Effect of Atogepant on the Vestibulo-Ocular Reflex in Healthy Adults and Adults With Migraine (VOR-GRIP)

The Role of CGRP in Human Vestibulo-Ocular Reflex (VOR) - a Randomized, Blinded, Placebo-controlled, Cross-over Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy Adult Participants; Migraine Disorders, Brain; Vestibulo-Ocular Reflex
• Intervention / Treatment: Drug: Atogepant 60 mg; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Vergil V Mavrodiev, MD; Phone Number: +41 43 253 64 03; Email: Vergil.Mavrodiev@usz.ch
• Study Contact Backup: Name: Konrad P Weber, Prof.; Phone Number: +41 44 255 55 49; Email: Konrad.Weber@usz.ch

Study Locations

• Switzerland
  • Canton of Zurich
    • Zurich, Canton of Zurich, Switzerland, 8091
      • University Hospital Zurich, Department of Neurology
      • Contact: Vergil V Mavrodiev, MD; Phone Number: +41 43 253 64 03; Email: Vergil.Mavrodiev@usz.ch
      • Contact: Ricarda Wurm, MD; Phone Number: +41 43 253 03 65; Email: Ricarda.Wurm@usz.ch
      • Principal Investigator: Konrad P Weber, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence AB: Atogepant then Placebo; Drug: Atogepant; Drug: Placebo	Drug: Atogepant 60 mg; Single oral dose of atogepant 60 mg, administered once during the trial. The marketed Aquipta® 60 mg film-coated tablet, authorised in Switzerland, is over-encapsulated into a size 000 hard-gelatine capsule filled with mannitol (Ph. Eur.) by an independent pharmacy in order to maintain blinding; the active substance and the tablet itself are not modified. The capsule is swallowed with a glass of water under the direct supervision of the investigator, and the date and time of administration are documented.; Other Names: Qulipta; Aquipta; Drug: Placebo; Sequence AB: Atogepant then Placebo · Sequence BA: Placebo then Atogepant
Experimental: Sequence BA: Placebo then Atogepant; Drug: Placebo; Drug: Atogepant	Drug: Atogepant 60 mg; Single oral dose of atogepant 60 mg, administered once during the trial. The marketed Aquipta® 60 mg film-coated tablet, authorised in Switzerland, is over-encapsulated into a size 000 hard-gelatine capsule filled with mannitol (Ph. Eur.) by an independent pharmacy in order to maintain blinding; the active substance and the tablet itself are not modified. The capsule is swallowed with a glass of water under the direct supervision of the investigator, and the date and time of administration are documented.; Other Names: Qulipta; Aquipta; Drug: Placebo; Sequence AB: Atogepant then Placebo · Sequence BA: Placebo then Atogepant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in vestibulo-ocular reflex (VOR) gain measured by video head impulse test (vHIT)	VOR gain of the horizontal semicircular canals, measured by video head impulse test as the ratio of eye velocity to head velocity (unitless), under atogepant 60 mg compared with placebo. The intra-individual difference between the atogepant condition and the placebo condition is the quantity of interest. A difference of 0.10 in VOR gain is considered clinically meaningful.	Assessed 90-120 minutes after dosing in each of the two treatment periods (Visit 1 and Visit 2, separated by a washout of at least 5 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Caloric response	Total caloric response, calculated as the sum of the peak slow-phase eye velocities (°/s) of the four irrigations (warm and cool, left and right ear), under atogepant 60 mg compared with placebo.	Assessed 90-120 minutes after dosing in each of the two treatment periods (Visit 1 and Visit 2, separated by a washout of at least 5 days)
Rotary chair VOR gain (sinusoidal harmonic acceleration)	VOR gain during sinusoidal harmonic acceleration on the rotary chair (ratio of eye velocity to chair velocity, unitless), measured across the frequency range 0.01-0.5 Hz, under atogepant 60 mg compared with placebo.	Assessed 90-120 minutes after dosing in each of the two treatment periods (Visit 1 and Visit 2, separated by a washout of at least 5 days)
Nausea assessed by visual analogue scale	Description: Severity of nausea, assessed on a 100 mm visual analogue scale anchored at "no nausea" (0 mm) and "worst imaginable nausea" (100 mm), with higher scores indicating more severe nausea. The change from before to after the vestibular test battery is compared between the atogepant 60 mg condition and the placebo condition.	Immediately before and immediately after the vestibular test battery at each of the two treatment visits (approximately 90 and 180 minutes after dosing)
Motion sickness symptoms assessed by the Motion Sickness Assessment Questionnaire (MSAQ)	Motion sickness symptoms following caloric and rotary chair testing, assessed with the Motion Sickness Assessment Questionnaire (MSAQ). The MSAQ total score is reported as a percentage of the maximum possible score, with higher scores indicating more severe symptoms. The change from before to after the vestibular test battery is compared between the atogepant 60 mg condition and the placebo condition.	Immediately before and immediately after the vestibular test battery at each of the two treatment visits (approximately 90 and 180 minutes after dosing)
Spinning vertigo assessed by visual analogue scale	Severity of spinning vertigo, assessed on a 100 mm visual analogue scale anchored at "no spinning vertigo" (0 mm) and "worst imaginable spinning vertigo" (100 mm), with higher scores indicating more severe vertigo. The change from before to after the vestibular test battery is compared between the atogepant 60 mg condition and the placebo condition.	Immediately before and immediately after the vestibular test battery at each of the two treatment visits (approximately 90 and 180 minutes after dosing)
VOR latency	Latency (milliseconds) between the onset of the head movement and the onset of the compensatory eye movement during video head impulse testing, under atogepant 60 mg compared with placebo.	Assessed 90-120 minutes after dosing in each of the two treatment periods (Visit 1 and Visit 2, separated by a washout of at least 5 days)
Compensatory saccades	Presence and characteristics of compensatory overt and covert saccades during video head impulse testing, under atogepant 60 mg compared with placebo.	Assessed 90-120 minutes after dosing in each of the two treatment periods (Visit 1 and Visit 2, separated by a washout of at least 5 days)
Prepulse inhibition of the blink reflex	Prepulse inhibition of the blink reflex, expressed as the percentage reduction of the blink reflex response amplitude when preceded by a prepulse stimulus, under atogepant 60 mg compared with placebo.	Time Frame: 90-150 minutes after dosing in each treatment period.

