1. Prof. dr. Davor Eterović EBM-2011/Klinička biostatistika
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. Multi-arm trial (2) 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

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. Factorial designs (3) 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
* There are however studies with a factorial design which specifically anticipate an interaction

17. 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 B A
Second 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. Crossover trials 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

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. Patient preference trials
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

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. A cluster RCT
Randomise Providers
Control
Experimental

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. Cluster trials 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

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. Zelen’s design 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