Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids

Abstract

Background: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Coenrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations.Methods: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-totreat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the cointerventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable-and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. | 157 SCHJØRRING et al. 1 | INTRODUC TI ON When accepting co-enrolment in randomized clinical trials, assessment of possible interaction between interventions is important, 1-3 both to establish the possible impact of co-enrolment on the results of each trial, and to identify inconspicuous interactions. Intensive care unit (ICU) patients receive numerous interventions, but the knowledge about any potential interaction between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique option to investigate such interactions. The Centre for Research in Intensive Care (CRIC) has initiated four randomized clinical trials in adult ICU patients. All interventions tested were considered standard of care in everyday clinical practice in ICUs. All trials were generally conducted in the same sites, had overlapping inclusion criteria and inclusion periods, and co-enrolment was allowed. The trials were the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial investigating pantoprazole versus placebo in patients at risk of gastrointestinal bleeding; 4,5 the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial investigating a lower versus a higher oxygenation target in patients with acute hypoxaemic respiratory failure; 6,7 the Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU) trial investigating haloperidol versus placebo in patients with delirium 8 and the Conservative versus Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial investigating restrictive versus standard intravenous fluid therapy in patient...

Feasibility of Extracting Meaningful Patient Centered Outcomes From the Electronic Health Record Following Critical Illness in the Elderly

“…DAOH has surfaced as a promising pragmatic patient centered outcome but further refinement is required prior to more widespread use ( 22 ). There is heterogeneity in the intervals of measurements from hospital discharge or time of randomization to ranges in between 28 days and 365 days ( 51 – 55 ). The accuracy of DAOH calculation from EHR is limited since long term acute care days may be imprecisely accounted for ( 22 ), similar to our experience.…”