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

Overview

Researchers want to find out how a substance in the body called CGRP affects balance. CGRP (calcitonin gene-related peptide) is a small protein involved in migraine. Several approved migraine medicines work by blocking it. Studies in animals suggest that CGRP also helps a reflex called the vestibulo-ocular reflex, or VOR. The VOR keeps vision steady when the head moves: when the head turns, the eyes move the opposite way by the same amount, so the world does not appear to jump. Animals that lack the CGRP receptor have a weaker VOR. It is not known whether blocking CGRP weakens the VOR in people. This study tests whether a single dose of atogepant changes the VOR in people. Atogepant is approved in Switzerland for the prevention of migraine and blocks the CGRP receptor. In this study it is used in a different way than it is approved for. Eighty people will take part at the University Hospital Zurich. The study runs in two parts. First, 40 healthy people join. After that, 40 people who have episodic or chronic migraine join. Everyone receives both of the following, in random order: one capsule containing atogepant 60 mg one capsule containing placebo (a capsule with no active medicine) The two test visits are at least 5 days apart. A computer decides which capsule each person receives first. Neither the participants nor the study team know which capsule is which until the study is finished. At each test visit, the participant swallows the capsule at the study centre and stays for at least 90 minutes. Balance and eye-movement tests then begin, about 90 to 120 minutes after the capsule. The tests record eye movements while the head is moved quickly, while warm and cool air or water is placed in the ear canal, while a chair turns gently from side to side, and while the whole body is tilted. Participants also answer short questionnaires about nausea and dizziness before and after the tests. Each test visit lasts about 2 hours and 45 minutes. A short follow-up visit or telephone call takes place within 7 days after the second test visit. People aged 18 to 65 can take part if they have no balance disorder and meet the other study requirements. People cannot take part if, for example, they are allergic to atogepant, have taken a CGRP-blocking medicine in the past 6 months, have severe kidney or liver problems, have unstable heart disease, have a pacemaker, or are pregnant or breastfeeding. Participants are not expected to get a health benefit from taking part. The study is done to learn more about how CGRP works in the balance system, which may help in developing treatments for dizziness and migraine in the future.

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.