Analyzing Randomized Control Trial: ITT vs. PP vs. AT

Proceedings from Journal club…..

Vikash

Basic Analysis of RCT:• To calculate:

– Relative Risk (RR)– Relative Risk Ratio (RRR)– Attributable Risk (AR)– Absolute Risk Reduction (ARR)– Number Needed to treat (NNT)

• For Time dependant analysis – Survival Analysis by Kaplan- Mier or by Cox

Proportional Model.• Then, Apply test of Significance.

• For Dichotomous Outcome:

• RR = ID (Exposed)/ ID (Unexposed) = a/a +b / c /c +D• RRR = 1 – RR• ARR = ID (Unexposed) - ID (Exposed)

Disease Present

Disease Absent

Total

Experimental Group

a b a + b

Control Group

c d C + d

• Attributable Risk = (OR – 1) PE / 1+ [ (OR-1) PE] x 100• Where OR = Odds Ratio = ad / bc

• Number Needed to treat (NNT) = 1/ARR

• RR = 0. 4 /0.5 = 0.8• RRR = 0.2• ARR = 0.2 – 0.25 = - 0.05• NNT = 1/ARR = 20

TB No TB Total

Cont. Isoniazid

40 160 200

Isoniazid 6 month

50 150 200

Intention to treat Analysis• Also called As randomized or Method Effectiveness

analysis.• Compare outcome according to the randomized group

(Gold Standard).• Adherence to intervention not necessary.

Advantages:• Randomization is maintained:

– Treatment assignment is based on chance alone.– Randomization provides Theoretical foundation for

Statistical test of significance. Disadvantages:

– Doesn’t take into account Protocol violation.

• Group may not be comparable at the end.– Not adhering to treatment or vice versa.– Eligibility for the trial was incorrect.– Loss to follow up.

• Estimates of non – complied in the efficacy dilutes difference between groups.

• Analysis may underestimate adverse effect.

Why gold standard ?

• Randomization is maintained• Difficulty in defining compliance.• Effect in complied group may be due to factor of

compliance.

Per Protocol Analysis:

• Analyze only those who fully complied to protocol.• Doesn’t included cross- over in final analysis.• Provides fair idea of efficacy for treatment.• May be Biased (randomization compromised)

As treated Analysis:

• Subject analyzed according to treatment taken or not. (no relation with randomization).• Non compliant from treatment and vice versa analyzed

accordingly.• AT is shown if ITT shows no effect ( why trial done).

InterventionGroup

ControlGroup

Randomize

GotTreatment

Did NOT gettreatment

GotTreatment

Did NOT gettreatment

YESYES NO NOInterntion-to-Treat

YES

YES

DROP

NO

DROP

YES

NO

NO

Per protocol

As Treated

• Hypothetical Example: RCT to see the effect of Aspirin in incidence of

Myocardial Re-infarction in patient with h/o MI.

• ARR by ITT = 20.833% - 16.66% = 4.17%• ARR by PP = 23% - 16.66% = 6.34%• ARR by AT = 21.25% - 16.25% = 5%

Re- infarct No Re-infarct

Total (adhered to t/t)

Aspirin 40 (5) 200 240 (210)Placebo 50 (4) 190 240 (200)

References:• Redmond C, Armitage P editors. Biostatics in Clinical

Trials. 1st ed. Sussex. John Wiley & Sons ltd. 2001. p243- 6.

• Haynes RB, Sacket DL, Guyat GH, Tugwell P. Clinical Epidemiology. 3rd ed. Baltimore. Lippincott Williams & Wilkins.2006. p 95 & 116.

• Fletcher RW, Fletcher SW. Clinical Epidemiology: the essential. 4th ed. Baltimore. Lippincott Williams & Wilkins. 2005. p 136-9.