Clinical trial NCT02447991
Conditions: Vestibular Migraine Migrainous Vertigo
Sponsor: Robert W. Baloh
Start date: 2014-12-01; Completion date: 2020-07-31
Enrollment: 223 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Suffering from dizzy spells and migraine headaches?

Vestibular Migraine (VM), a newly recognized type of migraine that causes bouts of dizziness.

University of California, Los Angeles (UCLA) and The Mayo Clinic is seeking people with VM to participate in a research study. The purpose of this study is to look at the natural history of VM and learn more about common symptoms. Investigators also want to learn the effects, both positive and negative, of the commonly used migraine drug, rizatriptan, when it is used for spells of dizziness in people with VM.

Patients may be eligible to participate if:

* Patients are between the ages of 18 \& 65
* Patients have a history of vestibular migraine
* Patients are able to maintain a vestibular symptom diary

The study includes 3 visits with compensation. All participants must complete questionnaires on dizziness, headache symptoms, general health and well-being, mental health, and a questionnaire on patient's satisfaction with study medication.

Detailed description:
The primary Specific Aim is to conduct the first successful controlled study of a treatment for Vestibular Migraine. The investigators hypothesize that rizatriptan will be superior to a look alike inactive capsule for:

1a. Reducing the severity and duration of vertigo attacks in patients with Vestibular Migraine,

1b. Reducing the severity of symptoms commonly associated with vertigo attacks in patients with Vestibular Migraine (e.g., nausea, vomiting, motion sensitivity, gait disturbance, headache, light and sound sensitivity), and

1c. Improving treatment satisfaction and health-related quality of life in patients with Vestibular Migraine, and that

1d. Rizatriptan will be well tolerated by patients with Vestibular Migraine.

Arms: arm 1: During the Treatment Phase, three placebo capsules will be administered to each subject. One capsule will be taken during one acute episode, until three episodes are treated with the study drug. arm 2: During the Treatment Phase, three Rizatriptan capsules will be administered to each subject. One capsule will be taken during one acute episode, until three episodes are treated with the study drug.
Interventions: intervention 1: Rizatriptan intervention 2: Placebo
Intervention descriptions: intervention 1: During the study either placebo or Rizatriptan will be given to subjects to take during the treatment phase of this study. intervention 2: During the study either placebo or Rizatriptan will be given to subjects to take during the treatment phase of the study.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
A Phase II/III Trial on Rizatriptan for Vestibular 
Migraine 
 
 
 
 
 
 
 
 
NCT02447991 
 
 
 
 
 
 
June 22, 2018 
 


SPECIFIC AIMS 
 
Vestibular migraine (VM), also known as migrainous vertigo or migraine-associated vertigo, is characterized by 
recurrent vestibular attacks often accompanied by migraine headaches.  It is a prevalent presenting complaint 
to physicians in primary care, otolaryngology, and neurology. Epidemiologic data suggest that VM may affect 
1% of the general population and 10% of patients seeking treatment for recurrent attacks of vertigo. Yet, the 
clinical spectrum of VM and its underlying pathophysiological mechanisms remain unclear, with much debate 
about the causal relationship of vestibular symptoms and headache, no evidence-based guidelines for clinical 
management, limited characterization of its disease burden, and no information about its negative impact on 
health-related quality of life.  Currently there is no proven therapy for VM.  Vestibular suppressants such as 
meclizine and dimenhydrinate are often used for symptomatic relief, but they do not prevent attacks and may 
have sedating side effects. Uncontrolled case reports suggest that migraine abortive and prophylactic 
medications are effective for treating VM. Triptans, in particular, hold promise for aborting vestibular attacks in 
patients with VM based on the results of several uncontrolled studies and one underpowered controlled trial.  
However, substantial placebo response rates are well documented in controlled treatment trials for migraine, 
making it impossible to know if patients in these studies of VM responded to specific pharmacologic effects of 
study medications or non-specific elements of treatment. 
 
