RCT

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

2. RCT • T –pokus dokazuje kauzalnost • C –kontrola male učinke razlučuje od nule, veće mjeri ... • R - …bez omaški zbog randomskog usklađivanja

3. RCT: vrline i mane • Najjači dizajn (najpouzdaniji zaključci) • Nezamjenjiv za male, ali važne efekte ali ponekad i • Teško provodiv, kompliciran, skup • Etički dvojben • Dvojbene primjenjivosti na praksu (netipični bolesnici, netipični tretmani, preintenzivno praćenje) Zbog toga: • Zahtijeva pilot pokus i detaljan protokol: obrazložena hipoteza, plan izvođenja i analize podataka i • Hipoteza valja biti vrlo vjerojatna (etički problem kontrola kod teških ishoda; alternativa- nekontrolirani pokus) • Većinom ne otkriva novo, već potvrđuje/precizno evaluira, slijedi nakon opservacijskih istraživanja/nekontroliranih pokusa

4. Kako generirati slijed pridruživanja • Jednostavna randomizacija (generator slučajnih brojeva) • Korištenje blokova zbog podjednakih skupina • Eksplicitna kontrola kovarijabli: stratifikacija ili minimizacija

5. Kako ne devalvirati randomizaciju • Zatajivanje pridruživanja (allocation concealment)- meta analize: vrlo važno, uvijek moguće • Maskiranje ispitanika, medicinskog osoblja, statističara; nekad nije moguće • ITT (intention-to-treat) analiza, žrtvuje se eventualni lažno negativan rezultat da se ne naruši randomska usklađenost; za nuspojave ne, već- PP (per protocol) analiza

6. Faze izvođenja RCT Nakon planiranja (pilot pokusa) i dobivanja dopuštenja 1. Izbor ispitanika 2. Mjerenje karakteristika 3. Randomizacija 4. Intervencija 5. Praćenje (evaluacije) ishoda, mjerenja Slijedi izvješće, po strogim pravilima (CONSORT)

7. Kako izvijestiti rezultate RCT (1) • CONSORT guidelines • Dijagram toka • Karakteristike 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 između skupina, ili ako je bilo dosta izgubljenih podataka, prikaži i PP rezultate

8. Kako izvijestiti rezultate RCT (2) 5. Ako randomizacija nije perfektna, prikaži i usklađene rezultate: (a) kontinuirane varijable: ANOVA, multipla regresija (b) kategorije: Mantel-Haenszelov test (jedna kovarijabla) ili logistička regresija (više kovarijabli), Poissonova regresija (za stope), Coxova regresija (preživljenje) 6. Ako su planirane/opravdane, prikaži i analize po podskupinama 7. Prikaži nuspojave i neželjene učinke (bez formalnog testiranja; PP prikaz) 8. Analiziraj i (eventualne) sekundarne ishode

9. Simple 2-arm trial • Patients are randomised to study or control group Study population Study Control (50%) (50%) • Can have n:m rather than 1:1 allocation • E.g. 2:1 active:control

10. Why extend simple 2-arm RCT? • #1: Compare >1 intervention • May 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 preferences • With a chance of getting 1 of 2 interventions more subjects may be willing to be randomised • With 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

11. RCTs for more than one intervention • Multi-arm trials • Factorial designs • Crossover designs

12. Multi-arm trial • Simplest extension to simple RCT • Patients randomised to two or more study groups or control group Study population Intervention 1 Intervention 2 Control (33%) (33%) (33%)

13. Advantages: still simple to design allows head to head comparisons Disadvantages: requires a larger overall sample size to achieve the same level of power Multiple comparisons rarely have power to detect significant differences between the interventions Multi-arm trial (2)

14. Factorial design (1) • Compares more than one intervention • Multiple layers of randomisation • Notation: • 2x2 - indicates 2 trts each with 2 levels • 2x2x2 - indicates 3 trts each with 2 levels • Fractional factorial designs • Many treatments, patients get a selection

15. Factorial design (2) - 2x2 example • Vitamin D and/or calcium supplementation to prevent re-fracture (RECORD)

16. Advantages: reduced loss of power compared with multi-arm trial very efficient - ‘two trials for the price of one’ allows possibility of exploring interaction effects Disadvantages: requires no interaction between treatments for full power* more difficult to operationalise Factorial designs (3) * There are however studies with a factorial design which specifically anticipate an interaction

17. Second period B A Crossover trials • Useful when studying patients with a chronic (long-term) disease • Allows patients to receive both treatments sequentially • “patient acts as their own control” First period A B

18. Crossover trial - example • Renal dialysis - each patient receives dialysis 3 times a week • Two types of dialysis solution available - acetate and bicarbonate • Thought that bicarb may reduce nausea and other symptoms • Crossover trial: • each patient does a month on one solution followed by month on the other • for each patient, the starting solution is assigned randomly

19. Advantages: requires fewer patients as each get both treatments background “noise” reduced as comparison is within-patient Disadvantages: must be no “carryover” effect Washout periods > 2 periods? Loss to follow up can only be used for short term outcomes e.g. symptom control requires chronic and stable illness - patients require same level of illness for both treatments Crossover trials

20. Why extend simple RCT - reason 2 • Some RCTs compare very different treatments eg surgery vs. long term medication • Patients with strong preferences not willing to be randomised • Simple RCTs have to exclude those patients

21. Patient preference trials • If patients have a strong preference for a therapy they get that therapy • If no strong preference, patients randomised • Primary analysis still based on randomised groups • Two studies – a randomised study and an observational study

22. Patient preference trial - example • Two treatments for reflux disease: • medical management • surgical management • Four trial groups: • prefer surgery • prefer medical • randomised to surgery • randomised to medical

23. Advantages: recruitment maximised motivational factors maximised in the preference groups motivational factors equalised in the randomised groups results potentially more generalisable Disadvantages: harder to analyse and possibly to interpret may be unequal distribution across the four trial groups more complex informed consent Patient preference trials

24. Why extend a simple RCT - reason 3 • There 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

25. Cluster randomised trial • Intact groups (known as clusters) rather than individuals randomised to each intervention • Unit of randomisation should minimise risk of contamination eg family, practice, hospital ward

26. Randomise Providers Control Experimental A cluster RCT

27. Cluster trials - issues • Outcomes within a group of patients, or cluster, may be more similar than those across clusters - they are no longer ‘independent’ • A statistical measure of this similarity within clusters is the intra-cluster correlation • Because patients not independent, study loses power • The larger the intra-cluster correlation the larger the inflation required to the sample size to redress the loss of power

28. Advantages: minimises contamination between groups may be easier to organise practically Disadvantages: requires larger trial patients within clusters not independent standard analysis techniques not appropriate analysis more complex Cluster trials

29. Different model for randomisation (1) • Standard procedure - get informed consent then randomise • Potential problems: • patients may withdraw if they do not get the treatment they hoped for • patients may comply poorly if they get the control treatment - thinking the experimental treatment is better anyway

30. Different model for randomisation (2) • Alternative approach - Zelen’s design: • randomise before obtaining consent • only seek consent from those randomised to experimental treatment • ‘control’ patients not approached for consent • Debate surrounds ethics of this approach - eg MRC do not accept this design as ethical

31. Advantages: does not raise hopes of a new treatment which can then be denied by randomisation may avoid downward bias in those allocated to ‘control’ Disadvantages: ethics are debateable Zelen’s design