Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials.

GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin, norepinephrine, and dopamine transporters. Two randomized, placebo- and active-controlled, double-blind studies examined the efficacy and safety of GSK372475 in outpatients (aged 18-64 years) with a diagnosis of major depressive episode associated with major depressive disorder (MDD). Patients were randomized 1:1:1 to placebo, GSK372475 (1-2 mg/d), or active control (Study 1: venlafaxine XR 150-225 mg/d; Study 2: paroxetine 20-30 mg/d). GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints (six-item Bech scale, IDS-Clinician Rated, MADRS) in either study. Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints. The most common adverse effects (AEs) with GSK372475 were dry mouth, headache, insomnia, and nausea. AEs were more frequent for GSK372475 versus placebo for sleep, anxiety-related, gastrointestinal, and tachycardia events. Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups. Completion rates were lower for GSK372475 (49%, 58%) compared with placebo (67%, 74%), venlafaxine XR (63%), or paroxetine (77%). GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies.

Modelling placebo response in depression trials using a longitudinal model with informative dropout.

Dropouts are common events in longitudinal studies in depression. Ignoring missing information may lead to biased and inconsistent assessment of study results. A non-linear model was recently developed to describe the time-course of HAMD-17 clinical score in the placebo arms of antidepressant clinical trials. In this paper we complemented this model by introducing an informative dropout component to jointly estimate HAMD-17 time-course and dropout mechanism. The aims of this work were to: (a) characterise typical placebo response in depression trials in presence of dropouts, (b) explore which dropout mechanism better describe the time-varying probability of a subject to dropout from the trial, and (c) define a framework for the development of clinical trial simulation in depression. A meta-analytic approach was used on placebo data collected in 6 clinical trials including 695 subjects suffering from Major Depressive Disorders. Alternative hypotheses for "missingness" were evaluated using different hazard models. The "Missing Not At Random" performed statistically (p<0.01) better than "Missing At Random", that in turn performed better (p<0.01) than "Missing Completely At Random" model. This finding provided new insights on the validity of the analyses currently used in many longitudinal clinical trials to support the registration of a new medicinal product.