In many cases there is a need to compare novel treatments to active treatments where interest focuses on non-inferiority, instead of superiority of the novel treatment. The study design can strictly focus on the non-inferiority hypothesis of efficacy or safety with the assumption of no other differences between the two treatments of interest; or it can focus on the non-inferiority of efficacy with a gain (superiority) in other treatment characteristics. The literature on the design, conduct and analysis of non-inferiority trials is continuously evolving. From the initial introduction of concepts and terminology, researchers have dedicated full efforts towards improving the overall conduct of these trials. Several design issues continue to be debated including the choice of the active control, choice of non- nferiority margin and utility of early stopping guidelines. The RAMPART study investigators have faced study design challenges that encompass each of these issues. Although there is not overall consensus on the ‘right’ approach among the clinical trial community, there is guidance on acceptable approaches to choice of margin and active control with very limited published material on interim analysis and early stopping guidelines. The RAMPART study provides a unique opportunity to further research the design and analysis concepts of non-inferiority studies and potentially offer further guidance on the optimal conduct of these studies.