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Received: 13 April 2024 | Accepted: 3 August 2024 DOI: 10.1111/head.14835

RESEARCH SUBMISSION

A placebo controlled, randomized clinical trial of galcanezumab for vestibular migraine: The INVESTMENT study

1 Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA 2 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA 3 Department of Neurology, University of California, San Francisco, San Francisco, California, USA Correspondence Jeffrey D. Sharon, 6960 Norfolk Rd., Berkeley, CA 94075, USA. Email: jeffrey.sharon@ucsf.edu

Abstract Objective: To study if galcanezumab is effective for vestibular migraine (VM). Background: There are currently no placebo-controlled trials showing that treatment is effective for VM. Therefore, we performed the first placebo controlled, randomized clinical trial of a calcitonin gene–related peptide–targeted monoclonal antibody for VM. Methods: This was a single site, prospective, double-blind placebo controlled randomized clinical trial. Key inclusion criteria were as follows: participants aged 18–75years with a diagnosis of VM or probable VM per Barany Society criteria. The primary outcome was change in VM-PATHI (Vestibular Migraine Patient Assessment Tool and Handicap Inventory) score, and secondary outcomes included change in DHI (Dizziness Handicap Inventory) score, and count of definite dizzy days (DDDs). Participants were randomized 1:1 to 3months of treatment with galcanezumab or placebo via subcutaneous injection with a pre-filled syringe, 240mg the first month, and 120mg for the second and third months. Results: Forty participants were randomized, and 38 participants were in the modified intent to treat analysis. VM-PATHI score was reduced 5.1 points (95% confidence interval [CI] −13.0 to 2.7) for placebo ( N = 21), and 14.8 points (95% CI −23.0 to −6.5) for galcanezumab ( N = 17), a difference of −9.6 (95% CI −20.7 to 1.5, p = 0.044). DHI dropped 8.3 points in the placebo arm (95% CI −15.0 to 1.6), and 22.0 points in the galcanezumab arm (95% CI −31.9 to −12.1), a difference of −13.7 (95% CI −20.4 to −8.5, p = 0.018). The count of DDDs per month dropped from 18days (standard deviation [SD] 7.6) in the baseline month to 12.5 days (SD 11.2) in month 4 for those in the placebo arm, and from 17.9 days (SD 7.9) in the baseline month to 6.6 days (SD 7.3) in month 4 for those in the galcanezumab arm, a difference of −5.7 days (95% CI −10.7 to −0.7, p = 0.026). No serious adverse events were observed. Conclusions: In this pilot study, galcanezumab was effective in treating VM. Plain Language Summary Vestibular migraine is a common cause of dizziness. In this study, we investigated whether treatment with a drug called galcanezumab worked better than placebo for

Funding information Eli Lilly and Company

Abbreviations: CGRP, calcitonin gene–related peptide; CI, confidence interval; DDD, definite dizzy days; DHI, Dizziness Handicap Inventory; mITT, modified intent to treat; PROMIS SF, Patient-Reported Outcomes Measurement Information System Short Form; PROMs, patient-reported outcome measures; SD, standard deviation; VM, vestibular migraine; VM-PATHI, Vestibular Migraine Patient Assessment Tool and Handicap Inventory.

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Headache. 2024;64:1264–1272.

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15264610, 2024, 10, Downloaded from https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14835 by University Of Michigan Library, Wiley Online Library on [21/10/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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treating dizziness. We found that galcanezumab reduced dizziness more than placebo in patients with vestibular migraine.

KEYWORDS dizziness, galcanezumab, vestibular migraine

INTRODUCTION

randomized 1:1 and treated with either galcanezumab or placebo for 3 months. Blocking was used in increments of 10 participants to ensure equitable distribution of participants into the two treatment arms and to allow blocks to be analyzed separately if an early stopping rule was applied. In addition, stratification by sex and VM versus probable VM was used to ensure equal al location. Randomization was achieved with randomization tables that were generated prior to the start of the trial by the study statistician using www.random.org. The onsite research phar macist handled stratification and randomization; the investiga tors with participant contact had no access to the randomization tables and never saw them until data lock, ensuring allocation concealment. There were four study visits over 4 months: study visit 1 (SV1) for screening and informed consent (day 0); study visit 2 (SV2) for base line data collection, randomization, and treatment (day 30); study visit 3 (SV3) for continued treatment and monitoring (day 60); and study visit 4 (SV4) for final data collection (day 120). The first treat ment was with a loading dose of two preloaded syringes of 120mg (total dose 240mg) of galcanezumab or placebo, and each subse quent injection was with 120mg of galcanezumab or placebo. Both participants and investigators were blind to the treatment arm. All participants were enrolled by either J.D.S. or R.K., who would alert the research pharmacist prior to SV2, and provide the participant's sex and diagnosis. If the participant then met final eligibility criteria and agreed to proceed, a study coordinator would collect the study medication from the research pharmacist. Two prefilled syringes would be provided at SV2, and then again at SV3. Galcanezumab and placebo (excipients only) were supplied as visually indistinguishable 1 ml, single-dose, prefilled, disposable syringes with study-specific labels. At SV2, both syringes containing 120mg of galcanezumab or placebo were administered, whereas at SV3, one syringe was ad ministered, and the second was given to the participant in a cold pack, with instructions for storage and home administration at day 90. Home administration was confirmed by the study coordinator on day 90, and the empty syringe was returned to the study team during SV4 to ensure compliance. Eligible participants were aged 18 to 75 at the time of screen ing, with a diagnosis of VM or probable VM per Barany Society criteria. 2,15 They had to be fluent in English and have access to a cell phone and email. During the baseline period (SV1-SV2), partic ipants had to have > 4 definitive dizzy days (DDDs) and score > 25 on the VM-PATHI (Vestibular Migraine Patient Assessment Tool and Handicap Inventory). Patients were excluded if they had vestibular hypofunction, a history of ear surgery other than ear tubes, a history

