ABSTRACT
This paper investigates the use of a general multi-arm multi-stage (MAMS) approach for time-to-event outcomes that would streamline simultaneous comparison of a large number of promising therapies in clinical trials, thus significantly reducing the time and the number of patients needed to evaluate the treatment. Controlling type I error in this setting is different than regular clinical trials as this approach incorporates both multiple comparison between arms and multiple stages. Historically, pairwise (PWER) and familywise (FWER) type I error rates have been primarily used to regulate the type I error in such designs. This paper will focus on constructing the efficacy and futility boundaries for a MAMS clinical trial in two different scenarios. In the first, it is assumed that the same outcome is used throughout the clinical trial for both intermediate and final assessments. In this scenario, we propose using the generalized Dunnett procedure that controls FWER. In the latter scenario, where intermediate and final outcomes are different in nature, we propose modifications to the existing method that originally concentrated on controlling PWER and extend the method to include FWER in the design. We also explore the performance of the proposed MAMS design in a setting where the proportional hazard assumption is violated in the presence of a delayed treatment effect and demonstrate the loss of power because of that. An alternative test statistic that can help circumvent this problem to maintain the desired power is also suggested.
Subject(s)
Medical Futility , Research Design , HumansABSTRACT
BACKGROUND: While often grouped with other noise aversions, fearful behaviour during storms is considered more complex than noise aversion alone. The objective here was to assess the effect of imepitoin for the treatment of storm anxiety in dogs. METHODS: In this double-blind, placebo-controlled randomised study, eligible dogs completed a baseline then were randomised to receive either imepitoin (n = 30; 30 mg/kg BID) or placebo (n = 15) for 28 days. During storms, owners rated their dog's intensity for 16 behaviours using a Likert scale. Weekly, owners rated intensity and frequency of these behaviours. Summary scores were compared to baseline and between groups. RESULTS AND CONCLUSIONS: Imepitoin was significantly superior to placebo in storm logs and weekly surveys for weeks 2 and 4, and in the end-of-study survey. Mild/moderate adverse events were reported in 26 patients (24 active: two placebo); the most frequent adverse event was ataxia. Owners of dogs in the imepitoin group, compared to placebo, were significantly more likely to report that treatment reduced their dogs fear and anxiety during storms (p < 0.001) and other noise events (p < 0.001). Twice daily administration of imepitoin decreased anxiety scores in dogs with storm anxiety. Future work may evaluate optimal dosage regimens.
