Markus Harboe Olsen1,2, Aksel Karl Georg Jensen3, Josef Dankiewicz4, Markus B Skrifvars5, Matti Reinikainen6, Marjaana Tiainen7, Manoj Saxena8, Anders Aneman9,10, Christian Gluud11,12, Susann Ullén13, Niklas Nielsen14, Janus Christian Jakobsen11,12. 1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. markus.harboe.olsen@ctu.dk. 2. Department of Neuroanaesthesiology, The Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. markus.harboe.olsen@ctu.dk. 3. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 4. Department of Clinical Sciences, Cardiology, Lund University, Skåne University Hospital Lund, Lund, Sweden. 5. Department of Emergency Care and Services, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. 6. Department of Anaesthesiology and Intensive Care, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland. 7. Department of Anesthesiology, Intensive Care, and Pain Medicine, Helsinki University and Helsinki University Hospital, Helsinki, Finland. 8. Critical Care Division, the George Institute for Global Health, University of New South Wales, Sydney, Australia. 9. Intensive Care Unit, Liverpool Hospital, South Western Sydney Local Health District, Sydney, Australia. 10. South Western Clinical School, University of New South Wales, Sydney, Australia. 11. Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 12. Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. 13. Clinical Studies Sweden - Forum South, Skåne University Hospital, Lund, Sweden. 14. Department of Clinical Sciences Lund, Anesthesiology and Intensive Care, Lund University, Helsingborg Hospital, Helsingborg, Sweden.
Abstract
BACKGROUND: Randomised clinical trials with a factorial design may assess the effects of multiple interventions in the same population. Factorial trials are carried out under the assumption that the trial interventions have no interactions on outcomes. Here, we present a protocol for a simulation study investigating the consequences of different levels of interactions between the trial interventions on outcomes for the future 2×2×2 factorial designed randomised clinical Sedation, TEmperature, and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial in comatose patients after out-of-hospital cardiac arrest. METHODS: By simulating a multisite trial with 50 sites and 3278 participants, and a presumed six-month all-cause mortality of 60% in the control population, we will investigate the validity of the trial results with different levels of interaction effects on the outcome. The primary simulation outcome of the study is the risks of type-1 and type-2 errors in the simulated scenarios, i.e. at what level of interaction is the desired alpha and beta level exceeded. When keeping the overall risk of type-1 errors ≤ 5% and the risk of type-2 errors ≤ 10%, we will quantify the maximum interaction effect we can accept if the planned sample size is increased by 5% to take into account possible interaction between the trial interventions. Secondly, we will assess how interaction effects influence the minimal detectable difference we may confirm or reject to take into account 5% (small interaction effect), 10% (moderate), or 15% (large) positive interactions in simulations with no 'true' intervention effect (type-1 errors) and small (5%), moderate (10%), or large negative interactions (15%) in simulations with 'true' intervention effects (type-2 errors). Moreover, we will investigate how much the sample size must be increased to account for a small, moderate, or large interaction effects. DISCUSSION: This protocol for a simulation study will inform the design of a 2×2×2 factorial randomised clinical trial of how potential interactions between the assessed interventions might affect conclusions. Protocolising this simulation study is important to ensure valid and unbiased results. TRIAL REGISTRATION: Not relevant.
BACKGROUND: Randomised clinical trials with a factorial design may assess the effects of multiple interventions in the same population. Factorial trials are carried out under the assumption that the trial interventions have no interactions on outcomes. Here, we present a protocol for a simulation study investigating the consequences of different levels of interactions between the trial interventions on outcomes for the future 2×2×2 factorial designed randomised clinical Sedation, TEmperature, and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial in comatose patients after out-of-hospital cardiac arrest. METHODS: By simulating a multisite trial with 50 sites and 3278 participants, and a presumed six-month all-cause mortality of 60% in the control population, we will investigate the validity of the trial results with different levels of interaction effects on the outcome. The primary simulation outcome of the study is the risks of type-1 and type-2 errors in the simulated scenarios, i.e. at what level of interaction is the desired alpha and beta level exceeded. When keeping the overall risk of type-1 errors ≤ 5% and the risk of type-2 errors ≤ 10%, we will quantify the maximum interaction effect we can accept if the planned sample size is increased by 5% to take into account possible interaction between the trial interventions. Secondly, we will assess how interaction effects influence the minimal detectable difference we may confirm or reject to take into account 5% (small interaction effect), 10% (moderate), or 15% (large) positive interactions in simulations with no 'true' intervention effect (type-1 errors) and small (5%), moderate (10%), or large negative interactions (15%) in simulations with 'true' intervention effects (type-2 errors). Moreover, we will investigate how much the sample size must be increased to account for a small, moderate, or large interaction effects. DISCUSSION: This protocol for a simulation study will inform the design of a 2×2×2 factorial randomised clinical trial of how potential interactions between the assessed interventions might affect conclusions. Protocolising this simulation study is important to ensure valid and unbiased results. TRIAL REGISTRATION: Not relevant.