Vestibular migraine (VM) is one of the most common vestibular dis orders, affecting 2.7% of the US population. 1 Diagnostic criteria are available from the Barany Society, recognizing both VM and prob able VM. 2 Clinical features include vertigo, dizziness, headache, motion sensitivity, photophobia, phonophobia, aural pressure, tin nitus, and brain fog. 3–6 No consistent pathophysiologic finding has yet been found; a careful history, physical exam, and audiometry are needed to rule out vestibulopathy that can present similarly, includ ing Meniere's disease, superior canal dehiscence, and persistent pos tural perceptual dizziness. 7 Despite its prevalence, there is a paucity of evidence of VM. This was highlighted in an expert panel review in 2022. 7,8 Two Cochrane Reviews from 2023 found little evidence for the use of abortive or prophylactic medications for VM. 9,10 This included only one placebo- controlled randomized clinical trial for prophylaxis, with 95mg of metoprolol. 11 Calcitonin gene–related peptide (CGRP) has been shown to be an excellent target for the treatment of headaches due to mi graine. 12 A prospective observational cohort study found that monoclonal antibodies targeting both the CGRP receptor and CGRP ligand were highly effective for VM, with 90% of partici pants experiencing at least a 50% reduction in vertigo attacks. 12,13 Animal studies also suggest a link between CGRP and vestibulop athy. Rahman et al. found that CGRP infusion worsened balance and increased anxiety in mice. 14 CGRP is expressed in vestib ular organs, and CGRP knockout mice display abnormalities of vestibulo-ocular reflex gain. 15 The INVESTMENT (Investigating Vestibular Migraine Emgality Treatment) trial was designed to assess whether CGRP blockade with galcanezumab is effective in reducing dizziness in VM. We hy pothesized that it would be. To our knowledge, this is the first con trolled trial of CGRP antagonist treatment for VM.

METHODS

The INVESTMENT trial was conducted at a single study site in San Francisco from October 2020 until March 2023 at a tertiary care ves tibular clinic. The study protocol was published on clinic altrials.gov (NCT04417361), and research was approved by the University of California, San Francisco Institutional Review Board, reference number 19-29340. Enrolled participants first underwent a base line period without intervention, lasting 1 month. They were then

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of other vestibular disorders other than treated benign paroxys mal positional vertigo, a failure of treatment with > 4 prophylactic medications for VM, prior or current prophylactic treatment with a CGRP medication, or serious medical or psychiatric conditions at the discretion of the investigator. Participants were allowed to continue up to two prophylactic VM medications on a stable dose during the trial. All participants provided written informed consent. They were also allowed to use abortive treatment as needed. The only major change to the protocol during the trial was increasing the age of eli gibility from 65 to 75. This was done very early in the trial, 2months after the first participant was recruited, based on consensus that it would both increase generalizability and recruitment, without signif icant negative trade-offs. Each day of the trial, participants were texted the following: “Over the last 24 hours, what is the highest level of dizziness that you have experienced?” Answer choices were (0) no dizziness, (1) mild dizzi ness, (2) moderate dizziness, and (3) severe dizziness. If the partici pant chose moderate or severe dizziness, they would get a second question asking about usage of medications for relief, and if they answered in the affirmative, a third text provided an opportunity to give the medication names and dosages. Responses were auto matically entered into the REDCap database via Twilio. 2,15,16 Any day with moderate or severe dizziness was considered a DDD. The primary outcome measure was the change in VM-PATHI score, comparing baseline (SV2) to after 3 months of treatment (SV4). VM-PATHI is a validated, disease-specific patient-reported outcome measure for VM. 17 It consists of 25 items, like “dizziness with head or body movements,” which participants rate as (0) no problem, (1) mild problem, (2) moderate problem, (3) severe problem, or (4) prob lem as bad as it can be. VM-PATHI shows good test–retest reliability, discriminant validity, and responsiveness. Scores range from a maxi mum of 100 to a minimum of 0. Secondary outcome measures included the change in the Dizziness Handicap Inventory (DHI), comparing scores at baseline to after 3months of treatment (SV4). 18 The DHI is the most widely used metric of vestibular outcomes. Scores range from a maximum of 100 to a minimum of 0. The minimal clinically important differ ence has been calculated at 11 points; however, a recent study found that the minimal detectable change was 18 points. 19,20 Another sec ondary endpoint was the change in PROMIS SF (Patient-Reported Outcomes Measurement Information System Short Form) v1.2 Global Health score, which generates both a physical and mental subscale score. Reduction in DDDs from baseline to month 4 was a secondary outcome measure. No changes were made to endpoints after the trial commenced. Additional data collected included vital signs, physical exam, assessment of adverse events and serious adverse events, medical history, concomitant medications, Headache Impact Test, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, complete Outcomes

blood count, comprehensive metabolic panel, a pregnancy test, an electrocardiogram, and an end of study form at the final visit. The end of study form asked whether participants believed they re ceived drug or placebo. It also asked, “How effective was the med ication you received in the trial?” which was rated as: “not at all,” “helped a little,” “it helped a moderate amount,” “helped quite a lot,” or “I felt cured.”

