The Role of CGRP in Human Vestibulo-Ocular Reflex (VOR) - a Randomized, Blinded, Placebo-controlled, Cross-over Trial
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Change in vestibulo-ocular reflex (VOR) gain measured by video head impulse test (vHIT)
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
In addition to the participants, the care providers, the investigators and the outcomes assessors, the person performing the statistical analysis and the independent trial monitor also remain blinded to the treatment allocation until database lock. The only unblinded persons are the independent physician who generates and holds the randomisation list, who takes no part in the conduct, data collection or analysis of the trial, and the designated staff of the independent pharmacy who label the study kits. Blinding is maintained by over-encapsulating the marketed film-coated tablet in a hard-gelatine capsule identical in appearance to the mannitol-filled placebo capsule; kit labels carry only the study identifier, randomisation number, treatment period, batch number and expiry date.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Sequence AB: Atogepant then Placebo
Drug: Atogepant; Drug: Placebo
干预措施: Placebo (Drug)
Sequence BA: Placebo then Atogepant
Drug: Placebo; Drug: Atogepant
干预措施: Placebo (Drug)
Sequence BA: Placebo then Atogepant
Drug: Placebo; Drug: Atogepant
干预措施: Atogepant 60 mg (Drug)
Sequence AB: Atogepant then Placebo
Drug: Atogepant; Drug: Placebo
干预措施: Atogepant 60 mg (Drug)
结局指标
主要结局
Change in vestibulo-ocular reflex (VOR) gain measured by video head impulse test (vHIT)
时间窗: 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)
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.
次要结局
- Caloric response(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)(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(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)(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(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(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(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(Time Frame: 90-150 minutes after dosing in each treatment period.)
研究者
Konrad Peter Weber
Prof. Dr. med.
University of Zurich