Clinical Trials

❘❙❚■ Chapter 29 | Multiplicityoutcome. Patients answer a whole list of questions, and a summary measureindicating their quality of life is then generated. This strategy is also useful in theanalysis of data with repeated measurements when a summary measure is derivedfrom those multiple measures. This summary measure is then used to evaluate apossible treatment difference in a single statistical test. For example, the areaunder the curve and peak value (C max) are often used as a primary endpoint inbioequivalence studies (see Chapters 13 and 28).Define a combined composite endpointAnother strategy is to define a composite endpoint as the first occurrence ofany of a list of several major events of interest. An example of this is the RITA(Randomized Intervention Trial of Angina) 3 trial, which assessed an initialconservative strategy (medical therapy) versus an initial interventional strategy(angiography and subsequent revascularization, if indicated) in patients withunstable angina or non-ST-segment elevation myocardial infarction (MI) [12].The co-primary trial endpoints were the occurrence of the first of either death,nonfatal MI, or refractory angina at 4 months, and death or nonfatal MI at 1 year.The co-primary endpoints reflect major complications of unstable angina that thetreatment strategies aim to reduce. The interventional treatment prevented abouta third of these complications at 4 months compared to the conservative strategy.However, caution is needed in interpreting the results as this difference wasentirely driven by a reduction in refractory angina, and there were few differencesbetween the groups in terms of deaths or nonfatal MIs.Use a multivariate approach/overall hypothesisaccounting for all the endpointsA further problem that must be considered when dealing with multiple outcomemeasures is that there can be a greater tendency for patients to have severaloutcomes together than just one: so a patient avoiding a heart attack is also likelyto avoid a reduction in his quality of life. There are specific statistical methods thatadjust for such correlations between endpoints, while the capacity for clinicalinterpretation of each component is maintained.One of these methods, the Wei–Lachin procedure [13], was used in a trialinvestigating the effects of mitoxantrone in patients with multiple sclerosis [14].In this trial, five clinical measures indicating the severity of multiple sclerosis(changes of two different severity scores reflecting the disability of patients,number of relapses requiring steroid treatment, time to first treated relapse,and changes in the standardized score of neurological status) were tested in oneoverall hypothesis that the treatment affects all of those measures.336