Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘ExampleA 2 × 3 factorial design was used in the evaluation of several drug regimens asinitial antiretroviral therapy for HIV-1 infection [6].• The first randomization step assigned HIV-1-infected individualsto treatment with either didanosine and stavudine (DDI + D4T)or zidovudine and lamivudine (ZDV + 3TC).• The second randomization step evaluated the effect of efavirenzalone (EFV), nelfinavir (NFV) alone, or the combination of both(EFV + NFV).Thus, the first randomization step contained two levels, and the secondrandomization assigned individuals to three groups: a 2 × 3 factorial study resultingin six different treatment groups (see Table 3).In the previously mentioned ISIS-4 study, a 2 × 2 × 2 factorial design was usedto evaluate 58,050 individuals with suspected acute myocardial infarction whowere randomized to receive oral captopril (OC), oral mononitrate (OM), and/orintravenous magnesium sulfate (IMS) [2]. This design required three randomizationsteps, and over 7,000 individuals were randomized to each of the resulting eighttreatment groups (see Table 3):• placebo• OC alone• OM alone• IMS alone• OC + OM• OC + IMS• OM + IMS• OC + OM + IMSIncreasing the interventionsSince a factorial design makes it is possible to analyze more than one interventionin a single trial, it is tempting to extend the design to a study that investigatesthree or more interventions by performing an expanded factorial design.As outlined above, for every additional two-level intervention evaluated, there isa resulting two-fold increase in the final number of treatment groups. Moreover,the more interventions evaluated, the more likely it is to uncover an interactionbetween interventions. It is therefore advisable to keep the number ofinterventions as low as possible, unless there is certainty that all of theinterventions will work independently.107