Statistical analysis

In total, 50 participants were planned for randomization. Assuming a dropout rate of 80% and a standard deviation of VM-PATHI of 16, this would provide 80% power to detect a 15-point difference between placebo and galcanezumab arms, with an alpha of 0.05, with a two-tailed t -test. The modified intent to treat (mITT) analy sis included all participants who were randomized and treated with galcanezumab or placebo and who completed the minimum data necessary for analysis. The per protocol analysis included all par ticipants who completed the trial without a major protocol devia tion. The primary outcome measure was a difference in differences analysis comparing placebo to galcanezumab. The difference in VM- PATHI score between baseline (SV2) and month 4 (SV4) compared placebo change from baseline to galcanezumab change from base line. This was assessed using an independent groups Student's t -test, both one- and two-tailed tests. Similarly, change in each group (pla cebo and galcanezumab) in DHI between baseline (SV2) and month 4 (SV4) was calculated and compared in an independent groups two-tailed Student's t -test. The change in monthly DDD count from baseline to month 4, comparing placebo to galcanezumab, was also assessed the same way. Given the small size of the trial, no interim analysis was planned. Statistical analyses were carried out in Stata/ SE version 14.2 (StataCorp LLC, College Station, TX). This study was funded by Eli Lilly and Company as an investigator-initiated trial. The study team designed and executed the study and performed all data analysis and manuscript writing. Descriptive statistics were used to summarize all the clinical characteristics and demographic outcomes. These were summa rized overall, by treatment group, by assessment time, and by treat ment group and time. Continuous variables were summarized using means, medians, standard deviations, and ranges. Categorical data were summarized by number and percent. Bivariate analyses com paring groups and time points were summarized using independent groups Student's t -tests and one-way analysis of variance for con tinuous variables that were not extremely skewed and by Wilcoxon rank sum and the Mann–Whitney U test for variables requiring non- parametric statistics. Categorical analyses used chi-squared tests of independence, Fisher exact tests, and Z -tests of proportions. Effect sizes were calculated using Cohen's d , with the standard deviation of the control group as the denominator. Significance was assessed using an alpha of 0.05. Missing data were minimized by daily mon itoring of text message data by the study coordinator and an elec tronic survey design that did not allow for skipping questions.

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RESULTS

4, found that galcanezumab outperformed placebo at each criterion, but the results were not statistically significant. This included the percentage of participants with 100% reduction for galcanezumab versus placebo (18% vs. 10%, p = 0.475), 75% reduction (53% vs. 38%, p = 0.374), 50% reduction (77% vs. 48%, p = 0.074), and 25% reduction (82% vs. 57%, p = 0.102). Those in the galcanezumab arm experienced greater reductions in both mental and physical subscales of the PROMIS Global Health v1.2, although differences were not statistically significant. For the physical subscale, those in the galcanezumab arm increased their t - score by 5.3 points (95% CI 1.7 to 8.9), whereas those in the placebo arm increased their t -score by 1.9 points (95% CI −0.97 to 4.8), two tailed t -test p = 0.129. For the mental subscale, those in the galca nezumab arm increased their t -score by 4.8 points (95% CI 2.1 to 7.5), whereas those in the placebo arm increased their t -score by 3.2 points (95% CI −0.58 to 7.0), two tailed t -test, p = 0.494. At the final study visit, participants were asked to rate how ef fective the medication they received was. The options were “not at all” (0), “helped a little” (1), “it helped a moderate amount” (2), “helped quite a lot” (3), and “I felt cured” (4). Of the 17 participants in the galcanezumab arm, 1 chose “I feel cured,” 6 chose “It helped quite a lot,” 5 chose “It helped a moderate amount,” 4 chose “It helped a little,” and 1 chose “not at all.” Of the 21 participants in the placebo arm, 5 chose “it helped quite a lot,” 7 chose “it helped a little,” and 9 chose “not at all.” Therefore, the mean score in the galcanezumab arm was 2.1 (SD 1.1), and the mean score in the placebo arm was 1.0 (SD 1.2), two tailed t -test with p = 0.0067. The effect size, as measured by Cohen's d , is 0.89, which is considered a large treat ment effect. Dividing treatment into two groups, of little to no help (“helped a little” and “not at all”), and moderate or greater treatment effect (“helped quite a lot,” “I felt cured,” and “it helped a moder ate amount”), 71% of participants in the galcanezumab arm had a moderate or greater treatment effect, compared to 24% of those in the placebo arm (chi-squared test, p = 0.004). Participants were also asked to guess whether they received study drug or placebo, and 71% of participants guessed correctly (chi-squared test, p = 0.008). There were 12 adverse events during the study in 11 partici pants, and no serious adverse events. Four adverse events occurred in the galcanezumab arm, including two participants with injection site reactions of erythema and swelling and two participants with worsening of their VM. The adverse events in the placebo arm in cluded injection site soreness, injection site bruising, participant weight gain (no weight change documented), low blood pressure, increased headaches, hair loss, palpitations, and constipation.

