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Fig. 1 | BMC Medical Research Methodology

Fig. 1

From: Drug*placebo interaction effect may bias clinical trials interpretation: hybrid balanced placebo and randomized placebo-controlled design

Fig. 1

Models of Positive and Negative Drug*Placebo Interaction Effect in Balanced Placebo and Conventional Randomized Placebo-Controlled Designs. a and b depict balanced placebo design. c and d depict conventional randomized placebo-controlled design. A positive drug*placebo interaction model is presented in a and c. A negative drug*placebo interaction model is presented in b and d. Hydroxyzine is used as the model drug. a & b Under the balanced placebo design, ooutcome measures in received placebo/told placebo represent none-specific passive changes (baseline); in received placebo/told hydroxyzine, placebo effect and baseline; in received hydroxyzine/told placebo, drug effect and baseline; and in received hydroxyzine/told hydroxyzine, drug, placebo, drug*placebo interaction effects, and baseline. The total effect of ingesting a hydroxyzine capsule is the difference between received hydroxyzine/told hydroxyzine and received placebo/told placebo and consists of drug, placebo, and drug*placebo interaction effects. The interaction model-estimated drug effect is the difference between received hydroxyzine/told placebo and received placebo/told placebo and consists of the drug effect only. The model predicts two different estimates of the placebo effect: placebo effect-1, the difference between received hydroxyzine/told hydroxyzine and received hydroxyzine/told placebo, which consists of the placebo and the drug*placebo interaction effects; and placebo effect-2, the difference between received placebo/told hydroxyzine and received placebo/told placebo, which consists of the placebo effect only. Placebo effect-1 is larger than placebo effect-2 if there is positive interaction effect (a) and smaller if there is negative interaction effect (b). c & d Under the conventional randomized placebo-controlled design, outcome measures in received hydroxyzine/told unknown represent the drug effect, part of the placebo effect (because of participants’ knowledge that there is 50% chance of receiving hydroxyzine) and consequently part of the drug*placebo interaction effect, and baseline; and in received placebo/told unknown, part of the placebo effect (because of participants’ knowledge that there is 50% chance of hydroxyzine) and baseline. Conventionally estimated drug effect is the difference between received hydroxyzine/told unknown and received placebo/told unknown and consists of the drug effect and part of the interaction effect. It is larger than the interaction model-estimated drug effect if there is positive interaction effect (compare a and c) and smaller if there is negative interaction effect (compare b and d)

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