits from.treatmentq

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    RandomizationRandomization

    andomisation procedure will beandomisation procedure will be- ,omputer and web based using,omputer and web based using.ermuted blocks.ermuted blocks andomisation will be stratifiedandomisation will be stratifiedyy

    ,entre,entre ( , > ),ge 60 years 60 years( , > ),ge 60 years 60 years genderender ime between symptom onset and timeime between symptom onset and time- (< , -f rt PA bolus 2 hours 2 3- (< , -f rt PA bolus 2 hours 2 3, > ).ours 3 hours> ).ours 3 hours

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    Aspirin will be administered within 1.5hours after the rt-PA bolus.

    Patient and treating physician are notblinded for treatment allocation.

    Why Aspirin intravenously?

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    Treatment of acute ischemicTreatment of acute ischemicstrokestroke

    . / ( )nfuse 0 9 mg kg maximum dose 90 mg over 60 minutes%ith 10 of the dose given as a bolus over 1.inute

    dmit the patient to an intensive care or stroke.nit for monitoring

    erform neurological assessments every 15 minutesuring the infusion and every 30 minutes

    ,hereafter for the next 6 hours then hourly.ntil 24 hours after treatment ,f the patient develops severe headache acute

    , , ,ypertension nausea or vomiting discontinue the( )nfusion if rtPA is being administered and

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    Blood pressure should not belowered with medication prior to

    - .rt PA treatment

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    Rescue therapyRescue therapy

    - , >If during rt PA administration SBP 180> ,mmHg or DBP 105 mmHg administer 10

    - .mg labetalol iv in 1 2 minutes

    -Repeat every 10 20 minutes until bloodpressure is below 180 mmHg systolic or

    .below 105 mmHg diastolic

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    Rescue therapyRescue therapy

    150 mg labetalol is the maximum dose in.24 hours

    During this treatment blood pressure

    .should be measured every 15 minutes If the blood pressure does not respond

    , . -to labetalol iv nitroprusside 0 5 10/ / ,g kg minute should be added with

    .continuous blood pressure monitoring

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    All medication used before the stroke,may be continued except

    .anticoagulants Simvastatin dipyridamole

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    OUTCOME MEASURESOUTCOME MEASURES

    The primary endpoint is poor functionalhealth at 3 months defined as

    ( - ).dependency or death mRS 3 6

    difi d ki

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    Modified Rankin ScoreModified Rankin Score(mRS)(mRS)

    corecore escriptionescription0 o symptoms at allo symptoms at all1 ;o significant disability despite symptoms able;o significant disability despite symptoms ableo carry out all usual duties and activitieso carry out all usual duties and activities2 ;light disability unable to carry out all;light disability unable to carry out all,revious activities but able to look after own,revious activities but able to look after ownffairs without assistanceffairs without assistance3 ; ,oderate disability requiring some help but able; ,oderate disability requiring some help but ableo walk without assistanceo walk without assistance4 ;oderately severe disability unable to walk;oderately severe disability unable to walkithout assistance and unable to attend to ownithout assistance and unable to attend to ownodily needs without assistanceodily needs without assistance5 ; ,evere disability bedridden incontinent and; ,evere disability bedridden incontinent andequiring constant nursing care and attentionequiring constant nursing care and attention6 Deadead

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    v rimary outcome will be assessed by a blindesearch nurse from the clinical trial

    ,ffice of the coordinating centre whoill score the mRS by telephone using a

    .tructured interview

    v -o increase the inter observer reliabilityhe number of research nurses will be

    .imited to a maximum of three

    S dS d t

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    Secondary outcomeSecondary outcomemeasuresmeasures

    v Complications within 48 hours after randomisationincluding the occurrence of SICH and serious

    .systemic bleeding

    v SICH is defined as -CT documented haemorrhage Clinical deterioration leading to 4 or more

    points increase on the National Institute of( )Health Stroke Scale NIHSS as compared to

    .the best score on the NIHSS since admission

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    What is the NIHSS?What is the NIHSS?

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    Secondary outcomeSecondary outcomemeasuresmeasures

    neurological symptoms quantified by the NIHSS 7 -10 days after randomisation or at discharge if the

    patient is discharged within 7 days;

    survival at 3 months;

    disability at 3 months assessed by the AMC Linear

    Disablility Scale

    functional health at 3 months non-dichotomized(ordinal mRS);

    causes of poor outcome

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    Data collectionData collection

    Age,

    sex,

    ethnicity,

    medical history,

    pre-stroke medication,

    pre-stroke mRS,

    blood pressure,

    Glasgow Coma Scale (GCS),

    National Institutes of Health Stroke Scale (NIHSS),

    time of symptom onset,

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    v -Baseline CT scans will be collected from

    participating centres and assessed

    blindly centrally at the coordinatingcentre by an independent blinded

    - .neuro radiologist

    v

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    - ,At follow up neurological deficits are- .assessed by the NIHSS at 7 10 days

