Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants.
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.
Eli Lilly Italia S.p.A., Neuroscience, Via A. Gramsci 731/733, 50019 Sesto Fiorentino, FI, Italy. Electronic address: mancini_michele@lilly.com.
Michele
M
Mancini
CPS Research, Glasgow, UK.
Alan G
AG
Wade
University of Pisa, Institute of Psychiatry, Pisa, Italy.
Giulio
G
Perugi
Lilly UK, Medical Department, Basingstoke, UK.
Alan
A
Lenox-Smith
Lilly Deutschland GmbH, Global Biostatistics, Bad Homburg, Germany.
Alexander
A
Schacht
D000328:Adult; D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000627:therapeutic use*; D016208:Databases, Factual; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011569:Psychiatric Status Rating Scales; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D017603:Signal Detection, Psychological; D013876:Thiophenes / Q000627:therapeutic use*; D055815:Young Adult
D000928:Antidepressive Agents; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride
Duloxetine; Effect size (ES); Hamilton Depression Rating scale (HAM-D); Major depressive disorder (MDD); Placebo; Signal detection