This randomized, placebo-controlled, double blind, phase 2-3 trial had a two-stage adaptive design, with selection of the propranolol regimen (dose and duration) at the end of stage 1 (interim analysis) and further examination of the selected regimen for efficacy and safety in stage 2. The primary efficacy endpoint was success or failure based on change of the target infantile hemangioma from baseline to week 24.

Careful simulations were required for this clinical trial during the planning of the trial to study operating characteristics. At first, enrollment was slow due to a randomization ratio which was balanced and included a placebo arm. With good communication with regulatory authorities, it was agreed to move to an imbalanced randomization design limiting likelihood of assignment to the placebo group and the protocol was amended. Enrollment increased more than anticipated, contributing to "overrun" at the interim analysis. We will discuss how this situation was handled.

This study demonstrated that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma (Clinical Trials.gov number NCT01056341). It is one of the first case -studies of a successful confirmatory adaptive design trial with methods for dose-selection and unblinded sample size reassessment. Here, challenging research situations were successfully handled. These studies must be undertaken with careful planning and careful attention to study implementation and conduct to manage these new challenges and to avoid study bias. This study is an excellent example of a study which was undertaken well, maintained excellent communications with both the EMA and FDA, was carefully executed and achieved its goals. Nevertheless, there were challenges such as "overrun" which had to be managed and the sponsor, and regulatory authorities have shared information on their deliberations.