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    SAESAE

    ,Clinical deterioration defined as a 4 or,more points increase on the NIHSS

    -will be followed by CT scan and

    ( )registration as serious adverseevents including possible cause by.each participating site

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    All adverse event reported by the subjects

    or observed by the treating physicians

    .will be recorded

    ( ),In case of serious adverse events SAE the

    principal investigator will be notified

    .by email or telephone within 24 hours

    The principal investigator subsequently

    reports SAE to the Data Safety Monitoring

    ( ).Board DSMB

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    DSMBDSMB

    safety surveillances

    recommend the Steering Committee toterminate the trial if clear evidence

    .of harm

    unblinded

    interim analysis on the

    primary outcome to assess the strengthof the efficacy data

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    DecisionsDecisions

    :Possible decisionsContinue with trial as planned

    :Stop safety problem

    :Stop efficacy established: (Stop new knowledge usually from other trials

    )suggesting risks: .Stop futile Trial unlikely to show a result

    Modify trial design

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    Haemorragic stroke trialHaemorragic stroke trial

    To evaluate the safety and

    effectiveness of lowering blood

    pressure using nicardipine in personswith acute hypertension associated

    .with intracerebral hemorrhage

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    Inclusion criteriaInclusion criteria

    .Age older than 18 years Onset of new neurological signs of a

    stroke within 12 hours of the time to

    evaluation AND initiation of treatment.with intravenous nicardipine Clinical signs consistent with the

    ,diagnosis of stroke including

    , ,impairment of language motor function, / , ,cognition and or gaze vision or.neglect

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    Inclusion criteriaInclusion criteria

    he total GCS score is greater than 8 at the time of.nrollment

    T scan demonstrates intraparenchymal hematoma with.anual hematoma volume measurement less than 60 cc

    ,CH is supratentorial and is located in lobar basal,anglionic or thalamic based on the initial CT scan.ppearance

    dmission systolic blood pressure greater than 170 mmg on two repeat measurements at least 5 minutes.part

    .vidence of chronic hypertension ubject is not considered a surgical candidate by the

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    AVERTAVERTA Very Early RehabilitationA Very Early Rehabilitation

    TrialTrial

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    To determine if very early mobilization( )VEM of stroke patients in addition to

    standard care compared to standard

    ( )care SC alone is more effective in, ,lowering mortality disability andseverity of complications at 3 months

    and at improving quality of life at 12

    .months

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    :Primary Outcome

    .Modified Rankin Score at 3 months

    Secondary outcome

    .barthel pdf

    ARISTOTLEARISTOTLE

    http://smb//tmp/svpf5.tmp/barthel.pdfhttp://smb//tmp/svpf5.tmp/barthel.pdfhttp://smb//tmp/svpf5.tmp/barthel.pdf
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    ARISTOTLEARISTOTLE

    APIXABAN FOR THEPREVENTION OF STROKE INSUBJECTS WITH ATRIAL

    FIBRILLATION

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    ,s a p i x a b a n a n i n v e s t i g a t i o n a l,s a p i x a b a n a n i n v e s t i g a t i o n a ln t i c o a g u l a n t i s a s e f f e c t i v e a sn t i c o a g u l a n t i s a s e f f e c t i v e a s( )t a n d a r d t h e r a p y w a r f a r i n i n( )t a n d a r d t h e r a p y w a r f a r i n i nr e v e n t i n g s t r o k e a n d s y s t e m i cr e v e n t i n g s t r o k e a n d s y s t e m i cm b o l i s m i n s u b j e c t s w i t h a t r i a lm b o l i s m i n s u b j e c t s w i t h a t r i a li b r i l l a t i o n a n d r i s k f a c t o r s f o ri b r i l l a t i o n a n d r i s k f a c t o r s f o rt r o k e ?t r o k e ?

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    Inclusion CriteriaInclusion Criteria

    Males and females 18 yrs with AF one or more of the following risk

    :factors for stroke

    ,Age 75 ,previous stroke ,TIA or Systemic Embolism symptomatic congestive heart failure or left ventricular dysfunction with LVEF

    %,40 diabetes mellitus or hypertension requiring pharmacological

    .treatment

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    :r i m a r y O u t c o m e :r i m a r y O u t c o m e onfirmed stroke or systemiconfirmed stroke or systemic. (mbolism time to first(mbolism time to first)ccurrence)ccurrence

    :e c o n d a r y O u t c o m e :e c o n d a r y O u t c o m e ,onfirmed ischemic stroke,onfirmed ischemic stroke,emorrhagic stroke systemic,emorrhagic stroke systemic, . (mbolism all cause death time to. (mbolism all cause death time to)irst occurrence)irst occurrence

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    -eath primary outcome in some.troke trials Problems

    voiding dependency is moremportant to stroke patients than.ying eath is inefficient statistically- nly a minority of patients inost trials

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    ConclusionConclusion

    Numerous trials in acute strokehave been performed

    Few advances made

    Sound knowledge of methodology

    of trials can supplement thescientific progress in basicresearch.

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