Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc.) for the prophylactic treatment of chronic daily headache (CDH).

BACKGROUND: Several open-label and small controlled trials suggest that BoNT-A may be effective in the prophylactic treatment of headache.

DESIGN AND METHODS: This was an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of patients aged 18 to 65 years old with 16 or more headache days per 30 days conducted at 13 North American study centers. Following a 30-day screening period and a 30-day, single-blind, placebo-response period to identify placebo responders, eligible patients from both the placebo responder and placebo nonresponder groups were injected with BoNT-A or placebo every 90 days and assessed every 30 days for 9 months, a period encompassing three treatment cycles. The primary efficacy measure was the change from baseline in the frequency of headache-free days in a 30-day period for the placebo nonresponder group at day 180, the chosen efficacy time point. The secondary efficacy measure was the proportion of patients with a decrease from baseline of 50% or more in the frequency of headache days per 30-day period for the placebo nonresponder group at day 180. The change from baseline in the frequency of headaches (per 30-day period), the proportion of patients with a decrease from baseline of 50% or greater in the frequency of headaches per 30-day period, acute medication use, and adverse events were also assessed.

RESULTS: Of 571 patients assessed over the baseline period, 355 (mean age, 43.5 years; 300/355 [84.5%] female) were enrolled and randomized. At the end of the placebo run-in period, 279 patients (79%) were classified as placebo nonresponders and 76 patients (21%) as placebo responders. Subsequently, patients were randomized within each group to receive either BoNT-A or placebo. In the placebo nonresponder stratum, the mean number of headache-free days at baseline was 5.8 (+/-4.7) for BoNT-A- versus 5.5 (+/-4.7) for placebo-treated patients. At day 180, placebo nonresponders treated with BoNT-A had an improved mean change from baseline of 6.7 headache-free days per 30-day period compared to a mean change from baseline of 5.2 headache-free days for placebo-treated patients. The between-group difference of 1.5 headache-free days favored BoNT-A treatment, although the difference between the groups was not statistically significant. However, a statistically significant difference was observed at day 180 endpoint for the secondary efficacy measure. A significantly higher percentage of BoNT-A patients had a decrease from baseline of 50% or greater in the frequency of headache days per 30-day period at day 180 (32.7% vs. 15.0%, P=.027). Also, the mean change from baseline in the frequency of headaches per 30-day period at day 180 was -6.1 for BoNT-A patients vs. -3.1 for the placebo patients (P=.013). Only 4 of 173 BoNT-A patients (2.3%) discontinued the study due to adverse events. The majority of treatment-related adverse events were transient and mild to moderate in severity.

CONCLUSIONS: BoNT-A treatment resulted in patients having, on average, approximately seven more (1 week) headache-free days compared to baseline. Although at the primary time point (day 180) the BoNT-A treatment resulted in a 1.5 between-group difference compared to placebo, this difference was not statistically significant. The treatment met secondary efficacy outcome measures, including the percentage of patients experiencing a 50% or more decrease in the frequency of headache days, in addition to statistically significant reductions in headache frequency. BoNT-A was also well tolerated in patients with CDH.