Rizatriptan vs Placebo for Attacks of Vestibular Migraine

Key Points

Question

Is rizatriptan effective for treating vertigo, unsteadiness/dizziness, headache, and other symptoms of vestibular migraine attacks?

Findings

In this randomized clinical trial, 134 adults treated 307 attacks of vestibular migraine with a single oral dose of rizatriptan 10 mg or placebo. The percentage of patients reporting reductions in vertigo, unsteadiness or dizziness, headache, and other migrainous symptoms 1 hour after taking the study drug did not differ between rizatriptan and placebo; rizatriptan had limited benefits for headache-related symptoms, but not vertigo, at 24 hours.

Meaning

This study found little benefit from rizatriptan for treating vestibular migraine attacks.

Abstract

Importance

Vestibular migraine has no established treatments.

Objective

To test the efficacy of rizatriptan for treating vestibular migraine attacks.

Design, Setting, and Participants

This double-blind, randomized clinical trial of rizatriptan vs placebo was conducted from December 2014 through July 2020 (data analyses in 2021 and sensitivity analyses in 2022 and 2024) at 2 tertiary neurotologic centers. Adults with vestibular migraine were included.

Intervention

All participants underwent prospective observation to confirm diagnosis and illness activity and were then randomized in a 2:1 ratio to receive rizatriptan 10 mg or placebo to treat up to 3 vestibular migraine attacks per participant.

Main Outcomes and Measures

Participants rated symptoms as absent, mild, moderate, or severe at scheduled intervals. Primary outcomes were the percentage of attacks with reductions in vertigo and unsteadiness/dizziness from moderate or severe to absent or mild at 1 hour. Secondary outcomes were the percentage of attacks with complete resolution of vestibular symptoms at 1 hour; reductions in headache and associated symptoms at 1 hour; use of rescue medications after 1 hour; reductions in vestibular, headache, and associated symptoms at 24 hours without rescue medications; treatment satisfaction and quality of life at 48 hours; and rates of serious adverse effects and discontinuation due to adverse effects.

Results

Of 222 total participants (mean [SD] age, 42.3 [11.7] years; 70.7% were women), 134 (60.4%) with active illness treated 307 attacks. Efficacy was tested using 240 attacks with vestibular symptoms rated as moderate or severe when participants took study drug. At 1 hour, rizatriptan did not differ from placebo for reducing vertigo (73/151 [48.3%] vs 50/88 [56.8%] attacks; odds ratio [OR], 0.71 [95% CI, 0.42-1.21]), unsteadiness/dizziness (29/151 [19.2%] vs 11/89 [12.4%] attacks; OR, 1.69 [95% CI, 0.80-3.57]), or any secondary outcomes. Similar percentages of participants in rizatriptan and placebo groups (26.4% for both groups) added rescue remedies after 1 hour. At 24 hours, rizatriptan had medium effects over placebo for unsteadiness/dizziness (OR, 2.65) and motion sensitivity (OR, 3.58). Post hoc analyses of all treated attacks found a medium effect favoring rizatriptan for headache and photophobia or phonophobia at 24 hours. Treatment satisfaction was equivocal. Quality of life was mixed. No participants experienced serious adverse effects or discontinued treatment for adverse effects.

Conclusions and Relevance

In this study, rizatriptan was ineffective at 1 hour for treating vestibular migraine attacks and had limited benefit on symptoms at 24 hours. Findings do not support using rizatriptan for vestibular migraine attacks.

Trial Registration

ClinicalTrials.gov Identifier: NCT02447991

This randomized clinical trial examines the efficacy of rizatriptan for treating vestibular migraine attacks.

Introduction

Vestibular migraine was defined in 2012 for the International Classification of Vestibular Disorders (ICVD)^1,2 and International Classification of Headache Disorders, third edition (ICHD-3),^3,4 with an updated review in 2022.⁵ Diagnostic criteria require a history of ICHD-3 migraine and 5 or more lifetime attacks of moderate or severe vestibular symptoms (spinning vertigo, swaying/rocking unsteadiness, nonvertiginous dizziness with nausea), as defined by the Bárány Society,⁶ accompanied by migrainous headache, photophobia or phonophobia, or visual aura. The ICVD included a diagnosis of probable vestibular migraine for patients with lesser associations between vestibular and migraine symptoms.¹ Lifetime population prevalence estimates for vestibular migraine are 1.0% to 2.7%,^7,8 making it the second most common cause of episodic vertigo after benign paroxysmal positional vertigo. In specialized dizziness centers, it is the primary diagnosis for 10% to 30% of patients.^9,10

