Sas application for pharmacokinetic evaluation and analysis of the effect of treatment with a new antidepressant drug in a population with major depression

A phase 2, double-blind, outpatient, randomized, fixed dose, placebo-controlled, parallel design study was conducted in 1998 at the Charter Hospital, Feighner Research Institute in San Diego, CA. Drug was administered subcutaneously once/day in two 5-day treatment cycles (from Monday to Friday) separated by two non-treatment days (Saturday and Sunday). Subjects meeting the entry criteria for major depression were randomly assigned to three treatment groups to receive either two cycles of drug, or one cycle of drug followed by the second cycle with placebo, or both cycles with placebo. The objective of the study was to evaluate tolerability, the safety profile and the effect of a second cycle of treatment versus placebo and versus the first cycle of treatment. Pharmacokinetic analysis, based on concentrations of drug in plasma, was used to evaluate the results. Requirements for enrollment included the following values for the psychometric tests at screening: 21-items Hamilton Depression Rating Scale (HAMD) >20, Carroll Self-Rating Depression Scale (CSRS) >18, and Global Impression Scale (Severity of Illness) >4. In addition Montgomery-Asberg Depression Rating Scale (MADR) and Visual Analog Scale (VAS) for mood, anxiety and mental clarity were used for efficacy evaluation. After two cycles of treatment, subjects had a 4-week follow-up period with one visit per week for clinical observation. Response to treatment was defined as 50% change (decrease) in HAMD from baseline. Plasma concentrations of INN 00835 were measured at 15 min., 30 min., and 1 hour after dosing. The highest observed Cmax from each subject treated with drug was selected to calculate a Minimum Projected Therapeutic Concentration (MPTC) as a mean of Cmax over population. The most relevant timepoints for the statistical analysis were Day 6 or Day 8 after enrollment effect of the first cycle of treatment, Day 13 effect of two cycles, and Day 19 (a week after the end of the treatment), when the peak effect was predicted. All statistical hypothesis assumed a significance level of 0.05 using two-tailed tests.