The primary Specific Aim of this study is to conduct the first successful Phase II clinical trial of any medication 
for aborting vestibular attacks in subjects with VM, specifically to carry out a two-site, double blind, parallel 
arms, placebo controlled trial of rizatriptan.  We hypothesize that rizatriptan will be superior to placebo in:  
1a. Reducing the severity and duration of vestibular attacks in patients with VM, 
1b. Reducing the severity of symptoms commonly associated with vestibular attacks in patients with VM 
(e.g., nausea, vomiting, motion sensitivity, gait disturbance, headache, photophobia, and phonophobia), 
and 
1c. 
Improving treatment satisfaction and health-related quality of life in patients with VM, and that 
1d. Rizatriptan will be well tolerated by patients with VM. 
 
These efficacy and safety data will inform decisions about the feasibility of a Phase III clinical trial of rizatriptan 
for VM, but additional information will be needed to fully design such a trial. The sample size and duration of a 
Phase III trial will depend on the natural history of vestibular attacks in patients with VM. Subject selection 
criteria will depend on prevalence and confounding effects of comorbid conditions and use of co-existing 
therapies.  Therefore, the secondary Specific Aim of this study is to collect data that will be crucial for preparing 
detailed Manuals of Operating Procedures for future Phase III trials.  We hypothesize that needed data will 
include: 
2a. The natural range of frequency and severity of vestibular attacks in treatment-seeking patients with VM, 
2b. The type and severity of medical and psychiatric conditions that commonly coexist with VM, and  
2c. 
The types, doses, and frequency of use of prescription and non-prescription medications for VM,  
including data on the effects of these variables on the efficacy of rizatriptan for treating vertigo attacks in VM. 
 
To accomplish these Specific Aims, we propose to enroll 240 patients diagnosed with VM from the busy 
tertiary neurotology practices at UCLA and Mayo Clinic into a 2-phase investigation consisting of an 
Observation Period of up to 12 months, followed by a Treatment Period of up to 3 treated episodes or end of 
study, whichever comes first.  During the Observation Period we will prospectively characterize the frequency 
and severity of vestibular attacks and associated symptoms in VM, the prevalence and severity of comorbid 
conditions, and the use of abortive and prophylactic medications and non-prescription treatments in patients 
receiving usual clinical care. We will train patients to recognize vestibular spells appropriate for study treatment 
and stabilize potentially confounding comorbid conditions. We will measure subjects’ satisfaction with usual 
care and their health-related quality of life.  Approximately 120 persistently symptomatic subjects will be 
randomly assigned to treatment with either rizatriptan or placebo in a ratio of 2:1. We will measure the effects 
of study treatment on reducing or resolving vestibular and associated symptoms, reducing the need for 
additional symptomatic treatments, and improving treatment satisfaction and health related quality of life over 
the 48 hours that follow each treated attack.  We will capture the incidence and severity of treatment-emergent 
adverse effects. The results will provide data to guide future Phase III study designs. They also may yield 
insights into pathophysiologic processes that cause VM and suggest directions for future mechanistic 
investigations. 


 
RESEARCH STRATEGY 
 
I. SIGNIFICANCE 
 
A. What is vestibular migraine (VM)? 
The observation that migraine and dizziness often occur together dates back to the nineteenth century when 
Livening noted their connection in his classic book On Megrim: Sick Headaches and Some Allied Health 
Disorders.16  However, only in recent years have vestibular symptoms been recognized as part of the migraine 
syndrome. Vestibular migraine (VM), also known as migrainous vertigo and migraine-associated vertigo, 
affects about 1% of the general population and 10% of patients seen in dizziness and headache clinics.17  
Episodic vestibular symptoms occur in about 25% of unselected migraine patients.18 Vestibular symptoms can 
occur during headaches, but often occur during headache-free intervals.3-5,19,20 Only about one quarter of 
patients reliably experience headaches during vestibular attacks.5,19 Vestibular attacks in patients with VM 
typically last from minutes to days.3-5,21-23 If examined during an attack, patients with VM may show 
spontaneous or positional nystagmus that can have central or peripheral features, raising concerns about other 
neurotologic illnesses.3,24-26 These factors have made it difficult to characterize the relationship between 
migraine and vestibular symptoms.27  As a result, a causal relationship has not been proven. This problem has 
been used as an argument against the concept of VM, but it is no different than the situation with other 
transient symptoms that accompany migraine.28 For example, scintillating scotomata are universally accepted 
as migrainous phenomena, yet their pathophysiologic link with headache is still unknown after hundreds of 
years of clinical observation. Conventional migraine and VM share numerous features. Both have a marked 
female preponderance (2-3:1).5 Attacks of both can be precipitated by alcohol, lack of sleep, fasting, certain 
foods, and emotional stress.21,23,28 Patients with VM have past or present histories of migraine and often have 
family histories of both migraine and vestibular symptoms.29-30 Finally, case reports and case series suggest 
that migraine abortive and prophylactic agents, including triptans, may be effective for treating VM.1-4 
 