In early retrospective and observational studies, investigators used nonuniform constructs including migrainous vertigo, migraine-associated vertigo, and migraine-associated dizziness to suggest prophylactic benefits from tricyclic antidepressants,^11,12,13 β-blockers,^11,12,13 valproic acid,^11,13 calcium channel blockers,^{11,12,13,14,15,16} topiramate,^13,15 and others.^11,13,14 Not all findings were positive.¹¹ After the IVCD/ICHD-3 definition was published, researchers reinvestigated most of these medications,^{17,18,19,20,21,22,23,24,25,26} plus venlafaxine^22,24 and others,^18,20,21 in retrospective, observational, and parallel-group studies. The only randomized clinical trial (RCT) of any prophylactic agent for vestibular migraine was halted after 5 years because of recruitment difficulties. Among 130 participants, 6-month outcomes did not differ between metoprolol and placebo. Attack frequencies waned by 17% per month (>60% over 6 months) in both groups.²⁷ Two meta-analyses examined these studies.^28,29 One study found that valproic acid, propranolol, and venlafaxine were superior to placebo in reducing attack frequency.²⁸ The other found that propranolol and venlafaxine reduced dizziness-related handicap, but only propranolol outperformed placebo in decreasing attack frequency.²⁹

Two retrospective reviews,^30,31 an observational study,³² and a case report³³ suggested that erenumab,^30,31,32,33 galcanezumab,^30,32 fremanezumab,^30,32 and ubrogepant³⁰ may offer prophylaxis against vestibular migraine. A 2024 RCT found superior benefits from galcanezumab over placebo for reducing dizzy days per month in 40 patients with vestibular migraine or probable vestibular migraine.³⁴

For acute treatment of vestibular migraine attacks, retrospective studies reported that sumatriptan¹¹ and almotriptan³⁵ reduced vestibular and headache symptoms, but a report of 3 cases described increased headache with sumatriptan and rizatriptan.³⁶ A 2023 Cochrane review identified only 2 RCTs of acute treatments.³⁷ A trial of zolmitriptan failed due to enrollment problems and natural waning of participants’ attack frequencies.³⁸ Seventy-three patients were screened, 19 were enrolled, and 10 recorded responses to treatment of vestibular migraine attacks (3/8 positive responses to zolmitriptan and 2/9 positive responses to placebo).³⁸ The present study was found from its posting to ClinicalTrials.gov (NCT02447991).

Thus, medications recommended for migraine³⁹ are used widely to treat vestibular migraine without level 1 evidence. To address this gap, the primary aim of this study was to test the efficacy and safety of rizatriptan for acute treatment of vestibular migraine attacks in a double-blind, placebo-controlled RCT designed to overcome obstacles that thwarted previous efforts.^27,38 The primary hypothesis was that rizatriptan would be more efficacious than placebo and well-tolerated.

Methods

Oversight

Institutional review boards at the University of California at Los Angeles (UCLA) (12-001549) and Mayo Clinic in Rochester, Minnesota (14-004558), approved this investigation. A data safety and monitoring board convened by the National Institute on Deafness and Other Communicative Disorders reviewed progress semiannually.

Participants

Study participants were recruited from neurotologic practices at UCLA and Mayo Clinic during the funded enrollment period of December 2014 to January 2020, supplemented by individuals listed in research databases at both sites and respondents to advertisements in Minnesota. Before enrollment, potential participants underwent usual clinical evaluations at each site. History of active and lifetime vestibular and headache symptoms, coexisting illnesses, and medication use were obtained. Detailed neuro-otologic examinations were performed. Complete blood cell count; metabolic screening; video nystagmogram; positional/positioning, caloric, video head impulse, and rotary chair tests; cervical and ocular vestibular evoked myogenic potentials; clinical test of sensory integration and balance; brain magnetic resonance imaging; and temporal bone computed tomographic imaging were obtained as clinically indicated.

Eligible patients aged 18 to 65 years had a primary diagnosis of ICVD/ICHD-3 vestibular migraine with untreated attacks exceeding 2 hours to avoid confounds from natural resolution of shorter attacks. Potential participants were excluded for uncompensated peripheral or central vestibular deficits, other causes of episodic vestibular symptoms, migraine with brainstem aura, illnesses that increased risk for serious adverse effects from rizatriptan (eg, ischemic heart disease, coronary artery vasospasm, uncontrolled hypertension, stroke, transient ischemic attack), medications incompatible with rizatriptan, previous use of rizatriptan for vestibular migraine, known adverse reactions to triptans, unwillingness or inability to complete study procedures, and age older than 65 years, pregnancy, or breastfeeding due to lack of safety data.⁴⁰ Enrollees provided written informed consent before starting study procedures.

