Galcanezumab for Vestibular Migraine

Study Overview
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Brief Summary
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Vestibular migraine (VM) has been recognized a distinct subtype of migraine that causes dizziness as the predominant symptom. Criteria for diagnosis have been adopted by the Barany Society. Previous epidemiological research from the investigators has shown that VM affects 2.7% of the adult population of the United States. Yet, despite its high prevalence, there is very little data upon which to guide treatment decisions. A Cochrane review in 2015 concluded that there were no placebo controlled trials in VM, and none have been done since then. The investigators recently developed and validated a patient reported outcome tool for VM called VM-PATHI (VM- Patient Assessment Tool and Handicap Inventory). Anecdotal evidence suggests that CGRP antagonists, such as Galcanezumab, may be effective in reducing or eliminating symptoms in VM. Therefore, the investigators propose a pilot study of changes in VM-PATHI scores, comparing active treatment (Galcanezumab) to placebo arms.

Detailed Description
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Vestibular migraine (VM) is a distinct subtype of migraine that causes episodic vertigo/dizziness, sometimes with headache, and sometimes without. However, unlike traditional migraines, patients generally seek out care because of dizziness, and not because of headache. Therefore, these patients are cared for by a variety of providers who treat dizziness, including otolaryngologists and neurologists. Lifetime prevalence of VM in the general population is estimated to be 2.7%, and at least 10% of patients in a tertiary care vestibular clinic have VM. Furthermore, VM has been shown to decrease quality of life in multiple domains, including overall health, mental health, and emotional health. Since testing and imaging are usually normal, diagnosis can only be made on clinical grounds. Recently, consensus criteria for diagnosis was published by the Barany Society and the International Classification of Headache Disorders. Galcanezumab is a calcitonin gene related peptide (CGRP) antagonist that has been approved by the FDA for treatment of episodic and chronic migraine. Its effects with regards to VM have not been formally studied. However, there is ample evidence to suggest that aberrant trigeminovascular inflammation may be integral to the pathophysiology of VM, similar to migraine in general. This pilot study will be a single center, randomized double-blinded placebo-controlled trial comparing galcanezumab to placebo for treatment of VM. Screening data will be reviewed to determine subject eligibility. Participants who meet all inclusion criteria and none of the exclusion criteria will be entered into the study. Participants in the galcanezumab arm will receive 240 mg via subcutaneous injection with a pre-loaded syringe at month 1, followed by 120 mg at month 2, and 120 mg at month 3. Those in the placebo arms will receive subcutaneous injections at the same time intervals of placebo. Randomization will occur through the hospital research pharmacy. Allocation concealment will be ensured; study participants will be given an envelope from a folder of sequentially ordered identical envelopes that will contain study instructions and the allocated drug. The master file linking study ID with allocation will be created by a third party and kept secret until after data analysis is complete. This will ensure that both providers and participants are adequately blinded. Blocking will be used in increments of 10 subjects to ensure equitable distribution of subjects into the two treatment arms. In addition, stratification by sex and definite versus probable vestibular migraine status will be used to ensure equal allocation. Total duration of subject participation will be five months. Total duration of the study is expected to be 2 years. Data collection will be performed by the clinical research coordinator during each study visit. This data will be entered into the REDCap database by the research coordinator. VM- Patient Assessment Tool and Handicap Inventory (VM-PATHI), dizziness handicap inventory (DHI), General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Patient-Reported Outcomes Measurement Information System Short Form (PROMIS SF) v1.1- Global Health, and Headache Impact Test-6 (HIT-6) will be administered electronically via REDCap to the subject during the study visit. There will be no stopping rules for this trial, given the short duration of the study. Each adverse effect and serious adverse effect will be reviewed by the data safety monitoring team, and subjects may be unblinded and/or the study will be stopped early for serious safety concerns.

Official Title
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A Pilot Trial of Galcanezumab for Vestibular Migraine

Conditions
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Vestibular Migraine