Neurotologic conditions such as Meniere’s disease and benign paroxysmal positional vertigo (BPPV) share 
some symptoms with VM.6,31,32 Meniere’s disease may start with recurrent vertigo without ear symptoms; 
however, with Meniere’s disease, tinnitus and hearing loss invariably occur within a year of onset.32,33 Vertigo 
attacks in BPPV are positional and last no more than 1-2 minutes. Vertigo attacks in VM may have a positional 
element, but symptoms persist even when patients are still and typically last longer than 2 minutes.20 VM may 
coexist with Meniere’s disease,21 BPPV, chronic subjective dizziness (CSD),34 anxiety, depression,5 and other 
conditions that may alter its clinical presentation and morbidity. Recent advances in our understanding of the 
pathophysiologic mechanisms of migraine provide new hope for elucidating the link between periodic 
headaches and vestibular symptoms.35 The proposed study may increase our knowledge of these factors, too. 
 
The current (2nd) edition of International Classification of Headache Disorders (ICHD-II)36 does not contain VM, 
but the recently published beta version of the 3rd edition does.14 VM is defined the appendix of ICHD-3 (Table 
1), which is the first step toward full recognition in the official nomenclaure.14 These criteria define the types of 
vestibular symptoms; minimum number, severity, and duration of vestibular attacks; association of vestibular 
and migrainous symptoms; requirement for a migraine diagnosis; and absence of other causes of symptoms. 
 
Table 1.  Diagnostic criteria for vestibular migraine (as included in the appendix of ICHD-3, beta version)14 
A At least 5 episodes of fulfilling criteria C and D. 
B A current or past history of migraine without aura or migraine with aura. 
C Vestibular symptomsa of moderate or severe intensity,b lasting between 5 minutes and 72 hours. 
D At least 50% of episodes are associated with at least one of the following three migrainous features: 
1. Headache with at least two of: a) unilateral location, b) pulsating quality, c) moderate or severe 
intensity, d) aggravation by routine physical activity 
2. Photophobia and phonophobia 
3. Visual aura 
a. 
Vestibular symptoms qualifying for a diagnosis of vestibular migraine include: 1) spontaneous vertigo – false 
sensation of self motion or that the visual surround is spinning or flowing; 2) positional vertigo – vertigo occurring after 
a change in head position; 3) visually-induced vertigo – vertigo triggered by a complex or large moving visual 
stimulus; 4) head-motion induced vertigo – vertigo occurring during head motion; 5) head motion-induced non-
vertiginous dizziness with nausea, characterized by a sensation of disturbed spatial orientation. 


b. 
Moderate, interferes with but does not prohibit daily activities; severe, prevents daily activities. 
B. What is the public health burden of VM? 
Neuhauser et al.20 found a 1% prevalence of VM in the general population of Germany and concluded that VM 
is underdiagnosed, causing considerable personal and health-care burden. At a rate of 10%, VM is the third 
most common diagnosis in specialty neurotology centers.21 In our clinical practices, patients with VM have 
been symptomatic for an average of 4.5 years before referral and have seen 4-5 previous physicians for their 
symptoms.34 Most have missed significant work, school, or home obligations. 
 
