RESUMEN
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 (Pbest) 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 Pbest 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 Pbest 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 Pbest. Using Pbest 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 Pbest and the SUCRA, respectively. Thus, we chose Pbest 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 Pbest. Future work should consider whether other ranking methods may also be relevant for clinical trial design.
RESUMEN
OBJECTIVES: To systematically appraise the literature on the relative effectiveness of pharmacologic procedural distress management agents for children undergoing laceration repair. METHODS: Six databases were searched in August 2021, and the search was updated in January 2023. We included completed randomized or quasi-randomized trials involving ( a ) children younger than 15 years undergoing laceration repair in the emergency department; ( b ) randomization to at least one anxiolytic, sedative, and/or analgesic agent versus any comparator agent or placebo; ( c ) efficacy of procedural distress management measured on any scale. Secondary outcomes were pain during the procedure, administration acceptance, sedation duration, additional sedation, length of stay, and stakeholder satisfaction. Cochrane Collaboration's risk-of-bias tool assessed individual studies. Ranges and proportions summarized results where applicable. RESULTS: Among 21 trials (n = 1621 participants), the most commonly studied anxiolytic agents were midazolam, ketamine, and N 2 O. Oral midazolam, oral ketamine, and N 2 O were found to reduce procedural distress more effectively than their comparators in 4, 3, and 2 studies, respectively. Eight studies comparing routes, doses, or volumes of administration of the same agent led to indeterminate results. Meta-analysis was not performed because of heterogeneity in comparators, routes, and outcome measures across studies. CONCLUSIONS: Based on procedural distress reduction, this study favors oral midazolam and oral ketamine. However, this finding should be interpreted with caution because of heterogeneous comparators across studies and minor conflicting results. An optimal agent for procedural distress management cannot be recommended based on the limited evidence. Future research should seek to identify the minimal, essential measures of patient distress during pharmacologic anxiolysis and/or sedation in laceration repair to guide future trials and reviews.
