Randomized clinical trials of acute disease are usually designed as single-look, fixed sample size trials. This methodological study compares the conventional approach with a multiple-look, group sequential design with stopping rules for both treatment efficacy and for an inconclusive trial outcome, called trial futility. An ongoing trial on pre-hospital prophylaxis of sudden death in acute myocardial infarction forms the basis of the analysis. The effects of introducing multiple looks (or interim analyses) and tests for futility were obtained by binomial simulation. The introduction of four looks (that is, three interim and a final analysis) resulted in a modest increase in the maximal number of patients required. This was, however, fully compensated for by the high probability of early termination in case of treatment efficacy. The addition of futility tests, enabling termination at half the maximum trial size when there is no treatment difference, resulted in only a negligible reduction of overall power. We conclude that multiple-look, group sequential designs testing for both treatment efficacy and trial futility may improve the cost-effectiveness of randomized trials of acute disease.