Design

Participants entered an observation phase to verify the diagnosis of vestibular migraine prospectively, ensure sufficient illness activity after eliminating known dietary and lifestyle triggers, and stabilize coexisting but nonexcluded conditions (eg, mild to moderate hypertension, persistent postural-perceptual dizziness, anxiety and depressive disorders). Participants continued receiving preexisting medications with potential migraine-preventative actions if prescribed for other indications, but these were avoided when stabilizing coexisting conditions.

Participants had to achieve stability of coexisting illnesses and demonstrate active vestibular migraine by recording 2 spontaneous attacks with moderate or severe vestibular symptoms lasting more than 2 hours within 6 months of entering the observation phase or they were withdrawn. Observation was extended to 12 months during the first year of the study to improve retention. Immediately after meeting these requirements, participants entered the treatment phase and were randomized to rizatriptan or placebo groups using a simple 2:1 schedule created by an investigator (H.H.L.); group assignment was shared with research pharmacists, but blinded to participants and other investigators. Participants remained in the treatment phase until they treated 3 separate vestibular migraine attacks with a single oral dose of rizatriptan 10 mg or placebo or the study ended in July 2020.

Participants were instructed to self-administer the study drug at the onset of moderate or severe vestibular symptoms (primary study target), not headache or associated symptoms. Participants were asked to refrain from using other therapies for 1 hour after taking the study drug. Participants then could add their usual rescue remedies, except triptans, for unresolved symptoms.

Efficacy Measures

Participants were given paper diaries with instructions for rating 6 predefined symptoms (Supplement 1) of vertigo, unsteadiness or nonvertiginous dizziness, headache, photophobia or phonophobia, nausea or vomiting, and motion sensitivity on a scale of 0 to 3 (0 indicates absent; 1, mild [bothersome, not limiting]; 2, moderate [limiting activities]; or 3, severe [incapacitating]) when they took study drug (0 minutes), at 30 minutes, and at 1, 2, 4, 24, and 48 hours thereafter.

Primary efficacy outcomes were the percentage of treated attacks with (1) vertigo or (2) unsteadiness or dizziness reduced from moderate or severe to absent or mild at 1 hour, which was chosen as the primary end point because rizatriptan reaches maximum serum concentration 1 hour after oral ingestion (shorter time than other triptans).⁴¹ The International Headache Society guideline for RCTs of acute migraine treatments suggested a 2-hour end point, but allowed a shorter one, emphasizing nonmaleficence to minimize waiting time for rescue therapies.⁴²

Secondary efficacy outcomes were the percentage of treated attacks with complete relief of vestibular symptoms at 1 hour, attacks with headache and other symptoms reduced from moderate or severe to absent or mild at 1 hour, attacks in which participants took rescue remedies after 1 hour, and attacks with vestibular, headache, and other symptoms reduced from moderate or severe to absent or mild at 24 hours without rescue remedies.

Additional Outcomes

Other outcomes were rates of serious adverse events, rates of drug discontinuation for any adverse event, and treatment satisfaction and quality of life at 48 hours. Investigators assessed adverse events using the National Cancer Institute Common Toxicity Criteria Scale version 4.0.3.⁴³ Participants rated satisfaction with the study drug using the Treatment Satisfaction Questionnaire for Medication,⁴⁴ a 14-item self-report of effectiveness, adverse effects, and convenience, and quality of life using the Medical Outcomes Study Short Form 12,⁴⁵ a 12-item self-report of physical and mental well-being.

Sample Estimation

Data from US Food and Drug Administration registration trials of rizatriptan for migraine showed large effects over placebo (odds ratios [ORs] of 5.7 and 7.4).^46,47 The failed RCT of zolmitriptan for vestibular migraine showed a small effect over placebo (OR of 2.1).³⁸ That trial was too small to inform reliable sample estimation, but hinted that effects of triptans for vestibular migraine might be less than for migraine without vestibular symptoms. We targeted an OR of 3.2, half of the mean from the US Food and Drug Administration registration trials,^46,47 which is considered a medium effect, the smallest that is considered clinically useful,⁴⁸ and consistent with 1-hour outcomes in data pooled from 7 development trials of rizatriptan for migraine.⁴⁹ For a double-blind design with 2:1 randomization of active drug to placebo and type I error of .05 for 2-sided tests, 80% power to detect this result suggested enrollment of 120 participants to treat 360 attacks.^50,51 With estimated attrition of 40% based on the zolmitriptan RCT,³⁸ we set enrollment at 200 participants for the observation phase.

