A comparison of alternative ranking methods in two-stage clinical trials with multiple interventions: An application to the anxiolysis for laceration repair in children trial

Abstract

Background/aims: Multi-arm, multi-stage trials frequently include a standard care to which all interventions are compared. This may increase costs and hinders comparisons among the experimental arms. Furthermore, the standard care may not be evident, particularly when there is a large variation in standard practice. Thus, we aimed to develop an adaptive clinical trial that drops ineffective interventions following an interim analysis before selecting the best intervention at the final stage without requiring a standard care.

Methods: We used Bayesian methods to develop a multi-arm, two-stage adaptive trial and evaluated two different methods for ranking interventions, the probability that each intervention was optimal (P_best) and using the surface under the cumulative ranking curve (SUCRA), at both the interim and final analysis. The proposed trial design determines the maximum sample size for each intervention using the Average Length Criteria. The interim analysis takes place at approximately half the pre-specified maximum sample size and aims to drop interventions for futility if either P_best or the SUCRA is below a pre-specified threshold. The final analysis compares all remaining interventions at the maximum sample size to conclude superiority based on either P_best or the SUCRA. The two ranking methods were compared across 12 scenarios that vary the number of interventions and the assumed differences between the interventions. The thresholds for futility and superiority were chosen to control type 1 error, and then the predictive power and expected sample size were evaluated across scenarios. A trial comparing three interventions that aim to reduce anxiety for children undergoing a laceration repair in the emergency department was then designed, known as the Anxiolysis for Laceration Repair in Children Trial (ALICE) trial.

Results: As the number of interventions increases, the SUCRA results in a higher predictive power compared with P_best. Using P_best results in a lower expected sample size when there is an effective intervention. Using the Average Length Criterion, the ALICE trial has a maximum sample size for each arm of 100 patients. This sample size results in a 86% and 85% predictive power using P_best and the SUCRA, respectively. Thus, we chose P_best as the ranking method for the ALICE trial.

Conclusion: Bayesian ranking methods can be used in multi-arm, multi-stage trials with no clear control intervention. When more interventions are included, the SUCRA results in a higher power than P_best. Future work should consider whether other ranking methods may also be relevant for clinical trial design.

Keywords: Bayesian adaptive trial; Surface Under the Cumulative Ranking curve; clinical trial design; multi-arm multi-stage trial; paediatric emergency department.

Figure 1.

A pictorial representation of the decision-making in the proposed two-stage trial design. The first and second scenarios proceed to the final analysis stage, where at least two interventions are evaluated at the maximum sample size. Superiority is declared at the interim analysis stage in the final scenario, so the trial is terminated early and no interventions continue to the maximum sample size.