Six hundred eighty participants underwent screening, 53 signed consent, and 40 of those met all inclusion/exclusion criteria and were randomized to either galcanezumab or placebo. This is sum marized in a Consolidated Standards of Reporting Trials (CONSORT) diagram (Figure 1 ). The intent to treat baseline analysis included 40 participants. Of those, two were randomized to placebo and acci dentally given galcanezumab for the third and fourth months (error by the research pharmacy). One other voluntarily left the study for unrelated medical problems (nephrolithiasis). In addition, the study sponsor unexpectedly stopped supplying galcanezumab and pla cebo in March 2023, leading to premature study termination. At that time, two participants were in the baseline month, and another had been treated with placebo. So, of the 40 participants who were randomized and treated, data beyond SV2 were available for 38, and these participants were included in the mITT analysis of results (placebo N = 21, galcanezumab N = 17). The per protocol analysis in cluded 36 participants who were randomized, treated with placebo or galcanezumab, and completed the final study visit. Demographics and disease characteristics were similar between arms (Table 1 ). Most participants were female (75%), with a diagno sis of VM per Barany Society criteria (88%), and White (75%), with a history of migraine headaches (93%). Rates of daily dizziness text completion were the same between arms: galcanezumab 114.6 en tries (standard deviation [SD] 6.8) versus placebo 113.3 entries (SD 8.0), two tailed t -test p = 0.598. There were no other missing data. Study results are summarized in Table 2 . Change in VM-PATHI score from the baseline month to month 4 was the primary outcome measure. Those in the placebo arm dropped 5.1 points (95% confi dence interval [CI] −13.0 to 2.7), while those in the galcanezumab arm dropped 14.8 points (95% CI −23.0 to −6.5). This difference of 9.6 points was statistically significant with a one tailed t -test ( p = 0.044), but not with a two tailed t -test ( p = 0.087). The effect size for the change in VM-PATHI score, calculated with Cohen's d , is 0.56, which is considered a medium effect size. Change in DHI score, from the baseline month to month 4, was a secondary endpoint. Those in the placebo arm dropped 8.3 points (95% CI −15.0 to 1.6), while those in the galcanezumab arm dropped 22.0 points (95% CI −31.9 to −12.1). This difference of 14.4 points was statistically significant with a two tailed t -test ( p = 0.018). The effect size for the change in DHI, calcu lated with Cohen's d , is 0.98, which is considered a large effect size. The count of DDDs per month dropped from 18.0days (SD 7.6) in the baseline month to 12.5days (SD 11.2) in month 4 for those in the placebo arm and from 17.9days (SD 7.9) in the baseline month to 6.6days (SD 7.3) in month 4 for those in the galcanezumab arm, a significant difference ( t -test p = 0.026; Figure 2 ). In addition, the drop in DDDs from baseline to month 3 was 4.7days (SD 7.9) for those in the placebo arm, compared to 10.6days (SD 7.6) for those receiving galcanezumab, a significant difference (two tailed t -test p = 0.025). The effect size for the decrease in DDDs, calculated with Cohen's d , is 1.02, which is considered a large effect size. A responder anal ysis, looking at percent reduction in DDDs from baseline to month

DISCUSSION

To our knowledge, this is the first randomized, controlled trial of a CGRP-blocking medication for VM. In this study, we found that galcanezumab outperformed placebo in the treatment of VM across multiple outcomes. We found that galcanezumab re duced DDDs by 11.3 days, comparing month 4 to baseline. In other

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Assessed for Eligibility:680

Excluded: 627

• • • • • • • • • • • •

Complex medical history Secondary vestibular diagnosis ( N = 232) ( N = 46) Prior or current CGRP use ( N = 44) Severe psychiatric disease ( N = 11) Other neurologic disease ( N = 37) Prior e >4 failed prophylactics ( N = 11) ar surgery ( N = 14)

Pregnant/breastfeeding English fluency ( N = 13)

( N = 5)

Symptoms too infrequent ( N = 46) No response/not interested ( N = 183)

Other ( N = 83)

Signed Consent: 53

Excluded: 13 • Did not meet DDD/VM-PATHI baseline score ( N =11) • Was on protocol in baseline when study terminated early ( N =2)

Randomized: 40

• On protocol when study terminated early ( N =1), finished SV2

• Withdrew from study due to unrelated medical problems ( N =1) after SV2

Galcanezumab ITT: 17

Placebo- ITT: 21

N =38

• Treated with placebo at SV2, accidentally crossed over to placebo for SV3 ( N =2)

Placebo PP: 19

Galcanezumab PP: 17

N =36

FIGURE 1 CONSORT diagram for the INVESTMENT trial. CGRP, calcitonin gene–related peptide; CONSORT, Consolidated Standards of Reporting Trials; DDD, definite dizzy day; INVESTMENT, Investigating Vestibular Migraine Emgality Treatment; ITT, intent to treat; PP, per protocol; SV, study visit; VM-PATHI, Vestibular Migraine Patient Assessment Tool and Handicap Inventory.

words, those in the galcanezumab arm had a 63% reduction in the number of DDDs in the third month of treatment, compared to a 31% reduction for those in the placebo arm. We also found that

galcanezumab improved the DHI during the 3 months of treatment by 22 points, compared to an 8.3-point improvement for placebo. Finally, galcanezumab improved the VM-PATHI score by 14.8

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TABLE 1 Baseline demographics for the INVESTMENT trial.

Placebo

Galcanezumab

Total

Diagnosis (%VM) Sex (% female)

19 (86%) 16 (73%)

16 (89%) 14 (78%)

35 (88%) 30 (75%)

Age

47.3 (SD 14.5)

55.0 (SD 11.0)

50.8 (SD 13.5)

Race (% White) Race (% Asian) Race (% Black) Race (% other)

16 (73%) 2 (9%) 0 (0%) 4 (18%)

14 (78%)

30 (75%)

1 (6%) 1 (6%)

8% 3%

2 (11%)

15% 93% 60%

History migraine (%)

90% 59%

94% 61%

Family history migraine (%)

Count of triggers

8.9 (SD 7.6) 4.6 (SD 1.3)

9.4 (SD 7.8) 4.2 (SD 1.7)

9.1 (SD 3.0) 4.4 (SD 1.5)

Count of associated symptoms

Count of migraine prophylactic medications

SV2 VM-PATHI score

45.7 (SD 9.9) 56.7 (SD 19.1)

47.3 (SD 12.0) 61.4 (SD 14.9) 17.9 (SD 7.9)

46.4 (SD 10.8) 58.8 (SD 17.3) 18.0 (SD 7.7)

SV2 DHI score DDD baseline

18 (SD 7.6)

Note : p -value uses chi-squared test for categorical variables, t -test for numeric variables. Abbreviations: DDD, definitive dizzy day; DHI, Dizziness Handicap Inventory; INVESTMENT, Investigating Vestibular Migraine Emgality Treatment; SD, standard deviation; SV2, study visit 2; VM, vestibular migraine; VM-PATHI, Vestibular Migraine Patient Assessment Tool and Handicap Inventory.