Collaborators and Investigators

• Sponsor: Konrad Peter Weber
• Investigators: Principal Investigator: Konrad P Weber, Prof., University Hospital Zurich, Department of Neurology

Publications and helpful links

General Publications

• Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018 Jun;14(6):338-350. doi: 10.1038/s41582-018-0003-1.
• Gianaros PJ, Muth ER, Mordkoff JT, Levine ME, Stern RM. A questionnaire for the assessment of the multiple dimensions of motion sickness. Aviat Space Environ Med. 2001 Feb;72(2):115-9.
• MacDougall HG, Weber KP, McGarvie LA, Halmagyi GM, Curthoys IS. The video head impulse test: diagnostic accuracy in peripheral vestibulopathy. Neurology. 2009 Oct 6;73(14):1134-41. doi: 10.1212/WNL.0b013e3181bacf85.
• Ailani J, Lipton RB, Goadsby PJ, Guo H, Miceli R, Severt L, Finnegan M, Trugman JM; ADVANCE Study Group. Atogepant for the Preventive Treatment of Migraine. N Engl J Med. 2021 Aug 19;385(8):695-706. doi: 10.1056/NEJMoa2035908.
• Jones SM, Vijayakumar S, Dow SA, Holt JC, Jordan PM, Luebke AE. Loss of alpha-Calcitonin Gene-Related Peptide (alphaCGRP) Reduces Otolith Activation Timing Dynamics and Impairs Balance. Front Mol Neurosci. 2018 Aug 24;11:289. doi: 10.3389/fnmol.2018.00289. eCollection 2018.
• Luebke AE, Holt JC, Jordan PM, Wong YS, Caldwell JS, Cullen KE. Loss of alpha-calcitonin gene-related peptide (alphaCGRP) reduces the efficacy of the Vestibulo-ocular Reflex (VOR). J Neurosci. 2014 Jul 30;34(31):10453-8. doi: 10.1523/JNEUROSCI.3336-13.2014.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: September 10, 2026
• First Submitted That Met QC Criteria: September 16, 2026
• First Posted (Actual): September 17, 2026

Study Record Updates

• Last Update Posted (Actual): September 17, 2026
• Last Update Submitted That Met QC Criteria: September 16, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Healthy volunteers; Migraine; Vestibular function; CGRP; Cross-over study; Atogepant; vHIT; Prepulse inhibition; Vestibulo-ocular reflex; Caloric testing; Calcitonin Gene-Related Peptide; Gepant; CGRP receptor antagonist; VOR gain; Otolith function; Video head impulse test; Rotary chair; Sinusoidal harmonic acceleration; Blink reflex
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; atogepant
• Other Study ID Numbers: BASEC 2024-02190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared. The participant information and informed consent form for this investigator-initiated, single-centre trial do not cover the further use of the collected data for research purposes beyond this project, and under the Swiss Human Research Act data may not be shared for purposes that are not covered by the participants' consent. In addition, the dataset is small (80 participants from a single centre) and contains detailed oculomotor and clinical measurements, so a meaningful risk of re-identification would remain after de-identification.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No