Interim Analyses

The data and safety monitoring board performed a planned midway analysis. Attrition from the observation phase was 40% as expected, but continued into the treatment phase. The data and safety monitoring board authorized a 1-year extension to increase enrollment and recommended no other changes. Before closing the study, we reviewed diaries of all participants to enumerate attacks treated strictly per the protocol. After excluding attacks with vertigo and unsteadiness or dizziness rated less than moderate or severe at 0 minutes and attacks during which participants used rescue remedies early, we counted 240 attacks available to test 1-hour outcomes. After excluding attacks during which participants used rescue remedies as allowed after 1 hour, we counted 160 attacks available to test 24-hour outcomes. With α = .05 for 2-sided tests, N = 240 yielded greater than 80% likelihood of detecting type I errors in results of medium effect size,^48,51 suggesting that we had an adequate sample for clinically meaningful analyses of 1-hour outcomes, although smaller than intended for 24-hour outcomes.

Tests of a Priori Hypotheses (Completed 2021)

Patient characteristics were summarized using means and SDs for continuous variables and frequency counts and percentages for categorical variables. Differences between groups and sites were assessed using 2-sample t tests for continuous variables and χ² tests for categorical variables. Differences in efficacy between rizatriptan and placebo at 1 and 24 hours, use of rescue remedies after 1 hour, and safety through 48 hours were tested using binary logistic regression models with a random intercept accounting for within-participant variability. Differences in treatment satisfaction and quality of life at 48 hours were tested using linear regression models with a random intercept accounting for within-participant variability. Models testing efficacy outcomes were restricted to attacks treated strictly per the protocol. Models testing safety, treatment satisfaction, and quality of life used all treated attacks. Due to statistically significant differences in patient demographics between study sites, but not between treatment groups, models were adjusted for site.

Post Hoc Analyses (Added 2022 and 2024)

We identified 4 nonrandom effects in our data: (1) exclusion of 67 attacks from analyses of 1-hour outcomes because participants missed the treatment target of moderate or severe vestibular symptoms (n = 60) or used rescue remedies early (n = 7), leaving 240 of 307 attacks (78.2%) treated strictly per the protocol; (2) unequal sorting of vertigo severity between groups at 0 minutes because more attacks included in 1-hour analyses qualified by severity of unsteadiness/dizziness (231/240 [96.2%]) than vertigo (142/239 [59.4%]); (3) exclusion of 80 attacks from analyses of 24-hour outcomes because participants used rescue remedies as permitted after 1 hour; and (4) withdrawal of 40 of 134 participants (29.9%) from the treatment phase before they treated 3 attacks primarily because of waning of attack frequency. To assess the sensitivity of results to the first 3 effects, we performed 2 analyses, first adjusting a priori tests of primary outcomes for symptom severity at 0 minutes and then incorporating all 307 attacks into linear regression models of continuous changes of symptom severity from 0 minutes to 24 hours adjusting for site and symptom severity at 0 minutes with a random intercept accounting for within-participant variability. To assess sensitivity to the fourth effect, we conducted 25 imputations from available data for participants who treated fewer than 3 attacks. We also extended comparisons of adverse effects to reports of any severity and examined consistency of treatment responses within participants across attacks.⁴²

Missing data were minimal for reported attacks (<1% for primary outcomes; <5% overall), so a priori analyses used available data. Two-tailed P values <.05 were considered statistically significant. Effect sizes for percentages were reported as ORs with 95% CIs and ordinal designations as small (OR ≤2.34), medium (OR >2.34 and ≤3.91), or large (OR >3.91).⁴⁸ Effect sizes for continuous variables were reported as 95% CIs of coefficient estimates from regression models. Two investigators (A.M.L. and J.R.G.) performed statistical analyses in SAS version 9.4 (SAS Institute) and RStudio 3.6.2 (R Foundation for Statistical Computing).

Results

Participant Enrollment, Flow, and Demographics

Of 1364 potential participants with vestibular and headache symptoms screened for eligibility, 122 enrolled at UCLA and 100 enrolled at Mayo Clinic. Most participants were recruited from clinical practices (Figure 1). Participant demographics were similar between treatment groups (Table 1). Participants at UCLA were a mean of 3.4 years younger than those at Mayo Clinic, a clinically insignificant difference. Gender distribution was similar between sites, but racial and ethnic backgrounds differed, reflecting regional demographics and referral patterns.

Figure 1. CONSORT Diagram.

Enrollees were drawn primarily from patients referred to the investigators’ clinical practices (161/222 [72.5%]), supplemented by patients listed in research databases at both study sites (39/222 [17.6%]) and individuals responding to advertisements in Minnesota (Mayo Clinic classifieds, regional print and broadcast media) and online research listings (ClinicalTrials.gov) (22/222 [9.9%]). General social media yielded no participants. Clinical practices yielded a significantly higher rate of enrolled/screened patients (161/606 [26.6%]) than databases (39/495 [7.9%]) or advertisements (22/263 [8.4%]) (P < .001). Most participants (29/32 [91%]) who withdrew consent during the observation or treatment phases experienced remission of their vestibular migraine. ”Completed rizatriptan” and “completed placebo” indicate participants who treated 3 attacks with the study drug. Partial completion indicates participants who treated ≤2 attacks. Attacks causing moderate or severe vestibular symptoms that participants treated strictly in accordance with the study protocol were used to test a priori efficacy hypotheses. All treated attacks were used to test a priori safety, satisfaction, and quality of life hypotheses and for all post hoc analyses.