TABLE 2 Summary of outcomes for the INVESTMENT trial.

Placebo

Galcanezumab Difference

p -value Effect size

N (mITT)

Change in VM-PATHI score

−5.1 (SD 17.3) −8.3 (SD 15.0) −5.6 (SD 7.9) 1.1 (SD 1.2) −2.0 (SD 0.86) −3.0 (SD 4.4) 1.9 (SD 6.4) 3.2 (SD 8.3) −1.8 (SD 4.4)

−14.8 (SD 16.1) −22.0 (SD 19.3) −11.3 (SD 7.2) −3.9 (SD 4.2) −4.9 (SD 5.4) 5.3 (SD 7.0) 4.8 (SD 5.3) −3.5 (SD 3.3) 2.1 (SD 1.1)

−9.6 (95% CI −20.7 to −1.5) −13.7 (95% CI −20.4 to −8.5) −5.7 (95% CI −10.7 to −0.7) 1.1 (95% CI 0.3 to 1.8) −1.9 (95% CI −4.6 to 0.7) −1.9 (95% CI −5.2 to 1.3) 3.4 (95% CI −1.0 to 7.8) 1.6 (95% CI −3.1 to 6.3) −2.9 (95% CI −7.2 to 1.4)

0.044* 0.017 0.026 0.0067

0.56 0.98 1.02 0.89

Change in DHI

Change in DDD Count

Effectiveness

GAD-7 PHQ-9

0.152 0.232 0.129 0.494

PROMIS SF Global Health v1.2- Physical Subscale PROMIS SF Global Health v1.2- Mental Subscale

HIT-6 0.184 Note : Shown is the difference between questionnaire scores for SV2 and SV4. For change in DDD count, it is the difference between the baseline month, and the fourth (final) treatment month. Abbreviations: CI, confidence interval; DDD, definitive dizzy day; DHI, Dizziness Handicap Inventory; GAD-7, Generalized Anxiety Disorder-7; INVESTMENT, Investigating Vestibular Migraine Emgality Treatment; mITT, modified intent to treat; PHQ-9, Patient Health Questionnaire-9; PROMIS SF, Patient Recorded Outcome Measurement Information System Short Form; SD, standard deviation; SV, study visit; VM-PATHI, Vestibular Migraine Patient Assessment Tool and Handicap Inventory. *One tailed t -test, if not stated than two-tailed t -test was used. Effectiveness is using a Likert scale for a single question given at SV4, “How effective was the medication you received in the trial?” Effect size measured with Cohen's d , provided only if p < 0.05.

points during the 3 months of treatment, compared to a 5.1 point improvement for placebo. These changes are clinically meaning ful, exceeding the minimal clinically important difference for each measure used. 20 Other studies have shown mixed effects of prophylactic medi cations for VM. The PROVEMIG trial, which also ended early, was a double-blind, controlled, randomized clinical trial of 95 mg of daily

metoprolol versus placebo, comparing the count of vertiginous at tacks per 30days, in months 4 to 6. 11 At the time of study termina tion, 130 participants had been randomized, and 114 participants were able to be analyzed. No difference was seen between monthly vertigo attacks comparing metoprolol and placebo arms (incident rate ratio 0.983, 95% CI 0.902 to 1.071, p = 0.696). Another study randomized 64 participants to either venlafaxine or propranolol

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FIGURE 2 Count of definitive dizzy days (DDDs) by month, comparing placebo and galcanezumab arms ( N = 38). Error bars show the standard error. [Color figure can be viewed at wileyonlinelibrary.com ]

for the treatment of VM without a placebo arm. 21 They found that after 12weeks of treatment, venlafaxine reduced DHI scores by 31.0 points, and propranolol reduced DHI scores by 24.5 points; however, the difference was not significant (paired t -test p = 0.19). Flunarizine, a calcium channel blocker, was investigated in two placebo-controlled trials. Lepcha et al. analyzed 48 participants ran domized to either placebo or 10mg of flunarizine and found statisti cally significant improvements in both vertigo frequency and vertigo severity. 22 On the other hand, Yuan et al. analyzed 23 participants randomized to either placebo or flunarizine, and did not find any dif ferences, although arguably that study was underpowered. 23 To date, a handful of cohort studies have looked at CGRP treat ment for VM. In a retrospective review of 25 participants, Hoskins and Fife found that 21 participants reported some level of improve ment in their symptoms. 24 Lovato and colleagues examined 23 par ticipants treated with erenumab, and found an average reduction in DHI from 30.2 (SD 7.2) to 8.1 (SD 3.1; Mann–Whitney U test; p < 0.0001), a reduction in migraine days, and elimination of posi tional nystagmus in 10 of 11 participants. 25 Finally, Russo et al. con ducted a prospective cohort study of 50 participants with a variety of anti-CGRP monoclonal antibodies. 13 Participants were asked to complete a daily diary documenting vertigo/dizziness and headache. They found that the number of days per month with vestibular symp toms decreased from 10.3 (SD 1.9) to 6.4 (SD 1.4) after 3months of treatment ( p < 0.001). They were able to follow some participants much longer and found that days with vestibular symptoms contin ued to decline at 6 months, 9 months, 1 year, finally reaching 0.7 days (SD 0.2days) by 18months. Our study adds to these cohort studies by providing stronger evidence for the efficacy of anti-CGRP treat ment with a placebo-controlled, randomized clinical trial. The pathophysiology of VM is not completely understood. Our results suggest that CGRP is involved in the generation of dizziness

