LECTURE 13 2011

LECTURE 13 2011 - Common Designs for Controlled Clinical...

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Common Designs for Controlled Clinical Trials A. Parallel Group Trials 1. Simplest example - 2 groups, no stratification 2. Stratified design 3. Matched pairs 4. Factorial design B. Crossover Trials
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Parallel Group Design y ij = μ+ T i + e ij μ= overall mean T i = effect of i th treatment (i = A,B) e ij = error term for j th patient in i th group e ij ~ N(0, σ 2 ) y ij ~ N ( μ+ T i , 2 ) 2 = σ s 2 + e 2
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Diastolic BP (mmHg) 58 36 94 0.62 Serum cholesterol 1200 400 1600 0.75 (mg/dl) Viral load 0.16 0.09 0.25 0.64 (log 10 copies/mL) Overnight urine 325 625 950 0.34 excretion of Na + (meq/L) Carbohydrate intake 110 208 318 0.35 (% of calories) Estimates of σ and σ for Selected Response Variables 2 s 2 e 2 e σ 2 s σ 2 e σ 2 s σ 2 e σ 2 s σ + + ( 29 Total 2 s σ
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“Crossover” Trial (Also “Changeover” or Switchover”) 2n patients Drug A Drug B . . . or or Low Dose Low Dose
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Two-Period Crossover Trial 2n - Randomize Patients Drug A Drug B Drug B Drug A W A S H O U T 1 2 Period n n
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Schematic design of study to determine effects of dietary sodium on blood pressure in normotensive adults Low Sodium Diet -8 0 4 6 10 Weeks Group I (n=25) Group II (n=23) 100 mEq NaCI Placebo 100 mEq NaCI Placebo WASH-OUT SNaP
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Crossover Trial Advantages : Fewer patients required in most situations due to elimination of between subject component of variability, therefore: recruitment may be easier can be more easily done in single center fewer patients exposed to experimental treatment Less data collection Disadvantages : Interaction due to: differential carry-over effects of treatments treatment x period interaction differences between the two randomized groups (AB and BA) at baseline Patients must be observed longer Losses to follow-up/missing data Naturally occurring changes in underlying disease state
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Situations where crossover design is most applicable: 1. Rapid response and response is transitory 2. Variability between patients is large compared to variability within patients 3. Steady state physiological condition; disease or condition cannot be cured 4. No residual or carry-over effects of treatment expected
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General Model for 2-Period Crossover Trial y ijk = μ + π k + T u + λ v + γ ij + ε ijk = overall mean k = effect of kth period (k = 1, 2) T u = effect of uth treatment (u = A, B) (direct effect) v = residual effect of treatment given in first period on second period response (v = A, B) ( = 0 for first period measurements, i.e., when k = 1) Hills and Armitage Br J Clin Pharmac 1979; 8:7-20. Senn Stat Methods Med Res 1994;3:303-324.
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LECTURE 13 2011 - Common Designs for Controlled Clinical...

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