Clinical Trials

❘❙❚■ Chapter 4 | EndpointsOne rare example where all patients died in the timeframe of the study and,therefore, where time to death was the primary outcome measured, was a studyin Zambia where patients with HIV were given fluconazole for provencryptococcal meningitis [2]. In this case it was feasible to follow all patients todeath because the disease is rapidly fatal, even with treatment. Therefore, theendpoint of this trial was the mean time to death for each treatment group, andthe results showed that patients given fluconazole lived an average of 9 dayslonger than those who were not.Composite endpointsWhile some guidelines – such as the guidance on trial design in the InternationalConference on Harmonisation guidelines for Good Clinical Practice – prefera primary endpoint based on a single outcome that will be defined before thestudy begins, many studies include multiple outcomes as part of a compositeendpoint. Exploratory clinical investigations or early-phase studies are more likelyto have multiple outcomes, with some of these being developed during the study.An example of a clinical trial with a composite endpoint of multiple outcomesis the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events)study [3]. This study looked at the effects of clopidogrel in patients with acutecoronary syndromes without ST-segment elevation. In this trial, the primaryendpoint was a composite of the following clinical outcomes:• death from cardiovascular causes• stroke• nonfatal myocardial infarction (heart attacks)The second primary endpoint was the composite of the outcomes formingthe first primary endpoint plus refractory ischemia (angina unresponsive tomedical therapies).When multiple outcomes can be experienced by any of the patients it is often bestto present both the total number of outcomes per patient and hierarchical countsof outcomes. In the latter, only one outcome can be counted for each patient, andit is usually the most serious outcome that is recorded. The rules for the hierarchyof outcomes are usually established in advance of the trial, with a fatal outcometaking precedence over a nonfatal one.Another way of combining outcomes would be to compare the number ofrecurrences of identical outcomes, such as the number of seizures experienced bypatients with epilepsy during a follow-up period.40