Table 1. Demographics of Study Participants by Group and Study Site.

Characteristic	Observation phasea	Treatment phasea		P value
		Rizatriptan	Placebo
By phase of study and treatment group
Participants, No.	88	89	45
Age, mean (SD), y	41.4 (11.2)	45.5 (10.7)	42.9 (12.4)	Observation vs treatment phase, .14; rizatriptan vs placebo group, .21
Gender, No. (%)b
Women	57 (64.5)	68 (76.4)	32 (71.1)	Women vs men: observation vs treatment phase, .11; rizatriptan vs placebo group, .51
Men	31 (35.2)	21 (23.6)	13 (28.9)
Other/chose not to disclose	0	0	0
Race and ethnicity, No. (%)b
African American or Black	3 (3.4)	6 (6.7)	0	White (not Hispanic) vs other categories: observation vs treatment phase, .62; rizatriptan vs placebo group, .07
Asian American or Asian	6 (6.8)	9 (10.1)	5 (11.1)
Hispanic	10 (11.4)	8 (9.0)	2 (4.4)
Native American or Alaska Native	1 (1.1)	0	0 (0
White (not Hispanic)	61 (69.3)	60 (67.4)	37 (82.2)
Multiracial, other, or chose not to disclose	7 (8.0)	6 (6.7)	1 (2.2)
By study site	UCLA	Mayo Clinic		P value
Participants enrolled in observation phase, No.	122	100
Age, mean (SD), y	40.8 (12.2)	44.2 (10.7)		.03
Gender, No. (%)b
Women	85 (69.7)	72 (72.0)		Women vs men, .70
Men	37 (30.3)	28 (28.0)
Other/chose not to disclose	0	0
Race and ethnicity, No. (%)b
African American or Black	8 (6.6)	1 (1.0)		White (not Hispanic) vs all other categories, .001
Asian American or Asian	20 (16.4)	0
Hispanic	19 (15.6)	1 (1.0)
Native American or Alaska Native	1 (0.8)	0
White (not Hispanic)	62 (50.8)	96 (96.0)
Multiracial, other, or chose not to disclose	12 (9.8)	2 (2.0)
Participants advanced to treatment phase, No. (% enrolled in observation phase)	77 (63.1)	57 (57.0)		.35
No. of attacks treated during treatment phase, No. (% advanced to treatment phase)
3 Attacks	50 (64.9)	43 (75.4)		.33
1-2 Attacks	12 (15.6)	8 (14.0)
0 Attacks	15 (19.5)	6 (10.5)

^a Observation phase included individuals who only completed the observation phase; treatment phase included individuals who completed the observation phase and advanced to the treatment phase.

^b Gender, race, and ethnicity were self-selected by participants from the categorical choices listed in the table. Analyses of demographic variables were performed to test for potential confounds in recruitment patterns at each site and to provide a measure of compatibility with previously reported data.

Of 222 participants entering the observation phase, 134 (60.4%) progressed to the treatment phase. Ninety-four participants treated 3 attacks, 19 treated 1 or 2 attacks, and 21 treated no attacks. There were no differences between the observation and treatment phases or between the treatment groups in participant demographics. There were no differences between sites in the percentage of participants who advanced from the observation phase to the treatment phase or number of attacks treated (Table 1). Most participants who withdrew during the trial (29 of 32) and all participants withdrawn by investigators (n = 18) at study end experienced remissions of illness.

A Priori Analyses

Among treated attacks, 277 of 307 (90.2%) manifested moderate or severe vestibular symptoms and headache by the 1-hour mark, meaning that 9.8% occurred without noticeable cephalalgia (Figure 2). Considering 240 attacks treated per protocol, there were no significant differences between rizatriptan and placebo for any primary or secondary efficacy outcomes at 1 hour (Table 2). All effect sizes were small, except a medium effect for complete relief of unsteadiness or dizziness favoring rizatriptan at 1 hour (OR, 3.79 [95% CI, 0.51-28.4]), albeit with low rates of remission and a wide CI. Participants in both groups added rescue remedies in similar proportions. Rizatriptan was superior to placebo with medium effects for unsteadiness or dizziness and motion sensitivity at 24 hours. There were no significant differences for other symptoms and effects were small, except for a medium effect favoring rizatriptan for photophobia or phonophobia (OR, 2.77 [95% CI, 1.00-7.77]). Rizatriptan was significantly superior to placebo on overall treatment satisfaction and physical quality of life, but not subscales of treatment satisfaction or mental quality of life at 48 hours (Table 2). No participants experienced severe adverse effects. None withdrew because of adverse effects.

