Botulinum Toxin Type A (BOTOX®) for the Prophylactic Treatment of Chronic Daily Headache: A Randomized, Double‐Blind, Placebo‐Controlled Trial
Authors: Mathew Ninan T. , Frishberg Benjamin M. , Gawel Marek , Dimitrova Rozalina , Gibson John , Turkel Catherine ,   BOTOX CDH Study Group
Published: April 2005

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.