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Table 3 Summary of strategies for handling intercurrent events in trials for COVID-19. Suggestions relate to an objective of evaluating the effect of treatment if they were introduced into a healthcare system

From: Treatment estimands in clinical trials of patients hospitalised for COVID-19: ensuring trials ask the right questions

Strategy Explanation Truncation-by-deatha Treatment discontinuationb
Treatment policy Measures the effect of the original decision to undertake a treatment, where the intercurrent event (e.g. discontinuation) is taken to be part of the treatment strategy. Cannot be used for terminal events, such as mortality. Not applicable; relevant outcome data does not exist. Recommended strategy, as it most closely links to the objective of evaluating the effect of treatment if introduced into a healthcare system.
Composite The outcome definition is modified to incorporate the intercurrent event, e.g. ‘requirement for ventilation’ is modified to ‘requirement for ventilation or death’. Recommended strategy for patient benefit perspective, as it ensures death equates to a poor outcome. Care is required to ensure the outcome remains interpretable/clinically meaningful. Not recommended, as the outcome becomes less interpretable/clinically meaningful.
Hypothetical Measures the effect of treatment in a hypothetical setting where the intercurrent event would not occur, e.g. the treatment effect if there was no discontinuation. Not recommended; applies to a hypothetical setting which will never exist (no patients die), and so is difficult to interpret. Recommended in a secondary estimand for discontinuation due to external factors (e.g. supply issues/lack of PPE), to evaluate the effect of treatment in settings where there was no supply issues/lack of PPE.
While alive/while on treatment Uses data prior to the occurrence of the intercurrent event; e.g. for ICU days, the number of days a patient was in ICU before they died would be used. Recommended strategy for healthcare systems perspective, as it provides the real-world resource savings due to treatment. Not recommended, as estimand becomes less interpretable/clinically meaningful.
Principal stratum Measures the effect of treatment in the (unknown) subpopulation of patients for whom the intercurrent event would not occur. Not recommended, as interest for COVID-19 trials is likely to be a treatment effect in the entire population of patients, rather than in an unknown subpopulation. Not recommended, as interest for COVID-19 trials is likely to be a treatment effect in the entire population of patients, rather than in an unknown subpopulation.
  1. aTruncation-by-death acts as an intercurrent event for all outcomes considered in this manuscript except for all-cause mortality
  2. bTreatment discontinuation acts as an intercurrent event for all outcomes considered in this manuscript