OnabotulinumtoxinA for Treatment of Chronic Migraine

In reviewing the paper by Dodick et al, “OnabotulinumtoxinA for treatment of chronic migraine,” we were concerned by several issues. 1. The authors concede that the results of PREEMPT-1 (in which some secondary outcomes were not significant) influenced their decision to combine the 2 studies and change the primary outcome measure. 2. PREEMPT-1 and PREEMPT-2 took place at nearly the same time – the former started 2 weeks later and ended 4 weeks earlier. Why were the 2 studies not designed as 1 larger multi-center, multi-country study? 3. The authors frequently use the term “predefined. ” Typically, the use of predefined would imply “before the study (studies) started. ” The decision to pool the data from the 2 studies, however, was made after the results from PREEMPT-1 were available. 4. In describing their research design, the authors list 2 independent variables (the so-called main effects for the ANCOVA model) – treatment (onabotulinumtoxinA vs placebo) and stratum of symptomatic medication overuse. In this paper, however, the authors report the treatment results but not the findings for level of symptomatic medication overuse. They tell us that the results regarding the latter will be reported elsewhere, but we feel this is not sound practice. When there are 2 main effects (2 independent variables), readers need to know if there exist any interaction effects (ie, statistical interaction) between the 2 main effects. For example, perhaps there is a significant reduction in headache days for the onabotulinumtoxinA/ high overusers but not for the onabotulinumtoxinA/low overusers, or vice versa. 5. Although in their Discussion section the authors state that there were significant differences in adverse events between the 2 groups, in their Results section they do not report the relevant specifics. Specifically, in the Results section the authors report P values for all the primary and secondary outcomes but do not do so for adverse effects. Using the chi-square test, we calculated that the onabotulinumtoxinA group had more patients with adverse events (62.4% vs 51.7%, P < .0001), treatment-related adverse events (29.4% vs 12.7%, P < .0001), serious adverse events (4.8% vs 2.3%,P = .0133),and more who discontinued treatment due to adverse events (3.8% vs 1.2%, P = .0016). 6. The authors indicate that the pooled results are being published here in Headache (June 2010) while the papers describing the individual trials are in press. It strikes us as odd for the pooled analysis to precede the individual studies in the literature. 7. In their Discussion section the authors tell us that “approximately 85 possible predictors” were not found to be confounders, but they do not provide any specifics. At a minimum, we would like to know the specifics for age, gender, BMI, and other key variables. 8. OnabotulinumtoxinA patients saw their mean headache days over the final 4-week period (the primary outcome) decrease by 8 days, while the placebo group had a decrease of 7 days. With nearly 700 subjects per group, this difference is statistically significant (P < .001), but one might question whether a treatment-induced reduction of less than 2 headache days per month is clinically relevant. Supporting this relative lack of clinical impact is the failure of active treatment to reduce the intake of symptomatic medications. Finally, it may be worth noting that the onabotulinumtoxinA group already had 1 fewer headache episode and 1 fewer migraine episode per month at baseline when compared with the placebo group. In summary, the investigators changed their primary efficacy measure after a review of half of the data available (PREEMPT-1) rather than retain the predefined efficacy measure. While one may argue whether this change did or did not contaminate this study’s result, there remains the question of whether that result, while “positive” in the statistical sense, conveys clinical relevance.