RCT Prof. dr. Davor Eterović EBM-2011/Klinička biostatistika.

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<ul><li><p>RCTProf. dr. Davor Eterovi EBM-2011/Klinika biostatistika</p></li><li><p>RCTT pokus dokazuje kauzalnostC kontrola male uinke razluuje od nule, vee mjeri ...R - bez omaki zbog randomskog usklaivanja</p></li><li><p>RCT: vrline i maneNajjai dizajn (najpouzdaniji zakljuci)Nezamjenjiv za male, ali vane efekte ali ponekad iTeko provodiv, kompliciran, skup Etiki dvojben Dvojbene primjenjivosti na praksu (netipini bolesnici, netipini tretmani, preintenzivno praenje) Zbog toga:Zahtijeva pilot pokus i detaljan protokol: obrazloena hipoteza, plan izvoenja i analize podataka i Hipoteza valja biti vrlo vjerojatna (etiki problem kontrola kod tekih ishoda; alternativa- nekontrolirani pokus)Veinom ne otkriva novo, ve potvruje/precizno evaluira, slijedi nakon opservacijskih istraivanja/nekontroliranih pokusa </p></li><li><p>Kako generirati slijed pridruivanjaJednostavna randomizacija (generator sluajnih brojeva)Koritenje blokova zbog podjednakih skupinaEksplicitna kontrola kovarijabli: stratifikacija ili minimizacija</p></li><li><p>Kako ne devalvirati randomizacijuZatajivanje pridruivanja (allocation concealment)- meta analize: vrlo vano, uvijek mogueMaskiranje ispitanika, medicinskog osoblja, statistiara; nekad nije mogueITT (intention-to-treat) analiza, rtvuje se eventualni lano negativan rezultat da se ne narui randomska usklaenost; za nuspojave ne, ve- PP (per protocol) analiza </p></li><li><p>Faze izvoenja RCT Nakon planiranja (pilot pokusa) i dobivanja doputenja</p><p>1. Izbor ispitanika2. Mjerenje karakteristika3. Randomizacija4. Intervencija5. Praenje (evaluacije) ishoda, mjerenja Slijedi izvjee, po strogim pravilima (CONSORT) </p></li><li><p>Kako izvijestiti rezultate RCT (1)CONSORT guidelinesDijagram tokaKarakteristike ispitne i kontrolne skupine: tablica 1. + komentar uspjeha randomizacije, razlike ne testirati formalno (no p-values in table 1!)Tablica 2: Jednostavni, neposredni rezultati ITT analize glavnih ishoda (x+-95%CI)Ako je suradljivost bila slaba i (ili) varirala izmeu skupina, ili ako je bilo dosta izgubljenih podataka, prikai i PP rezultate</p></li><li><p>Kako izvijestiti rezultate RCT (2)5. Ako randomizacija nije perfektna, prikai i usklaene rezultate: (a) kontinuirane varijable: ANOVA, multipla regresija (b) kategorije: Mantel-Haenszelov test (jedna kovarijabla) ili logistika regresija (vie kovarijabli), Poissonova regresija (za stope), Coxova regresija (preivljenje)6. Ako su planirane/opravdane, prikai i analize po podskupinama7. Prikai nuspojave i neeljene uinke (bez formalnog testiranja; PP prikaz)8. Analiziraj i (eventualne) sekundarne ishode </p></li><li><p>Simple 2-arm trialPatients are randomised to study or control group Study populationStudyControl (50%) (50%)</p><p>Can have n:m rather than 1:1 allocationE.g. 2:1 active:control</p></li><li><p>Why extend simple 2-arm RCT?#1: Compare &gt;1 interventionMay be the more ethical design Can be cheaper to do 1 trial investigating 2 interventions than two separate trials#2: simple RCTs exclude those patients with strong preferencesWith a chance of getting 1 of 2 interventions more subjects may be willing to be randomisedWith data on those unwilling to be randomised the trial may be more generalisable#3: Contamination of treatment effects?So instead of randomising a patient, randomise a family, or a GP surgery, or a hospital cluster randomisation</p></li><li><p>RCTs for more than one intervention</p><p>Multi-arm trials</p><p>Factorial designs</p><p>Crossover designs</p></li><li><p>Multi-arm trialSimplest extension to simple RCTPatients randomised to two or more study groups or control groupStudy population</p><p> Intervention 1Intervention 2Control (33%) (33%) (33%)</p></li><li><p>Multi-arm trial (2)Advantages:still simple to designallows head to head comparisonsDisadvantages:requires a larger overall sample size to achieve the same level of powerMultiple comparisonsrarely have power to detect significant differences between the interventions</p></li><li><p>Factorial design (1)Compares more than one intervention </p><p>Multiple layers of randomisation</p><p>Notation:2x2 - indicates 2 trts each with 2 levels2x2x2 - indicates 3 trts each with 2 levels</p><p>Fractional factorial designsMany treatments, patients get a selection</p></li><li><p>Factorial design (2) - 2x2 exampleVitamin D and/or calcium supplementation to prevent re-fracture (RECORD)</p><p>Calcium</p><p>Vitamin D</p><p>No</p><p>Yes</p><p>No</p><p>Placebo </p><p>(25%)</p><p>Calcium only (25%)</p><p>Yes</p><p>Vitamin D only </p><p>(25%)</p><p>Calcium and vitamin