Effect of Atogepant on the Vestibulo-Ocular Reflex in Healthy Adults and Adults With Migraine

Background and rationale

Calcitonin gene-related peptide (CGRP) is a neuropeptide with an established role in migraine pathophysiology, and CGRP receptor antagonists (gepants) are approved for migraine treatment and prevention. CGRP is also expressed in the vestibular periphery, where it is released by efferent neurons onto type II hair cells and calyx-bearing afferents. Mice lacking the CGRP gene or the CGRP receptor show reduced VOR gain, indicating that CGRP contributes to the sensitivity of the vestibular afferent response. Whether CGRP receptor antagonism produces a comparable reduction of VOR gain in humans has not been investigated. Because gepants are now widely prescribed, the question is of practical as well as mechanistic relevance, and it may also inform the pathophysiology of vestibular migraine.

Objective

The trial investigates whether acute pharmacological blockade of the CGRP receptor reduces the gain of the vestibulo-ocular reflex in humans. Semicircular canal function is assessed across the frequency spectrum (video head impulse test, caloric irrigation, sinusoidal harmonic acceleration on the rotary chair) and otolith function is assessed by the ocular counter-torsion response to static whole-body tilt. Prepulse inhibition of the blink reflex is assessed as an additional brainstem excitability measure.

Design

Single-centre, randomised, placebo-controlled, double-blind, two-period cross-over trial conducted in two consecutive phases: 40 healthy participants are enrolled first, and recruitment of 40 participants with episodic or chronic migraine (ICHD-3) begins only once enrolment in the healthy group is complete. Total enrolment is 80.

Each participant attends a screening visit (Visit 0, up to 28 days before or on the same day as Visit 1), two treatment visits (Visits 1 and 2) separated by a washout period of at least 5 days, and a safety follow-up (Visit 3) within 7 days after Visit 2. Each treatment visit lasts approximately 165 minutes.

Randomisation and blinding

Participants are randomised 1:1 to treatment sequence AB (atogepant at Visit 1, placebo at Visit 2) or BA. The allocation sequence is computer-generated with permuted blocks of variable length, stratified by group, by a physician independent of the study team who holds the random seed, the block lengths and the master code list and who releases the list only after database lock. Blinded kits are prepared and labelled to that sequence by an independent pharmacy. Participants, the sponsor-investigator, the sub-investigators, the study staff, the statistician and the monitor all remain blinded. One sealed code-break envelope per participant is held at the site for emergency unblinding.

Intervention

A single oral dose of atogepant 60 mg, or matching placebo, is administered under direct supervision at each treatment visit. To preserve the blind, the marketed film-coated tablet is over-encapsulated in a size 000 hard-gelatine capsule filled with mannitol; the placebo capsule contains mannitol only and is identical in appearance. The 5-day washout exceeds ten elimination half-lives of atogepant (t½ ≈ 11 h). Vestibular testing begins 90-120 minutes after dosing, and participants remain under observation at the site for at least 90 minutes after each dose.

Statistical analysis

The primary null hypothesis is that the mean intra-individual difference in VOR gain between the atogepant and placebo conditions is zero, tested two-sided at α = 0.05. Analyses use paired t-tests and repeated-measures ANOVA for within-group comparisons and mixed-effects models for comparisons between the healthy and migraine groups, accounting for the cross-over design. Sex is included as a covariate.

Oversight

Investigator-initiated trial, Category B under the Swiss Clinical Trials Ordinance. No Data Monitoring Committee is established; the rationale is given in the protocol. Risk-adapted monitoring is performed by an independent, blinded monitor.

Inclusion criteria

Healthy participants (Phase 1 of enrolment):

• Age 18 to 65 years
• No functional or structural vestibular disorder
• No history of unilateral or bilateral vestibulopathy
• No diagnosis of migraine
• Written informed consent provided by the participant

Participants with migraine (Phase 2 of enrolment):

• Diagnosis of episodic or chronic migraine according to the ICHD-3 criteria
• Age 18 to 65 years
• No functional or structural vestibular disorder
• No history of unilateral or bilateral vestibulopathy
• Written informed consent provided by the participant

Exclusion criteria

• Hypersensitivity to atogepant
• Intake of any CGRP-antagonist medication within the last 6 months
• Known impaired kidney function with a creatinine clearance below 30 mL/min, or known impaired liver function (Child-Pugh B or C)
• Insufficiently controlled, unstable or newly diagnosed cardiovascular disease, for example ischaemic coronary disease, coronary vasospasm or cerebral ischaemia
• Myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, cardiac surgery, stroke of any kind or transient ischaemic attack within the last 6 months (24 weeks)
• Medication overuse headache
• Cardiac pacemaker or other implanted electronic device
• Concomitant use of strong CYP3A4 inhibitors, of strong or moderate CYP3A4 inducers, or of OATP1B1/OATP1B3 inhibitors
• Pregnancy or breastfeeding; women of childbearing potential not using effective contraception during the study
• Participation in another clinical trial with an investigational medicinal product within 30 days before the screening visit
• Inability to understand the participant information or to give written informed consent