When enough is enough: how the decision was made to stop the FEAST trial: data and safety monitoring in an African trial of Fluid Expansion As Supportive Therapy (FEAST) for critically ill children
1 London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
2 Kilimanjaro Christian Medical University College, PO Box 2240, Moshi, Tanzania
3 Malawi Liverpool Wellcome Trust Clinical Research Program, University of Malawi College of Medicine, Blantyre, Malawi
4 Department of Pediatrics, Makerere University School of Medicine, PO Box 7072, Kampala, Uganda
5 Nuffield Department of Medicine, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK
6 Department of Epidemiology and Biostatistics, KCMC, PO Box 2240, Moshi, Tanzania
Trials 2013, 14:85 doi:10.1186/1745-6215-14-85Published: 26 March 2013
In resource-rich countries, bolus fluid expansion is routinely used for the treatment of poor perfusion and shock, but is less commonly used in many African settings. Controversial results from the recently completed FEAST (Fluid Expansion As Supportive Therapy) trial in African children have raised questions about the use of intravenous bolus fluid for the treatment of shock. Prior to the start of the trial, the Independent data monitoring committee (IDMC) developed stopping rules for the proof of benefit that bolus fluid resuscitation would bring. Although careful safety monitoring was put in place, there was less expectation that bolus fluid expansion would be harmful and differential stopping rules for harm were not formulated.
In July 2010, two protocol amendments were agreed to increase the sample size from 2,880 to 3,600 children, and to increase bolus fluid administration. There was a non-significant trend against bolus treatment, but although the implications were discussed, the IDMC did not comment on the results, or on the amendments, in order to avoid inadvertent partial unblinding of the study.
In January 2011, the trial was stopped for futility, as the combined intervention arms had significantly higher mortality (relative risk 1.46, 95% CI 1.13 to 1.90, P = 0.004) than the control arm. The stopping rule for proof of benefit was not achieved, and the IDMC stopped the trial with a lower level of significance (P = 0.01) due to futility and an increased risk of mortality from bolus fluid expansion in children enrolled in the trial. The basis for this decision was that the local standard of care was not to use bolus fluid for the care of children with shock in these African countries, and this was a different standard of care to that used in the UK. These decisions emphasize two important principles: firstly, the IDMC should avoid inadvertent unblinding of the trial by commenting on amendments, and secondly, when considering stopping a trial, the IDMC should be guided by the local standard of care rather than standards of care in other parts of the world.