  Aims: Combinations of treatments can offer additional benefit over the
treatments individually. However, trials of these combinations are lower
priority than the development of novel therapies, which can restrict funding,
timelines and patient availability. This paper develops a novel trial design to
facilitate the evaluation of novel combination therapies that combines elements
of phase II and phase III trials. Methods: This trial uses response adaptive
randomisation to increase the information collected about successful novel drug
combinations and Bayesian dose-response modelling to undertake a
comparative-effectiveness analysis for the most successful dose combination
against a relevant comparator. We used simulation methods to evaluate the
probability of selecting the correct optimal dose combination, the operating
characteristics and predictive power of this design for a trial in pain
management and sedation in paediatric emergency departments. Results: With 410
participants, 5 interim updates of the randomisation ratio and a probability of
effectiveness of 0.93, 0.88 and 0.83 for the three dose combinations, we have
an 83% chance of randomising the largest number of patients to the drug with
the highest probability of effectiveness. Based on this adaptive randomisation
procedure, the comparative effectiveness analysis has a type I error of less
than 5% and a 93% chance of correctly concluding non-inferiority when the
probability of effectiveness for the optimal combination therapy is 0.9. In
this case, the trial has a 77% chance of meeting its dual aims of dose finding
and comparative effectiveness. Finally, the Bayesian predictive power of the
trial is over 90%. Conclusion: The proposed trial has high potential to meet
the dual study objectives within a feasible level of recruitment, minimising
the administrative burden and recruitment time for a trial.
