OnabotulinumtoxinA Fails to Meet Primary End Point in Phase 3 PRECLUDE Trial for Episodic Migraine

Newly published data from the phase 3 PRECLUDE trial showed that 2 types of doses of onabotulinumtoxinA (onabotA) did not meet the primary end point of significantly reducing migraine days from baseline compared with placebo among patients with episodic migraine (EM). Although onabotA is an established preventive treatment for chronic migraine (CM), these findings underscored the potential need to further clarify the pathophysiological differences between the 2 types of migraine and determine whether a subset of patients with EM may benefit from the treatment.¹

Published in Cephalalgia, findings revealed that all treatment groups (onabotA 155 U, n = 257; onabotA 195 U, n = 261; placebo, n = 257) experienced a reduction in the frequency of monthly migraine days from baseline across months 5 and 6. However, researchers reported that both the onabotA 155 U group and the 195 U group did not demonstrate a statistically significant improvement on the least square (LS) mean changes compared with the placebo group (P >.05). Overall, the mean change from baseline at the primary time point, months 5 and 6 of treatment, was −3.6 days for placebo, −3.5 days for the onabotA 155 U group, and −3.4 days for the onabotA 195 U group.

“The PRECLUDE trial confirmed the safety profile of onabotA in EM but did not demonstrate significant efficacy of onabotA with respect to reducing migraine days in participants with EM compared to placebo in the trial population enrolled,” lead author Patricia Pozo-Rosich, MD, PhD, head of the neurology department at Vall d’Hebron University Hospital, and colleagues wrote.¹ “This does not necessarily rule out the potential benefit of onabotA for patients with EM characteristics, such as patients who experience 8–14 migraine days per month who fluctuate between [less than] 15 and [at least] 15 headache days. Future research to explore the biological differences between EM and CM may help refine treatment approaches and guide the development of new therapies.”

PRECLUDE was a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial with an open-label extension phase, that assessed the efficacy and safety of onabotA for the preventive treatment of EM. Investigators randomized 775 patients aged 18 to 65 years with a history of migraine attacks to receive placebo, onabotA 155 U, or onabotA 195 U. Participants recorded daily headache data and medication use through an electronic diary during a 4-week screening phase, 24-week double-blind phase, followed by a 24-week open-label extension phase. The primary end point of the trial was the change in the frequency of monthly migraine days from baseline across months 5 and 6.

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In the study, researchers also observed no statistically significant differences between onabotA and placebo groups on the secondary end points. All told, the LS mean changes in monthly headache days at months 5 and 6 were similar across groups (onabotA 155 U, −3.1; onabotA 195 U, −2.9 days; placebo, −3.2 days), and these differences were not statistically significant (P >.05). Similarly, the proportion of participants achieving at least a 50% reduction in monthly migraine days was 46.2% for the onabotA 155 U group and 47.1% for the 195 U group, compared with 44.9% for placebo; these differences were also not statistically significant (P >.05). Investigators noted that patient-reported outcomes displayed no significant differences between the treatment groups and placebo as well.

In the double-blind phase, researchers observed that the adverse event (AE) profiles were generally comparable across treatment groups and consistent with previous studies.^2,3 Across all groups, treatment-emergent AEs (TEAEs) were reported in 342 participants (onabotA 155 U, n = 117; onabotA 195 U, n = 119; placebo, n = 106), and none of the TEAEs suggested a distant spread of toxin. The incidence rate of serious TEAEs that led to withdrawal of trial treatment was also generally low, with less than 3%. Patients with treatment-related TEAEs of at least 1% included eyelid ptosis (2.2%), headache (1.8%), injection site pain (1.4%), migraine (1.4%) and injection site reaction (1.0%), with even further less instances of brow ptosis (0.8%) and neck pain (0.6%).

Safety findings from the open-label phase showed that the overall incidence of TEAEs was comparable across groups (onabotA 155 U, 33.3%; onabotA 195 U, 35.9%; placebo, 35.0%). Treatment-related TEAEs were reported in 9.7% of the placebo group but were notably lower in the onabotA groups (onabotA 155 U, 5.3%; onabotA 195 U, 5.8%), and the incidence of serious TEAEs was low, at 0.9% in the placebo group and 0.4% in both onabotA groups. Severe TEAEs were more frequently observed in the onabotA 155 U group at 1.3% compared with 0.5% in the placebo and 0.4% in onabotA 195 U groups. None of the TEAEs suggested a distant spread of toxin. Treatment-related TEAEs of at least 1% included eyelid ptosis (1.7%), injection site pain (1.1%), with migraine (0.9%) and the mephisto sign (0.6%).

“Overall, our findings stress the importance of exploring tailored treatment strategies for different migraine biotypes. Characterization of peripheral and central sensitization across the spectrum of migraine is warranted to further understand the migraine disease state and better define the CM biotype and chronification process, focusing on identifying clinical, functional and molecular biomarkers that correlate with CM and complement the current headache day frequency definition,” Pozo-Rosich et al noted.¹ “This aligns with the key headache research priorities outlined by international headache experts; specifically, understanding the evolution of migraine, risk factors for chronification and factors that predict improvement are key research priorities for diagnosis and management of migraine.”

REFERENCES
1. Pozo-Rosich P, Blumenfeld AM, Lipton RB, et al. OnabotulinumtoxinA for the preventive treatment of episodic migraine : Results from the phase 3, multicenter randomized, double-blind, placebo-controlled phase of the PRECLUDE trial. Cephalalgia. 2025;45(10):3331024251370769. doi:10.1177/03331024251370769
2. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793-803. doi:10.1177/0333102410364676
3. Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804-814. doi:10.1177/0333102410364677