Abstract
PurposeRun‐in periods are used to identify placebo‐responders and washout. Our aim was to assess the association of run‐in periods with clinical outcomes of antipsychotics in dementia.MethodsWe searched randomized placebo‐controlled trials of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia in electronic sources and references of selected articles. We extracted (a) the presence of a run‐in period, use of placebo/investigated drug during run‐in (versus washout only), and run‐in duration (1 week or more) and (b) the reduction in NPS, number of participants with somnolence, extrapyramidal symptoms (EPS), and deaths per treatment group. We pooled clinical outcomes comparing antipsychotic and placebo groups in trials with and without run‐in.ResultsWe identified 35 trials. Twenty‐nine trials used run‐in. The pooled standardized mean difference in the reduction of NPS was −0.170 (95% CI, −0.227 to −0.112) in trials with run‐in and −0.142 (95% CI, −0.331 to 0.047) in trials without run‐in. The pooled odds ratio for somnolence was 2.8 (95% CI, 2.3‐3.5) in trials with run‐in and 3.5 (95% CI, 1.2‐10.7) in trials without run‐in; for EPS, these ORs were 1.8 (95% CI, 1.4‐2.2) and 2.0 (95% CI, 1.3‐3.1) respectively, and for mortality 1.4 (95% CI, 1.0‐2.0) and 1.6 (95% CI, 0.7‐3.4). The use of placebo/investigated drug during run‐in and run‐in duration did not affect the estimates in a consistent way.ConclusionsThe use of run‐in in trials might have led to overestimated efficacy and especially underestimated risks of side effects of antipsychotics compared with placebo for NPS in dementia.
Highlights
Results of randomized controlled trials are important for regulatory and clinical decisions
If the standard deviation (SD) was not reported, it was calculated with the P value, range, or confidence interval reported for the difference in mean change
We identified 45 eligible RCTs, but four did not report whether a run-in period was used, four did not report any of the outcomes of interest, and two were ongoing
Summary
Results of randomized controlled trials are important for regulatory and clinical decisions. Researchers have sought to optimize treatment effects and identify patients that will benefit most from treatment. One way of enhancing trial design is using a run-in period between screening for eligibility and before randomization.[1,2] During this period of usually 1 to 2 weeks, drugs that the eligible patients already used are washed out. The drugs are replaced by placebo to blind the participants for the change in treatment. Patients with high placebo response, poor compliance, low treatment response, or intolerance for the drug can be identified.[3,4] At the end of the run-in phase, the researchers select the participants that are definitively included in the study. It is assumed that a run-in period will decrease placebo response and dropout during the trial and increase the effect size and the power of a trial.[5,6]
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