Figure 2. Percentage of Participants Who Rated Symptoms of Vestibular Migraine Attacks as Moderate or Severe.

Solid circle markers and lines represent attacks treated strictly per the protocol (n = 240) and unfilled circle markers and dashed lines represent all reported attacks (N = 307).

^aFor attacks treated per protocol, a higher proportion of participants rated vertigo as moderate/severe at 0 minutes in the rizatriptan vs placebo groups (P = .03). Rizatriptan did not differ from placebo for any symptoms at 1 hour.

^bFor attacks treated per protocol, rizatriptan was superior to placebo for reducing unsteadiness/dizziness (P = .04) and motion sensitivity (P = .006) at 24 hours with a medium effect size.

^cFor all attacks, rizatriptan was superior to placebo for reducing unsteadiness/dizziness (P = .004), headache (P = .03), photophobia/phonophobia (P  = .01), and motion sensitivity (P = .004) at 24 hours, with a medium effect size.

Table 2. Primary and Secondary Treatment Outcomes.

Outcome	No. of attacks/No. treated (%)		Site-adjusted P value	Odds ratio (95% CI)a	Effect size interpretation of odds ratiob
	Rizatriptan	Placebo
Primary outcome: reduction in vestibular symptoms from moderate/severe to absent/mild at 1 hc
Vertigo	73/151 (48.3)	50/88 (56.8)	.33	0.69 (0.33-1.46)	Small
Unsteadiness/dizziness	29/151 (19.2)	11/89 (12.4)	.18	1.86 (0.75-4.62)	Small
Secondary outcome: complete relief of vestibular symptoms at 1 hc
Vertigo	56/151 (37.1)	35/88 (39.8)	.63	0.83 (0.38-1.78)	Small
Unsteadiness/dizziness	12/151 (7.9)	2/89 (2.2)	.19	3.79 (0.51-28.4)	Medium
Secondary outcome: reduction in headache and associated symptoms from moderate/severe to absent/mild at 1 hc
Headache	44/149 (29.5)	38/89 (42.7)	.14	0.58 (0.28 1.19)	Small
Photophobia/phonophobia	59/151 (39.1)	33/89 (37.1)	.72	1.14 (0.55-2.38)	Small
Motion sensitivity	39/151 (25.8)	19/89 (21.3)	.48	1.32 (0.60-2.91)	Small
Nausea/vomiting	67/150 (44.7)	50/89 (56.2)	.35	0.71 (0.34-1.47)	Small
Secondary outcome: reduction in vestibular symptoms from moderate/severe to absent/mild without additional medication at 24 hc
Vertigo	97/109 (89.0)	54/61 (88.5)	.76	1.24 (0.32-4.78)	Small
Unsteadiness/dizziness	90/109 (82.6)	41/62 (66.1)	.04	2.65 (1.04-6.79)	Medium
Secondary outcome: reduction in headache and associated symptoms from moderate/severe to absent/mild without additional medication at 24 hc
Headache	94/109 (86.2)	46/62 (74.2)	.12	2.17 (0.81-5.82)	Small
Photophobia/phonophobia	95/109 (87.2)	45/62 (72.6)	.05	2.77 (1.00-7.77)	Medium
Motion sensitivity	95/109 (87.2)	42/62 (67.7)	.006	3.58 (1.44-8.88)	Medium
Nausea/vomiting	101/108 (93.5)	57/62 (91.9)	.67	1.35 (0.34-5.34)	Small
Secondary outcome: use of additional medication after 1 h (all treated attacks)
No./total No. (%)	52/197 (26.4)	28/106 (26.4)	.47	1.00 (0.58-1.71)	Small
Secondary outcome: adverse effects through 48 h (all treated attacks)
Serious adverse effects	0/197	0/106
Discontinuation due to adverse effects	0/197	0/106
Outcome	Estimate (95% CI) d				Site-adjusted P value
Secondary outcome: treatment satisfaction at 48 h (all treated attacks)
TSQM effectiveness	9.82 (−0.30 to 19.94)				.055
TSQM adverse effects	3.92 (−6.45 to 14.28)				.45
TSQM convenience	1.63 (−4.57 to 7.83)				.60
TSQM overall satisfaction	10.44 (0.65 to 20.23)				.04
Secondary outcome: quality of life at 48 h (all treated attacks)
SF-12 Physical subscale	4.65 (1.16 to 8.13)				.009
SF-12 Mental subscale	2.56 (−1.65 to 6.77)				.23

Abbreviations: SF-12, 12-Item Short Form Health Survey; TSQM, Treatment Satisfaction Questionnaire for Medication.