D</p><p> (25%)</p></li><li><p>Factorial designs (3)Advantages:reduced loss of power compared with multi-arm trialvery efficient - two trials for the price of oneallows possibility of exploring interaction effects</p><p>Disadvantages:requires no interaction between treatments for full power*more difficult to operationalise</p><p>* There are however studies with a factorial design which specifically anticipate an interaction</p></li><li><p>Crossover trialsUseful when studying patients with a chronic (long-term) diseaseAllows patients to receive both treatments sequentially patient acts as their own control</p><p>ABFirst period</p></li><li><p>Crossover trial - exampleRenal dialysis - each patient receives dialysis 3 times a weekTwo types of dialysis solution available - acetate and bicarbonateThought that bicarb may reduce nausea and other symptomsCrossover trial:each patient does a month on one solution followed by month on the otherfor each patient, the starting solution is assigned randomly</p></li><li><p>Crossover trialsAdvantages:requires fewer patients as each get both treatmentsbackground noise reduced as comparison is within-patientDisadvantages:must be no carryover effectWashout periods&gt; 2 periods?Loss to follow up can only be used for short term outcomes e.g. symptom controlrequires chronic and stable illness - patients require same level of illness for both treatments</p></li><li><p>Why extend simple RCT - reason 2Some RCTs compare very different treatments eg surgery vs. long term medication</p><p>Patients with strong preferences not willing to be randomised</p><p>Simple RCTs have to exclude those patients</p></li><li><p>Patient preference trialsIf patients have a strong preference for a therapy they get that therapyIf no strong preference, patients randomisedPrimary analysis still based on randomised groupsTwo studies a randomised study and an observational study</p></li><li><p>Patient preference trial - exampleTwo treatments for reflux disease:medical managementsurgical management</p><p>Four trial groups:prefer surgeryprefer medical randomised to surgeryrandomised to medical</p></li><li><p>Patient preference trialsAdvantages:recruitment maximisedmotivational factors maximised in the preference groupsmotivational factors equalised in the randomised groupsresults potentially more generalisable</p><p>Disadvantages:harder to analyse and possibly to interpret may be unequal distribution across the four trial groupsmore complex informed consent</p></li><li><p>Why extend a simple RCT - reason 3There is a worry that there will be contamination of treatments across patients eg trial comparing two dietary interventions - what if 2 members of same family randomised to different diets?Potential solution - randomise intact groups (families) rather than individuals</p></li><li><p>Cluster randomised trialIntact groups (known as clusters) rather than individuals randomised to each interventionUnit of randomisation should minimise risk of contamination eg family, practice, hospital ward</p></li><li><p>A cluster RCT</p></li><li><p>Cluster trials - issuesOutcomes within a group of patients, or cluster, may be more similar than those across clusters - they are no longer independentA statistical measure of this similarity within clusters is the intra-cluster correlationBecause patients not independent, study loses powerThe larger the intra-cluster correlation the larger the inflation required to the sample size to redress the loss of power </p></li><li><p>Cluster trialsAdvantages:minimises contamination between groupsmay be easier to organise practicallyDisadvantages:requires larger trialpatients within clusters not independentstandard analysis techniques not appropriate analysis more complex</p></li><li><p>Different model for randomisation (1)Standard procedure - get informed consent then randomise</p><p>Potential problems:patients may withdraw if they do not get the treatment they hoped forpatients may comply poorly if they get the control treatment - thinking the experimental treatment is better anyway</p></li><li><p>Different model for randomisation (2)Alternative approach - Zelens design:</p><p>randomise before obtaining consentonly seek consent from those randomised to experimental treatmentcontrol patients not approached for consent</p><p>Debate surrounds ethics of this approach - eg MRC do not accept this design as ethical</p></li><li><p>Zelens designAdvantages:does not raise hopes of a new treatment which can then be denied by randomisationmay avoid downward bias in those allocated to controlDisadvantages:ethics are debateable</p></li></ul>

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