and other symptoms of VM. Further research is needed to under stand the site of activity and mechanism of action. CGRP expression is anatomically complex and includes many structures that are part of the peripheral and central vestibular system: vestibular sensory organs, vestibular nucleus, cerebellum, thalamus, hippocampus, and cortical regions. 26 CGRP knockout mice show alterations of vestib ular reflexes, and CGRP infusion into mice causes impaired balance and nausea. 14,15,27 Therefore, it is possible that CGRP blockade in terrupts trigeminovascular inflammatory pathways that are present in the inner ear. Zhang et al. used a nitroglycerin-based rat model of chronic mi graine to investigate mechanisms of vestibular dysfunction. 28 They found that CGRP expression was elevated in the trigeminal nucleus caudalis and the vestibular nucleus in the chronic migraine rats, compared to controls. 29 These animals showed hyperalgesia and de creased vestibular function. Lentiviral vectors with CGRP RNA were then used to knock down CGRP in the chronic migraine rats, and this ameliorated hyperalgesia and vestibular dysfunction. VM is one of the most common causes of dizziness and vertigo, if not the most common. 1 Despite that, there is evidence of underdi agnosis, and many patients and providers lack understanding of this disease. 30 Large, prospective, placebo controlled randomized clinical trials are required to further investigate the efficacy of various mi graine treatments for VM. In addition to the obvious benefits of as certaining which treatments are effective, this would also help with educating the public and medical personnel regarding this common disease. Furthermore, there are still fundamental questions regard ing the relationship of VM to migraine headaches. This study adds to a body of evidence that VM is just another form of migraine and that the pathophysiology involves CGRP. This study included both participants with VM and probable VM to increase generalizability. However, 89% of participants in the mITT

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analysis had VM. This distribution is different from other VM studies from our center, in which the distribution was closer to even between VM and probable VM, and may reflect differences in the population re ferred for clinical trials. 17 The average baseline VM-PATHI score in this trial was very similar to average scores seen during the development of VM-PATHI, suggesting similar disease severity. Thirty-seven percent of potentially eligible participants were excluded based on secondary vestibular diagnoses. While this may seem high, VM is clearly related to many other vestibulopathies, and further study of CGRP-blocking antibodies in this population is warranted. 7 There were several limitations of this study. The first is that it was unexpectedly concluded early when the sponsor stopped supplying galcanezumab and placebo while two participants were in the baseline period, and one participant had already been treated. A second limita tion is that due to an error from the study pharmacist, two participants were accidentally crossed over from placebo to galcanezumab arms. Furthermore, this is a small-scale, single-center study. We also did not systematically obtain pre- and post-intervention vestibular testing, which would have been interesting in exploring the mechanism of ac tion of CGRP in VM. Despite these limitations, the data clearly show a beneficial effect for CGRP blockade in VM; however, larger, multi center trials are required to further investigate these findings. This study also had several strengths. First, it was a double-blind, placebo-controlled trial, which is necessary for vestibular trials, which have consistently shown high rates of placebo response. 31 Second, data were collected daily during the study with a text mes saging system, and response rates were quite high. Third, outcomes were assessed with several methods, including count of DDDs, and patient-reported outcome measures (PROMs), including the widely used DHI, which is a symptom-specific PROM, and the newly devel oped VM-PATHI, which is a VM disease-specific PROM, and a gen eralized impression of change scale, and results were in accordance across all those metrics. In conclusion, treatment of VM with galcanezumab improved the count of DDDs, dizziness handicap, and VM disease severity com pared to placebo. AUTHOR CONTRIBUTIONS Jeffrey D. Sharon: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project adminis tration; resources; software; supervision; validation; visualization; writing – original draft. Roseanne Krauter: Methodology; project administration; supervision. Ricky Chae: Investigation; project ad ministration; resources; software. Adam Gardi: Investigation; meth odology; project administration; resources; software. Maxwell Hum: Investigation; methodology; resources. Isabel Allen: methodology, data analysis, supervision. Morris Levin: Investigation; methodol ogy; project administration; resources. ACKNOWLEDGMENTS We would like to thank all three members of the Data Safety Monitoring Board, including Dr. John Carey (Department of Otolaryngology- Head and Neck Surgery, Johns Hopkins School of Medicine),

Dr. Kristen Steenerson (Department of Otolaryngology-Head and Neck Surgery, Stanford University), and Dr. Kevin Delucchi (Department of Psychiatry, University of California, San Francisco). CONFLICT OF INTEREST STATEMENT Jeffrey D. Sharon received research support for this study from Eli Lilly. In addition, he has received research funding from Advanced Bionics. He is on the medical advisory board for Otolith Labs, and serves as the senior VP of clinical science at Spiral Therapeutics. Roseanne Krauter, Ricky Chae, Adam Gardi, Maxwell Hum, Isabel Allen, and Morris Levin have no conflicts to disclose.

