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 Experiment al Group aba + b Control Group cdC + 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 = NNT = 1/ARR = 20 TB No TBTotal Cont. Isoniazid Isoniazid 6 month

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).

Hypothetical Example: RCT to see the effect of Aspirin in incidence of Myocardial Re-infarction in patient with h/o MI. ARR by ITT = % % = 4.17% ARR by PP = 23% % = 6.34% ARR by AT = 21.25% % = 5% Re- infarctNo Re- infarct Total (adhere d to t/t) Aspirin 40 (5) (210) Placebo50 (4) (200)

References: Redmond C, Armitage P editors. Biostatics in Clinical Trials. 1 st ed. Sussex. John Wiley & Sons ltd p Haynes RB, Sacket DL, Guyat GH, Tugwell P. Clinical Epidemiology. 3 rd ed. Baltimore. Lippincott Williams & Wilkins p 95 & 116. Fletcher RW, Fletcher SW. Clinical Epidemiology: the essential. 4 th ed. Baltimore. Lippincott Williams & Wilkins p