^a Reference is the placebo group.

^b Odds ratio (OR) equivalents for Cohen classification of effect size were defined as follows: small effect (OR ≤2.34), medium effect (OR >2.34 and ≤3.91), or large effect (OR >3.91).

^c Symptoms were rated on a scale ranging from 0 to 3 (0 indicates absent; 1, mild [bothersome, not limiting]; 2, moderate [limiting activities]; or 3, severe [incapacitating]).

^d Linear regression estimate: between-group differences in TSQM or SF-12 ratings; positive values favor rizatriptan.

Post Hoc Analyses

More attacks qualified for a priori analyses by severity of unsteadiness or dizziness (96.2%) than vertigo (59.4%). Randomization procedures did not account for this circumstance, inadvertently leading to a higher percentage of attacks treated per protocol with moderate or severe vertigo in the rizatriptan group at 0 minutes (97/150 [64.6%] vs 45/89 [50.6%]; P < .03) and, conversely, a higher percentage of attacks with absent or mild vertigo in the placebo group (35.4% vs 49.4%). Nonsignificant differences occurred in the same direction for headache and nausea or vomiting (Figure 2). These differences underlay the apparent but nonsignificant inferiority of rizatriptan vs placebo for reducing these 3 symptoms at 1 hour (Table 2). The percentage of attacks treated per protocol with absent or mild ratings increased numerically, but nonsignificantly, more in the rizatriptan group than in the placebo group from 0 minutes to 1 hour (eg, for vertigo: from 35.4% to 48.3% [12.9 percentage points] in the rizatriptan group vs 49.4% to 56.8% [7.4 percentage points] in the placebo group). Post hoc adjustments in efficacy analyses for differences in symptom severity at 0 minutes and imputations of data for participants who treated fewer than 3 attacks replicated the negative results for a priori outcomes (Table 3). Post hoc observations of all 307 attacks showed no clinically meaningful improvements in any symptoms over the first hour regardless of treatment group (Figure 2).

Table 3. Post Hoc Analysis Treatment Outcomes.

Outcome	No. of attacks/No. treated (%)		Site-adjusted P value	OR (95% CI)a	Effect size interpretation of odds ratiob
	Rizatriptan	Placebo
Primary outcome: reduction in vestibular symptoms from moderate/severe to absent/mild at 1 hc
Vertigo	73/151 (48.3)	50/88 (56.8)	.33	0.69 (0.33 to 1.46)	Small
Post hoc adjustment for severity at 0 min			.65	0.84 (0.39 to 1.78)	Small
Post hoc imputation of incomplete attack data			.53	0.82 (0.44 to 1.53)	Small
Unsteadiness/dizziness	29/151 (19.2)	11/89 (12.4)	.18	1.86 (0.75 to 4.62)	Small
Post hoc adjustment for severity at 0 min			.26	1.67 (0.68 to 4.08)	Small
Post hoc imputation of incomplete attack data			.31	1.45 (0.70 to 3.01)	Small
Outcome	Mean (SD)		Site-adjusted P value	Estimate (95% CI)a
Change in mean symptom severity rating from baseline to 24 h controlled for baseline severity, negative values indicates reduction in severity (all treated attacks)
Vestibular symptoms
Vertigo	−0.98 (1.34)	−0.67 (1.31)	.23
Unsteadiness/dizziness	−1.38 (1.21)	−1.11 (1.48)	.004	−0.48 (−0.79 to −0.16)
Headache symptoms
Headache	−1.03 (1.32)	−0.55 (1.30)	.03	−0.33 (−0.62 to −0.03)
Photophobia/phonophobia	−1.12 (1.24)	−0.86 (1.31)	.01	−0.35 (−0.63 to −0.08)
Motion sensitivity	−1.34 (1.36)	−0.94 (1.36)	.004	−0.49 (−0.81 to −0.16)
Nausea/vomiting	−1.14 (1.23)	−0.60 (1.09)	.11
Outcome	No. of attached/No. treated (%)		Site-adjusted P value	Odds ratio (95% CI)	Effect size interpretation of ORb
Rates of mild-moderate adverse effects (all treated attacks) through 48 h
Fatigue	42/196 (21.4)	6/105 5.7)	.01	4.52 (1.44 to 14.21)	Large
Sleepiness or drowsiness	49/197 (24.9)	10/106 (9.4)	.02	3.18 (1.20 to 8.44)	Medium

^a Linear regression estimate: between-group differences of change in symptoms (negative values favor rizatriptan).

