Interim analyses {21b}
ADVERSE EVENTS, POSTPARTUM BLEEDING, RECRUITMENT
The DMC is responsible for deciding whether to reveal the unblinded results (overall or for a particular subgroup) to the Trial Steering Committee (TSC) while the trial is underway. The DMC will do this only if two conditions are satisfied: (1) the results provide proof beyond reasonable doubt that treatment is either definitely harmful/inferior or definitely favourable for all or for a particular subgroup in terms of a major outcome and (2) the results are expected to substantially change the prescribing patterns of clinicians who are familiar with other existing trial results. The exact criteria for ‘proof beyond reasonable doubt’ are not and cannot be specified by a purely mathematical stopping rule but are strongly influenced by such rules. The DMC Charter will refer to the Peto-Haybittle stopping rule, whereby an interim analysis of a major outcome must involve a difference between the treatment and control of at least three standard errors to justify premature disclosure [We will present baseline data, outcome data, and data on adverse events that might be associated with postpartum bleeding or tranexamic acid use to the DMC. We will use the Peto-Haybittle stopping rules, which require extreme differences to justify premature disclosure and involve an appropriate combination of mathematical stopping rules and scientific judgement, with the advantage that the exact number and timing of interim analyses need not be pre-specified. If there is a difference of at least three standard errors in favour of tranexamic acid compared to placebo, this will be taken as proof of a treatment benefit, and we will stop recruitment into the placebo group. The trial will continue to assess the non-inferiority of IM tranexamic acid compared to IV tranexamic acid. While early stopping based on evidence of non-inferiority is not recommended, early stopping based on inferiority is recommended to minimise patient exposure to an inferior intervention. The Peto-Haybittle stopping rule is appropriate as both the treatment and active control are the same drug given via different routes, with no good biological reason to expect the inferiority of the IM route. If there is a difference of at least three standard errors in favour of IV tranexamic acid compared to IM tranexamic acid, this will be taken as proof of inferiority, and we will stop recruitment into the IM tranexamic acid group.