FORWARD Study: Evaluating the Comparative Effectiveness of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults With Chronic Migraine

Abstract

Objective: To compare effectiveness of onabotulinumtoxinA and topiramate for chronic migraine (CM) prevention.

Background: The efficacy* of onabotulinumtoxinA and topiramate has been established in placebo-controlled randomized clinical trials (*defined as the benefit of treatment under ideal conditions). The effectiveness* of the 2 preventive treatments, however, has not been established (*the benefit of treatment under real-world conditions, representing a blend of efficacy and tolerability).

Methods: In this multicenter, randomized, parallel-group, post-authorization, open-label prospective study (FORWARD; ClinicalTrials.gov, NCT02191579), we randomized adults with CM (1:1) to onabotulinumtoxinA 155 U every 12 weeks for 3 cycles or topiramate "immediate release" 50-100 mg/day to week 36. Primary outcome measure was proportion of patients achieving ≥50% reduction in headache days (weeks 29-32). Missing values were imputed using baseline observation carried forward (BOCF) methodology. After 12 weeks, patients initially randomized to topiramate could cross over to onabotulinumtoxinA treatment. We monitored and recorded all adverse events (AEs).

Results: We enrolled 282 patients (onabotulinumtoxinA, n = 140; topiramate, n = 142) and 148 patients completed randomized treatment (onabotulinumtoxinA, n = 120 [86%]; topiramate, n = 28 [20%]). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, n = 7 [5%]; topiramate, n = 27 [19%]) and AEs (onabotulinumtoxinA, n = 5 [4%]; topiramate, n = 72 [51%]). Eighty topiramate patients crossed over to onabotulinumtoxinA. In the BOCF analysis, a significantly higher proportion of patients randomized to onabotulinumtoxinA experienced ≥50% reduction in headache frequency compared with those randomized to topiramate (40% [56/140] vs 12% [17/142], respectively; adjusted OR, 4.9 [95% CI, 2.7-9.1]; P < .001). OnabotulinumtoxinA was superior to topiramate in meeting secondary endpoints. In a post hoc analysis using observed data, the 50% responder rates at week 12 were 45.6% for onabotulinumtoxinA (n = 125) and 29.4% for topiramate (n = 109) (P = .015). AEs were reported by 48% (105/220) of onabotulinumtoxinA and 79% (112/142) of topiramate patients. Results were similar in those who crossed over to onabotulinumtoxinA.

Conclusions: While using imputation methods of accounting for differences in discontinuation rates, we found onabotulinumtoxinA to have greater clinical utility than topiramate, largely because of tolerability issues associated with the latter and a relatively higher number of onabotulinumtoxinA patients remaining on treatment.

Keywords: botulinum toxin; chronic migraine prevention; clinical utility; safety; topiramate.

Figure 1

Study design. (A) The study comprised a 28‐day pretreatment (run‐in) period followed by randomization to either onabotulinumtoxinA or topiramate treatment that lasted up to 36 weeks. (B) Patients who discontinued topiramate treatment between weeks 12 and 36 could cross over to onabotulinumtoxinA and remain in the study until week 48.

Figure 2

Patient disposition. *80 patients randomized to topiramate discontinued and switched to onabotulinumtoxinA treatment; 55 of the 80 (69%) completed the study and 6 (8%) discontinued: treatment ineffective, n = 3 (4%) and other reasons, n = 3 (4%).

Figure 3

(A) Responder rates (≥50% decrease in frequency of headache from baseline) in patients receiving onabotulinumtoxinA and topiramate and (B) detailed at week 32. *Odds ratio = 2.4 (95% CI: 1.4‐4.1), P < .001; estimated using Fisher's exact test adjusted by baseline headache days for the 28‐day period between weeks 9‐12. Missing data imputed using baseline last observation carried forward imputation method. ^†Odds ratio = 4.9 (95% CI: 2.7‐9.1), P < .001; estimated using a logistic regression model adjusted by baseline headache days for the 28‐day period between weeks 29‐32. Missing data imputed using baseline last observation carried forward imputation method.

Figure 4

(A) Headache day frequency per 28‐day period for onabotulinumtoxinA and topiramate at weeks 12, 24, and 32 and (B) HIT‐6 scores for onabotulinumtoxinA and topiramate at week 30. HIT‐6 = 6‐item Headache Impact Test. *Change from baseline at week 32 assessment (weeks 29‐32); P value compares the change from baseline, assessed using analysis of covariance and adjusting for baseline headache days. Other time points were not tested for statistical significance. ^†Change from baseline for onabotulinumtoxinA vs topiramate at week 30; P value compares the change from baseline, assessed using analysis of covariance and adjusting for baseline headache days.

Figure 5

Responder rates (≥70% decrease in frequency of headache from baseline) in patients receiving onabotulinumtoxinA and topiramate (A) for the duration of the study and (B) detailed at 32 weeks. *Odds ratio = 4.1 (95% CI: 2.0‐8.2), P < .001; estimated using a logistic regression model adjusted by baseline headache days for the 28‐day period between weeks 29‐32. Other time points were not tested for statistical significance.

Figure 6

Responder rates (≥50% decrease in frequency of headache from baseline) in patients who crossed over to onabotulinumtoxinA. Missing data were imputed using baseline last observation carried forward imputation method.