ORCID Jeffrey D. Sharon

https://orcid.org/0000-0003-4892-5064

https://orcid.org/0000-0001-5014-9303

Ricky Chae

REFERENCES 1. Formeister EJ, Rizk HG, Kohn MA, Sharon JD. The epidemiology of vestibular migraine: a population-based survey study. Otol Neurotol . 2018;39(8):1037-1044. 2. Lempert T, Olesen J, Furman J, et al. Vestibular migraine: diagnostic criteria. J Vestib Res . 2012;22(4):167-172. 3. Benjamin T, Gillard D, Abouzari M, Djalilian HR, Sharon JD. Vestibular and auditory manifestations of migraine. Curr Opin Neurol . 2022;35(1):84-89. 4. Preysner TA, Gardi AZ, Ahmad S, Sharon JD. Vestibular mi graine: cognitive dysfunction, mobility, falls. Otol Neurotol . 2022;43(10):1216-1221. 5. Chae R, Krauter R, Pasquesi LL, Sharon JD. Broadening vestibular migraine diagnostic criteria: a prospective cohort study on vestibu lar migraine subtypes. J Vestib Res . 2022;32(5):453-463. 6. Benjamin T, Gardi A, Sharon JD. Recent developments in vestibular migraine: a narrative review. Am J Audiol . 2023;32:739-745. 7. Zhu RT, Van Rompaey V, Ward BK, Van de Berg R, Van de Heyning P, Sharon JD. The interrelations between different causes of dizzi ness: a conceptual framework for understanding vestibular disor ders. Ann Otol Rhinol Laryngol . 2019;128(9):869-878. 8. Mallampalli MP, Rizk HG, Kheradmand A, et al. Care gaps and recommendations in vestibular migraine: an expert panel summit. Front Neurol . 2021;12:812678. 9. Webster K, Dor A, Galbraith K, et al. Pharmacological interventions for prophylaxis of vestibular migraine. Cochrane Database Syst Rev . 2023;2023(4):CD015187. 10. Webster KE, Dor A, Galbraith K, et al. Pharmacological interven tions for acute attacks of vestibular migraine. Cochrane Database Syst Rev . 2023;4(4):CD015322. 11. Bayer O, Adrion C, Al Tawil A, Mansmann U, Strupp M, PROVEMIG Investigators. Results and lessons learnt from a randomized con trolled trial: prophylactic treatment of vestibular migraine with me toprolol (PROVEMIG). Trials . 2019;20(1):813. 12. Ferrari MD, Goadsby PJ, Burstein R, et al. Migraine. Nat Rev Dis Primers . 2022;8(1):2. 13. Russo CV, Saccà F, Braca S, et al. Anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of vestibular migraine: a prospective observational cohort study. Cephalalgia . 2023;43(4):3331024231161809. 14. Rahman SM, Hauser C, Faucher S, Fine E, Luebke AE. Both systemic calcitonin gene related peptide (CGRP) and a vestibular challenge promote anxiety-related behaviors and dynamic imbalance in mice. bioRxiv . 2023. doi:10.1101/2023.06.30.547257

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15. Jones SM, Vijayakumar S, Dow SA, Holt JC, Jordan PM, Luebke AE. Loss of α -calcitonin gene-related peptide ( α CGRP) reduces otolith activation timing dynamics and impairs balance. Front Mol Neurosci . 2018;11:289. 16. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational re search informatics support. J Biomed Inform . 2009;42(2):377-381. 17. Sharon JD, Krauter R, Kirk L, et al. Development and validation of VM-PATHI: vestibular migraine patient assessment tool and handi cap inventory. Otol Neurotol . 2020;41(4):e494-e500. 18. Jacobson GP, Newman CW. The development of the dizzi ness handicap inventory. Arch Otolaryngol Head Neck Surg . 1990;116(4):424-427. 19. Tamber AL, Wilhelmsen KT, Strand LI. Measurement properties of the dizziness handicap inventory by cross-sectional and longitudi nal designs. Health Qual Life Outcomes . 2009;7:101. 20. Rizk HG, Velozo C, Shah S, Hum M, Sharon JD, Mcrackan TR. Item level psychometrics of the dizziness handicap inventory in vestib ular migraine and Meniere's disease. Ear Hear . 2024;45:106-114. doi: 10.1097/AUD.0000000000001405 21. Salviz M, Yuce T, Acar H, Karatas A, Acikalin RM. Propranolol and venlafaxine for vestibular migraine prophylaxis: a randomized con trolled trial. Laryngoscope . 2016;126(1):169-174. 22. Lepcha A, Amalanathan S, Augustine AM, Tyagi AK, Balraj A. Flunarizine in the prophylaxis of migrainous vertigo: a random ized controlled trial. Eur Arch Otorrinolaringol . 2014;271(11): 2931-2936. 23. Yuan Q, Liu DL, Yu LS, Zhang QF. Flunarizine in the prophylaxis of vestibular migraine:a randomized controlled trial. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi . 2016;30(10):805-810. 24. Hoskin JL, Fife TD. New anti-CGRP medications in the treatment of vestibular migraine. Front Neurol . 2021;12:799002.

25. Lovato A, Disco C, Frosolini A, Monzani D, Perini F. Monoclonal an tibodies targeting CGRP: a novel treatment in vestibular migraine. Medicina . 2023;59(9):1560. doi:10.3390/medicina59091560 26. Warfvinge K, Edvinsson L. Distribution of CGRP and CGRP recep tor components in the rat brain. Cephalalgia . 2019;39(3):342-353. 27. Luebke AE, Holt JC, Jordan PM, Wong YS, Caldwell JS, Cullen KE. Loss of α -calcitonin gene-related peptide ( α CGRP) reduces the efficacy of the Vestibulo-ocular reflex (VOR). J Neurosci . 2014;34(31):10453-10458. 28. Zhang Y, Zhang Y, Tian K, et al. Calcitonin gene-related peptide facilitates sensitization of the vestibular nucleus in a rat model of chronic migraine. J Headache Pain . 2020;21(1):72. 29. He W, Long T, Pan Q, et al. Microglial NLRP3 inflammasome ac tivation mediates IL-1 β release and contributes to central sensi tization in a recurrent nitroglycerin-induced migraine model. J Neuroinflammation . 2019;16(1):78. 30. Chiao W, Krauter R, Kirk L, Steenerson K, Pasquesi L, Sharon J. Understanding dizzy patients a cross-sectional analysis of atti tudes toward diagnosis, providers, and treatment. Ann Otol Rhinol Laryngol . 2022;131(4):352-359. 31. Phillips J, Mikulec AA, Robinson JM, Skarinsky D, Anderson JJ. Efficacy of intratympanic OTO-104 for the treatment of ménière's disease: the outcome of three randomized, double-blind, placebo- controlled studies. Otol Neurotol . 2023;44(6):584-592.

