Anna Heath1,2,3, Juan David Rios4, Eleanor Pullenayegum4,5, Petros Pechlivanoglou4,5, Martin Offringa4,5,6, Maryna Yaskina7, Rick Watts7, Shana Rimmer7, Terry P Klassen8,9, Kamary Coriolano10, Naveen Poonai11,12. 1. Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Canada. anna.heath@sickkids.ca. 2. Dalla Lana School of Public Health, Division of Biostatistics, University of Toronto, Toronto, Canada. anna.heath@sickkids.ca. 3. Department of Statistical Science, University College London, London, UK. anna.heath@sickkids.ca. 4. Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Canada. 5. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. 6. Division of Neonatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 7. Women & Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada. 8. University of Manitoba, Winnipeg, Manitoba, Canada. 9. Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada. 10. London Health Sciences Centre, Children's Hospital, London, Ontario, Canada. 11. Departments of Paediatrics and Epidemiology & Biostatistics, Schulich School of Medicine and Dentistry, London, Canada. 12. Children's Health Research Institute, London Health Sciences Centre, London, Canada.
Abstract
BACKGROUND:Procedural sedation and analgesia (PSA) is frequently required to perform closed reductions for fractures and dislocations in children. Intravenous (IV) ketamine is the most commonly used sedative agent for closed reductions. However, as children find IV insertion a distressing and painful procedure, there is need to identify a feasible alternative route of administration. There is evidence that a combination of dexmedetomidine and ketamine (ketodex), administered intranasally (IN), could provide adequate sedation for closed reductions while avoiding the need for IV insertion. However, there is uncertainty about the optimal combination dose for the two agents and whether it can provide adequate sedation for closed reductions. The Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation (Ketodex) study is a Bayesian phase II/III, non-inferiority trial in children undergoing PSA for closed reductions that aims to address both these research questions. This article presents in detail the statistical analysis plan for the Ketodex trial and was submitted before the outcomes of the trial were available for analysis. METHODS/ DESIGN: The Ketodex trial is a multicenter, four-armed, randomized, double-dummy controlled, Bayesian response adaptive dose finding, non-inferiority, phase II/III trial designed to determine (i) whether IN ketodex is non-inferior to IV ketamine for adequate sedation in children undergoing a closed reduction of a fracture or dislocation in a pediatric emergency department and (ii) the combination dose for IN ketodex that provides optimal sedation. Adequate sedation will be primarily measured using the Pediatric Sedation State Scale. As secondary outcomes, the Ketodex trial will compare the length of stay in the emergency department, time to wakening, and adverse events between study arms. DISCUSSION: The Ketodex trial will provide evidence on the optimal dose for, and effectiveness of, IN ketodex as an alternative to IV ketamine providing sedation for patients undergoing a closed reduction. The data from the Ketodex trial will be analyzed from a Bayesian perspective according to this statistical analysis plan. This will reduce the risk of producing data-driven results introducing bias in our reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04195256 . Registered on December 11, 2019.
RCT Entities:
BACKGROUND: Procedural sedation and analgesia (PSA) is frequently required to perform closed reductions for fractures and dislocations in children. Intravenous (IV) ketamine is the most commonly used sedative agent for closed reductions. However, as children find IV insertion a distressing and painful procedure, there is need to identify a feasible alternative route of administration. There is evidence that a combination of dexmedetomidine and ketamine (ketodex), administered intranasally (IN), could provide adequate sedation for closed reductions while avoiding the need for IV insertion. However, there is uncertainty about the optimal combination dose for the two agents and whether it can provide adequate sedation for closed reductions. The Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation (Ketodex) study is a Bayesian phase II/III, non-inferiority trial in children undergoing PSA for closed reductions that aims to address both these research questions. This article presents in detail the statistical analysis plan for the Ketodex trial and was submitted before the outcomes of the trial were available for analysis. METHODS/ DESIGN: The Ketodex trial is a multicenter, four-armed, randomized, double-dummy controlled, Bayesian response adaptive dose finding, non-inferiority, phase II/III trial designed to determine (i) whether IN ketodex is non-inferior to IV ketamine for adequate sedation in children undergoing a closed reduction of a fracture or dislocation in a pediatric emergency department and (ii) the combination dose for IN ketodex that provides optimal sedation. Adequate sedation will be primarily measured using the Pediatric Sedation State Scale. As secondary outcomes, the Ketodex trial will compare the length of stay in the emergency department, time to wakening, and adverse events between study arms. DISCUSSION: The Ketodex trial will provide evidence on the optimal dose for, and effectiveness of, IN ketodex as an alternative to IV ketamine providing sedation for patients undergoing a closed reduction. The data from the Ketodex trial will be analyzed from a Bayesian perspective according to this statistical analysis plan. This will reduce the risk of producing data-driven results introducing bias in our reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04195256 . Registered on December 11, 2019.
Entities:
Keywords:
Bayesian adaptive design; Intranasal ketodex; Non-inferiority trial; Pediatric closed reduction; Procedural sedation and analgesia; Statistical analysis plan
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