^b Odds ratio (OR) equivalents for Cohen classification of effect size were defined as follows: small effect (OR ≤2.34), medium effect (OR >2.34 and ≤3.91), large effect (OR >3.91).

^c Symptoms were rated on a scale of 0 to 3 (0 indicates absent; 1, mild [bothersome, not limiting]; 2, moderate [limiting activities]; or 3, severe [incapacitating]).

Power to test a priori 24-hour outcomes was reduced by eliminating 80 attacks during which participants used rescue remedies as permitted after 1 hour. To check for false-negative errors, post hoc comparisons between groups utilized all treated attacks and continuous metrics for symptom severity (Table 3). These comparisons extended the efficacy results slightly in favor of rizatriptan over placebo, finding medium effects for headache (linear regression estimate, −0.33 [95% CI, −0.62 to −0.03]), photophobia or phonophobia (linear regression estimate, −0.35 [95% CI, −0.63 to −0.08 ]), unsteadiness or dizziness (linear regression estimate, −0.48 [95% CI, −0.79 to −0.16]), and motion sensitivity (linear regression estimate, −0.49 [95% CI, −0.81 to −0.16]) (Table 3).

Post hoc analyses also showed that rizatriptan caused higher rates of mild or moderate fatigue and sleepiness or drowsiness than placebo (Table 3), both of which are well-known adverse effects of rizatriptan.⁴⁰ There were no significant differences between the groups in rates of neurologic, chest, or abdominal adverse effects, fever/chills, anxiety, or agitation (range, 0.3%-8.6%; all P > .05). Participants showed no consistency in treatment responses from first through the third attack.

Discussion

A priori analyses found no differences between rizatriptan and placebo on any primary or secondary efficacy outcomes at 1 hour. Rizatriptan was superior to placebo for only 2 of 7 secondary efficacy outcomes at 24 hours. Outcomes were mixed for treatment satisfaction and quality of life at 48 hours. Post hoc analyses used the statistical power of the entire dataset to test the sensitivity of a priori results to the 4 nonrandom effects found in the data. These analyses, which included real-world patient behaviors of self-administering medication for vestibular or headache symptoms of any severity and using rescue remedies at any time, extended results favoring rizatriptan only slightly, finding benefits and adverse effects at 24 to 48 hours consistent with its existing labeling for migraine without vestibular symptoms.⁴⁰ Confidence in negative results for vestibular symptoms was bolstered by small effect sizes for 3 of 4 primary and secondary outcomes at 1 hour. The only exception, a medium effect for complete relief of unsteadiness/dizziness, had minimal clinical utility given the small proportion of participants (7.9%) who reached that end point. The significant medium reduction in unsteadiness/dizziness at 24 hours fell outside the desired timeframe for an acute treatment.

Limitations that halted previous RCTs^27,38 were largely overcome in this trial. Most patients presenting with vestibular and headache symptoms did not have vestibular migraine, so large numbers of potential participants were screened to enroll a sufficient sample. Attrition rates in both groups exceeded the 40% predicted, perhaps because per-protocol management of known triggers and comorbid illnesses enhanced natural waning of attack frequency, so the recruitment period was extended. Statistical power for testing 24-hour outcomes was reduced by unexpectedly high rates of rescue remedy usage in both groups, which supported the null results of the primary outcomes, but required post hoc analyses to buttress a priori analyses limited by available power.

Limitations

This study has some limitations. These results are most generalizable to tertiary neurotologic practices, from which 200 of 222 participants (90%) were drawn, but may not necessarily extend to community specialty or primary care settings. This study cohort was comparable in age and sex distributions to cohorts from prior reports of vestibular migraine.^{17,18,19,20,21,22,23,24,25,26,27,34,38} The percentage of screened patients who enrolled and the percentage of enrolled participants who completed the trail were similar to previous RCTs.^27,34,38 Waning of attack frequency was akin to the 2 longer trials.^27,38 Nevertheless, this is the only adequately powered study to date to report outcomes of treatment of vestibular migraine attacks with a triptan. Additional studies are needed to evaluate acute treatment options. As in previous RCTs, a minority of patients referred for vestibular and headache symptoms met diagnostic criteria for vestibular migraine.^27,34,38 These results may not apply to patients with probable vestibular migraine who were excluded from this RCT.¹

Conclusions

Results of this study do not support routine use of rizatriptan to treat vestibular migraine attacks. It was not efficacious for any symptoms at 1 hour and demonstrated no effects on vertigo. Adverse effects were minor and consistent with previous reports.

Supplement 1.

Trial protocol

Supplement 2.

Data sharing statement