How to cite this article: Sharon JD, Krauter R, Chae R, et al. A placebo controlled, randomized clinical trial of galcanezumab for vestibular migraine: The INVESTMENT study. Headache . 2024;64:1264-1272. doi: 10.1111/head.14835

Systematic Review and Meta-Analysis

Current Therapies in Patients With Posterior Semicircular Canal BPPV, a Systematic Review and Network Meta-analysis §Daibo Li, Danni Cheng, jj Wenjie Yang, §Ting Chen, §Di Zhang, yz Jianjun Ren, and yz Yu Zhao Department of Oto-Rhino-Laryngology; y West China Biomedical Big Data Center, West China Hospital; z Med-X Center for Informatics, Sichuan University; §Department of Otorhinolaryngology, Head and Neck Surgery, Meishan Municipal People’s Hospital, Dongpo Road, Meishan, Sichuan; and jj Center of Biostatistics, Design, Measurement and Evaluation, West China Hospital, Sichuan University, Chengdu, China

SUCRA ¼ 76.1%) and Epley maneuvers (rank second, SUCRA ¼ 65.3%) were effective in eliminating nystagmus during a Dix–Hallpike test. In the pairwise subgroup meta analysis, for patients younger than 55 years of age, the efficacy of the Epley maneuver was comparable to that of the Semont maneuver [rate ratio (RR): 0.99, 95% confidence interval (CI): 0.93–1.05]; for patients with a longer duration before treatment, the effect of the Epley maneuver was equivalent to that of a sham maneuver (RR: 1.07, 95% CI: 0.90–1.29). Conclusion: Among the 12 types of PC-BPPV treatments, the Epley, Semont, EVR, and Hybrid maneuvers were effective in eliminating nystagmus during a Dix–Hallpike test for PC-BPPV at 1 week of follow-up, whereas only the Epley and Semont maneuvers were effective at 1 month of follow-up. The duration before treatments and the age of patients might contribute to the efficacy of treatments. Key Words: Benign paroxysmal positional vertigo — Meta analysis — Treatment. Among three semicircular canals, the most common type is the posterior semicircular canal (PC-BPPV), accounting for 60 to 90% of all BPPVs (3). Accurate diagnosis of the affected canal of BPPV is crucial for treatment. The most popular test for diagnosing PC-BPPV and identifying the University (Z.Y., grant #20ZDYF3010, RJJ, grant #2019HXBH079, #2020SCU12049); The Science and Technology Department of Sichuan Province (Z.Y., grant #2020YFH0090, RJJ, grant#2020YFS0111); The Health Department of Sichuan Province (R.J.J., grant #20PJ030); China Postdoctoral Science Foundation (R.J.J., grant#2020M673250); The Foundation of National Clinical Research Center for Geriatrics (S.H., grant #Z20201013); National Natural Youth Science Foundation of China (R.J.J., grant #82002868). The authors disclose no conflicts of interest. Supplemental digital content is available in the text. DOI: 10.1097/MAO.0000000000003464 Otol Neurotol 43: 421–428, 2022.

Objective: To compare the efficacy of different treatments for posterior semicircular canal benign paroxysmal positional vertigo (PC-BPPV) by using direct and indirect evidence from existing randomized data. Methods: Randomized case-control studies that compared the efficacy of various nonsurgical treatments in PC-BPPV patients at 1 week and 1 month of follow-up were comprehensively screened. Bayesian network meta-analysis was performed to evaluate direct and indirect treatment comparisons. We further conducted subgroup pairwise meta analysis to explore the inconsistency between comparisons of the Epley versus a sham maneuver and the Epley versus the Semont maneuver. Results: A total of 41 parallel, randomized controlled studies were included. The Epley with vestibular rehabilitation (EVR), Epley, Semont and Hybrid maneuvers were effective in eliminating nystagmus during a Dix–Hallpike test at 1 week of follow-up (odds ratios [ORs]: 11.41–23.8, 95% credible interval [CrI]: excluding null), among which EVR showed the best efficacy (the surface area under the cumulative ranking curves [SUCRA] ¼ 77.5%). However, at 1 month of follow-up, only the Semont (rank first, Benign paroxysmal positional vertigo (BPPV) is a world wide inner ear disorder that accounts for 8% of patients with moderate to severe dizziness or vertigo (1), characterized by positional vertigo and nystagmus evoked by changes in head position with respect to gravity (2). Address correspondence and reprint requests to Yu Zhao, M.D., Ph.D., Department of Oto-Rhino-Laryngology, West China Hospital, West China Medical School, Sichuan University, No. 37 Guo Xue Alley, Chengdu, Sichuan, 610041, China; E-mail: yutzhao@VIP.163.com; Jianjun Ren, Ph.D., Department of Oto-Rhino-Laryngology, and West China Biomedical Big Data Center, West China Hospital, West China Medical School, Sichuan University, No. 37 Guo Xue Alley, Chengdu,

Sichuan, 610041, China; E-mail: Jianjun.Ren@scu.edu.cn D.L., D.C., and W.Y. contributed equally to this work.

Funding: This work was supported by West China Hospital, Sichuan University (Z.Y., grant #2019HXFH003, grant#ZYJC21027); Chengdu Science and Technology Bureau (R.J.J., grant #20GJHZ0193); Sichuan

2022, Otology & Neurotology, Inc.

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