Intervention / Treatment
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* Drug: Galcanezumab Prefilled Syringe
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18 to 75 years of age at Study Visit 1. Documentation of a vestibular migraine or probable vestibular migraine diagnosis according to the following criteria determined by the Barany Society: Vestibular migraine A: At least 5 episodes with vestibular symptoms of moderate or severe intensity, lasting 5 min to 72 hours B: Current or previous history of migraine with or without aura according to the International Classification of Headache Disorders (ICHD) C: One or more migraine features with at least 50% of the vestibular episodes: Headache with at least two of the following characteristics: one sided location, pulsating quality, moderate or severe pain intensity, aggravation by routine physical activity Photophobia and phonophobia Visual aura D: Not better accounted for by another vestibular or ICHD diagnosis Probable vestibular migraine At least 5 episodes with vestibular symptoms of moderate or severe intensity, lasting 5 min to 72 hours Only one of the criteria B and C for vestibular migraine is fulfilled (migraine history or migraine features during the episode) Not better accounted for by another vestibular or ICHD diagnosis Written informed consent obtained from subject and ability for subject to comply with the requirements of the study. Baseline and Study Visit 2 VM-PATHI score > 25 Baseline (month 0 to 1) definite dizzy days > 4 Fluency in English 80% adherence or better to daily text message during baseline phase Written informed consent Access to email, and cell phone Exclusion Criteria: Pregnant, breastfeeding, or unwilling to use approved form of birth control during participation in the study. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. Allergy to galcanezumab Prior treatment with galcanezumab History of ear surgery (other than ear tubes) Other vestibular diagnosis (excluding treated Benign Paroxysmal Positional Vertigo- BPPV). This includes Meniere's disease, superior canal dehiscence syndrome, vestibular neuritis, persistent postural perceptual dizziness, unilateral or bilateral vestibular loss, cerebellar or brainstem disease, multiple sclerosis, or Mal de Debarquement. Failure of treatment with > 4 prophylactic migraine medications Prior or current treatment with a CGRP medication Pregnant/breastfeeding if female History of serious medical or psychiatric disease, at the discretion of the treating physician (including significant coronary artery disease, peripheral vascular disease, cerebrovascular disease, kidney disease, liver disease, Raynaud's disease, uncontrolled psychiatric disease or past psychiatric hospitalization) History of mania, psychosis, or suicidal ideations Ok if on up to 2 migraine prophylactic medications (prescribed for that purpose), dose must be stable for 2 months prior to study start.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study drug will be administered with a subcutaneous injection of galcanezumab or placebo. The first dose (at month 1) will be a loading dose of two injections, or 240 mg in total. After that, at month 2 and month 3, each participant will get either a subcutaneous injection of galcanezumab 120 mg or placebo. The injections will be with a pre-loaded syringe containing either galcanezumab or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Galcanezumab<br>The galcanezumab arm will self-administer a subcutaneous injection of galcanezumab. The first dose (at month 1) will be a loading dose of two injections, or 240 mg in total. After that, at month 2 and month 3, each participant will receive an injection of galcanezumab 120 mg. The injections will be with a pre-loaded syringe containing galcanezumab. | Drug: Galcanezumab Prefilled Syringe<br>* Galcanezumab will be supplied in preloaded syringes, each with a dose of 120 mg. Participants will first receive the first month's supply (240 mg) at study visit 2, and then will receive a two month supply at study visit 3. So, at study visit 2 and 3, each participant will get two pre-filled syringes.<br>* Other names: Emgality;|
| Placebo Comparator: Placebo<br>The placebo arm will self-administer a subcutaneous injection of placebo. The first dose (at month 1) will be a loading dose of two injections, or 240 mg in total. After that, at month 2 and month 3, each participant will receive an injection of placebo 120 mg. The injections will be with a pre-loaded syringe containing placebo. | Drug: Placebo<br>* Placebo will be supplied in preloaded syringes, each with a dose of 120 mg. Participants will first receive the first month's supply (240 mg) at study visit 2, and then will receive a two month supply at study visit 3. So, at study visit 2 and 3, each participant will get two pre-filled syringes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in VM-PATHI (Vestibular Migraine-Patient Assessment Tool and Handicap Inventory) Score from Baseline to Month 4 | This is a recently developed and validated outcome measure for vestibular migraine from the investigators. It has been shown to be highly reliable and valid, and responsive to treatment changes. At this point, it is the only disease specific outcome measure for vestibular migraine. Scores are between 0 and 100, with 100 indicating higher levels of disease related suffering. | Change between baseline (month 0) and after treatment (month 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Number of Definitive Dizzy Days for Participants Measured Daily from Baseline to Month 4 via Text Message | Participants will receive a daily text message to rate their dizziness from 0 (no dizziness), 1 (mild dizziness), 2 (moderate dizziness), and 3 (severe dizziness). A score of 2 or higher will count as a definitive dizzy day. | Change between baseline (month 0) and after treatment (month 4) | 
| Change in Response Rates as Defined by Percentage Reduction in Definitive Dizzy Days via Text Message from Baseline to Month 4 | Response rates will be measured by the percentage of participants in each arm experiencing a 100%, 75%, 50%, 25%, 0% reduction in definitive dizzy days. | Change between baseline (month 0) to after treatment (month 4) | 
| Change in Dizziness Handicap Inventory Score from Baseline to Month 4 | This is the most widely used measure of dizziness severity, and consists of 25 questions. Questions ask about problems related to dizziness, and are scored as no (0 points), sometimes (2 points), or always (4 points). Total score is between 0 and 100, with higher scores indicating more disability. | Change between baseline (month 0) to after treatment (month 4) | 
| Change in Patient-Reported Outcomes Measurement Information System Short Form (PROMIS SF) v1.2- Global Health Scores | There are 10 questions on this quality of life measure, each with a score of 1-5. Higher scores correspond to a greater extent of the concept measured (e.g., more fatigue). Two summed scores are generated, one for global mental health (question #3, 6, 7, 8) and one for global physical health (question #2, 4, 5, 10). The remaining 2 questions are analyzed separately. Summed scores for physical health and mental health are converted into T-score values using the HealthMeasures Scoring Service available online. T-scores for physical health and mental health can be grouped into 5 categories based on the responses to question #1: In general, would you say your health is excellent, very good, good, fair, or poor? The cut points for each category is determined by calculating the midpoint between 2 adjacent means. For example, if the mean mental health T-score for Excellent is 61 and the mean T-score for Very Good is 51, then the cut point for these categories would be 56. | Change between baseline (month 0) to after treatment (month 4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vestibular migraine, galcanezumab, clinical trial