Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants |
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Affiliation: | 1. Eli Lilly Italia S.p.A., Neuroscience, Via A. Gramsci 731/733, 50019 Sesto Fiorentino, FI, Italy;2. CPS Research, Glasgow, UK;3. University of Pisa, Institute of Psychiatry, Pisa, Italy;4. Lilly UK, Medical Department, Basingstoke, UK;5. Lilly Deutschland GmbH, Global Biostatistics, Bad Homburg, Germany |
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Abstract: | An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was −0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (−0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (−0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (−0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy. |
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Keywords: | Effect size (ES) Major depressive disorder (MDD) Hamilton Depression Rating scale (HAM-D) Placebo Signal detection Duloxetine |
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