Analysis of adverse events in titration studies. (Q5939495)

The modeling of the dose-adverse event relationship in clinical studies of drugs that must be titrated is complicated due to confounding dose escalation and exposure time effects. We analyze the dose-adverse events over time of hypotension-related adverse events (dizziness, hypotension, postural hypotension, syncope, vertigo) in placebo-controlled benign prostatic hyperplasia studies of terazosin using two different methods. The first method uses a Cox regression model with time-dependent covariates to evaluate the time-to-first event data. The second method uses a logistic regression model with parameters estimated using generalized estimating equations to analyze multiple events.NEWLINENEWLINE Doses were assigned to both placebo and terazosin patients according to the titration scheme in each study. Three combined titration-to-efficacy response studies (231 placebo, 230 terazosin patients) had a significant difference in the incidence of hypotension-related adverse events between placebo \((7.4\%)\) and terazosin \((21.7\%)\), however, they did not exhibit a significant difference between treatments in the rate of adverse events by dose. Applying these methods to a larger, longer duration titration to response study (1031 placebo, 1053 terazosin totals) produced similar results.