P-005 - (Poster #5) A post hoc analysis of participants with migraine with aura from the TEAM (a phase 3 randomized, double-blind, sham-controlled Trial of eTNS for the Acute Treatment of Migraine) study

Despite the growing options for pharmaceutical treatment of migraine, these acute treatment options often have contraindications, poor tolerability and risk for medication overuse headache. This may be especially true for certain migraine subtypes such as those with migraine aura (MA) when compared to migraine without aura (MO). For example, triptans and ergotamines are contraindicated in migraine with brainstem aura and hemiplegic migraine. External trigeminal nerve stimulation (eTNS) is a noninvasive device which has been established for acute and preventive migraine management. It stimulates the supraorbital and supratrochlear branches of the ophthalmic division of the trigeminal nerve and has demonstrated safety and efficacy in double-blind, randomized, sham-controlled studies.

Purpose/Objectives:

Migraine with aura (MA) and migraine without aura (MO) are clinically distinct subtypes that may respond differently to acute therapies. While external trigeminal nerve stimulation (eTNS) has been shown to be a safe, effective, non-pharmacologic treatment for acute migraine, the influence of aura on treatment outcomes has not been well characterized. In this post hoc analysis, we examine the potential heterogeneity in migraine outcomes following 2-hour eTNS therapy between participants with MA and MO using data from the Trial of eTNS for the Acute treatment of Migraine (TEAM) study. Our objective was to evaluate whether the presence of aura is associated with differential treatment efficacy across key clinical outcomes, including pain freedom, symptom relief, and rescue medication use. By examining potential heterogeneity in treatment response, this analysis aims to inform more personalized therapeutic approaches and expand understanding of the underlying pathophysiology of migraine subtypes.

Methods:

Participants (N=538) were randomized 1:1 to verum (n=259) or sham (n=279) stimulation with participants and care providers blinded to intervention assignments. Primary endpoints from the TEAM study included: 1) pain freedom at two hours and 2) resolution of most bothersome migraine-associated symptom (MBS). Secondary endpoints included: 1) pain relief at two hours, 2) resolution of any migraine-associated symptoms at two hours, 3) sustain pain freedom at 24 hours, 4) sustained pain relief at 24 hours, and 5) use of rescue migraine therapy between two and 24 hours. This post hoc analysis compared the primary and secondary treatment endpoints between MA (n=224) versus MO (n=314) participants. First, we performed logistic regression for each posttreatment outcome and included aura sub-group x treatment arm as an interaction term in the model to explore the potential of a differential effect conditional on the total sample. We further explored direct treatment group comparisons between MA versus MO using chi-square analysis. We also compared treatment outcomes between MA and MO participants within the sham, the verum, and total sample using chi-square analysis. Finally, heterogeneity of treatment effect (HTE) was assessed using a 1% absolute treatment effect difference as the clinically relevant threshold.

Results:

In the MO group, the sham treatment group was slightly older than the verum treatment group (42.9ą12.4 vs. 40.0ą11.6, P = 0.038). Across the total sample, irrespective of treatment group, the MA group had a higher proportion of men (23.2%) compared to the MO group (13.7%), with a corresponding lower proportion of women (76.8% vs. 86.3%, P = 0.004). Moderate baseline headache pain was reported more frequently in the MO group compared to the MA group (67.2% vs. 49.1%, P < 0.001), while severe baseline headache pain was reported more often in the MA group (50% vs. 32.8%, P < 0.001).

In participants with MO, a significantly higher proportion experienced resolution of MBS after two hours of eTNS treatment in the verum group compared to the sham group (55.5% vs. 39.3%, P = 0.004). Verum-treated MO participants also reported significantly higher rates of pain relief at two hours (69.9% vs. 50.0%, P < 0.001) and sustained pain relief at 24 hours post-treatment (42.5% vs. 28.0%, P = 0.007) compared to the sham group.

When comparing post-eTNS treatment outcomes between MA and MO participants, the MO group used rescue medications at significantly higher rates than the MA group across the total sample (45.5% vs. 19.6%, P < 0.001), within the verum group (39.7% vs. 24.2%, P = 0.002), and within the sham group (50.6% vs. 18.0%, P < 0.001). Additionally, MA participants reported higher rates of pain relief at two hours following eTNS treatment (63.1% vs. 50.0%, P = 0.032) and sustained pain relief at 24 hours (44.1% vs. 28.0%, P = 0.005) compared to MO participants.

Regarding HTE, no significant subgroup-by-treatment interactions were observed for any outcomes. Though not statistically significant, clinically relevant HTE was observed in the use of rescue medication between 2- and 24-hours post-treatment, with the MO group demonstrating an absolute effect of -10.9% (95% CI = -0.137, 0.073) compared to 3.2% (95% CI = -0.002, 0.219) in the MA group (Figure 1). These findings suggest that eTNS stimulation results in a greater reduction of rescue medication use for MO participants relative to MA participants.

Conclusions/Implications for future research and/or clinical care:

E-TNS is a safe and effective therapy for the acute treatment of MA and MO. While patients with MA and MO may both benefit from eTNS treatment of acute migraine, there may be key differences in migraine outcome which will help providers counsel and select patients who may derive the most benefit from eTNS therapy. The findings from this study may also support prior studies indicating that treatment early in the prodrome or aura phase of migraine is associated with improved migraine outcomes. Further studies are needed to explore the potential interactions of trigeminal nerve stimulation and neurophysiological mechanisms of MA and CSD which may have substantial impact beyond headache medicine.