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Table 3 Design adjustments used to manage and understand placebo effects in trials for neuropsychiatric symptoms and syndromes

From: New approaches to symptomatic treatments for Alzheimer’s disease

Design Adjustment Purpose
Placebo lead-in Exclude patients who no longer meet trial entry criteria after 2 weeks of placebo treatment
Identify non-adherent patients whose participation in the trial would reduce power to observe a drug-placebo difference
Pre-randomization psychosocial intervention Exclude patients who no longer meet trial entry criteria after 1–2 weeks of psychosocial treatment
Participants meet entry criteria at screening and baseline Reduce chance of score improvement by regression to the mean
Central review of scales whose scores determine entry to the trial More reliable review of the data with fewer site influences
Patients have at least moderately severe symptoms at screening and randomization More severe symptoms are less likely to respond to placebo
Longer trials of 12 to 24 weeks Placebo responses are often greatest at study onset and become gradually less marked
Two-arm design with 1:1 randomization Placebo responses are higher in trials with several active treatment arms
Sequential parallel comparison design (SPCD) 2nd stage of the SPCD has only placebo non-responders in the placebo (and active) arm of the trials
Randomized discontinuation design All participants are on active treatment in the first period of the trial; only responders to active therapy are randomized to drug or placebo