OnabotulinumtoxinA for the preventive treatment of episodic migraine: Results from the phase 3, multicenter randomized, double-blind, placebo-controlled phase of the PRECLUDE trial

Background Migraine is a complex disabling neurological disease characterized by recurrent headache attacks lasting 4–72 h with moderate to severe intensity and other accompanying symptoms. While chronic migraine (CM) and episodic migraine (EM) are primarily differentiated by the frequency of headache and migraine days, underlying clinical and functional differences have been described. OnabotulinumtoxinA (onabotA) has been approved as a preventive treatment for CM with controlled clinical and real-world evidence suggesting potential benefits for treatment of EM. Given the lack of randomized controlled trial data, PRECLUDE, a prospective phase 3 trial was designed to evaluate the efficacy and safety of onabotA for the preventive treatment of EM. Methods The PRECLUDE trial was a phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group trial with an open-label onabotA 195 U extension phase. In total, 775 patients aged 18–65 years with a history of migraine attacks were randomized (1:1:1) to receive placebo, onabotA 155 U, or onabotA 195 U. Patients recorded daily headache data and medication use via an electronic diary (eDiary) during a four-week screening phase, 24-week double-blind phase, followed by a 24-week open-label extension phase. The primary endpoint was the change in the frequency of monthly migraine days from baseline across months 5 and 6. Results All treatment groups showed a reduction in the frequency of monthly migraine days from baseline; however, neither the onabotA 155 U group nor the 195 U group demonstrated a statistically significant improvement compared to the placebo group ( p >0 .05). Similarly, secondary endpoints, including changes in monthly headache days, 50% responder rates and monthly acute medication use days, did not reach statistical significance. Adverse events in this trial were consistent with previous findings for onabotA in CM and were generally mild to moderate in severity. Conclusions The PRECLUDE trial demonstrated that onabotA was well tolerated but did not show significant efficacy compared to placebo for the endpoint reducing migraine days from baseline in patients with EM as defined by the trial protocol. While onabotA is effective for CM, these findings highlight the need for further research to better understand the pathophysiological differences between EM and CM and to understand whether there is a potential subset of EM patients which respond to onabotA.