C. How is VM treated?  Why investigate an abortive versus a prophylactic therapy? 
Currently there is no proven therapy for VM. Vestibular suppressants such as meclizine and dimenhydrinate 
are frequently used for symptomatic relief of vestibular symptoms, but these medications do not prevent 
vestibular attacks and often have sedating side effects.3 Case reports1-4 and one uncontrolled trial7 suggest 
that commonly used migraine abortive and prophylactic drugs may be effective for treating vestibular attacks in 
patients with VM, but high placebo effects are well documented in controlled treatment trials for migraine 
headaches. A single placebo-controlled study suggested benefit for a triptan in VM, but the study failed to 
reach statistical significance for several important reasons (see “Prior Controlled Study” below).8 Advantages 
of studying an abortive rather than a prophylactic drug in this first-ever phase II treatment trial of VM include: 1) 
adequate phase I data exist to design a triptan trial for VM, 2) the target symptoms (discrete attacks) and 
primary outcome measure (response vs. no response) are straightforward, 3) patients prefer taking medication 
just at the time that symptoms occur, rather than daily medication, 4) potential confounds can be managed 
more easily in an abortive study than in a prophylactic trail, and 5) we will learn more about the clinical course 
and pathophysiology of VM (secondary Specific Aim), whether or not the abortive agent is effective.  
 
D. What is the scientific basis for treating VM with triptans? 
The serotonin system has long been implicated in the pathogenesis of migraine.37 Many common migraine 
drugs are thought to exert effects on serotonin receptors or serotonin uptake, including ergotamines, beta 
blockers, methysergide, and tricyclic antidepressants. The trigeminal vascular theory for migraine headaches38 
holds that trigeminal nerve fibers surrounding pial arteries on the ventral surface of the brain are activated, 
releasing substance P and calcitonin gene related protein, increasing vascular permeability, dilating cerebral 
vessels, and triggering a local inflammatory response that further activates pain fibers of the trigeminal 
vascular system. Triptans constrict pain-producing intracranial extracerebral blood vessels, reduce trigeminal 
sensory nerve activity, and inhibit vasoactive neuropeptide release,39 possibly via their strong affinity for 5HT1B 
and 5HT1D receptors,39,40 which are heavily expressed in the peripheral trigeminal system. These receptors are 
also present in vestibular ganglion cells and inner ear cells in rats and monkeys.41 Parallel expression of 5HT1B 
and 5HT1D receptors in the peripheral vestibular and trigeminal systems suggests that similar mechanisms may 
be at work to produce vertigo and headaches. Triptans could, therefore, be effective for treating both vertigo 
and headaches.41 Serotonin agonists decrease emesis in animal models of motion sickness.42-44 In three small 
placebo controlled studies, rizatriptan protected patients with migraine/VM from developing motion sickness 
triggered by vestibular stimulation (N=10, N=25),9,11 but not visual motion stimulation (N=10).10 In controlled 
studies for non-vestibular migraine headaches, rizatriptan significantly decreased the severity of nausea.45  
 
E. What are the risks of taking triptans? 
Triptans are well tolerated with minimal side effects, the most common being somnolence.46 Patients with 
ischemic or other heart disease, uncontrolled hypertension, and basilar migraine are typically excluded from 
treatment with triptans because of concerns about vasospasm. However, in vitro and in vivo data suggest 
minimal vasoconstrictor effects on coronary or peripheral arteries in normal human subjects.47-49 In an 
uncontrolled case series of three women with VM, triptan treatment resolved vertigo attacks but induced or 
aggravated headaches.2 This has not been reported in any other cases of VM patients treated with triptans, but 
it illustrates the importance of conducting a well controlled treatment trial measuring all VM symptoms. 
 
F. What are the pharmacokinetics and costs of rizatriptan versus other triptans? 
Rizatriptan is rapidly and near completely absorbed (~90%) from the gastrointestinal tract following 
administration of the oral tablet. Absolute bioavailability is 47% owing to moderate first-pass metabolism.50 The 
mean time to maximum plasma concentration (tmax) following a single rizatriptan 10-mg tablet in healthy 
volunteers is about 1 hour,50,51 which is shorter than that of other triptans.46 Rizatriptan has a relatively short 
plasma half-life of approximately 2–2.5 hours.50,51 Healthy males showed no unexpected accumulation of 


rizatriptan following administration of multiple 10 mg doses.52 Rizatriptan is also available in a wafer form that 
dissolves in the mouth but it is absorbed at a slower rate than the oral tablets (mean tmax 1.6–2.5 hours).  
 
Rizatriptan is eliminated primarily via oxidative deamination catalyzed by monoamine oxidase A and renal 
elimination which together account for 76% of total plasma clearance.50 Cytochrome P-450 inhibitors minimally 
affect rizatriptan pharmacokinetics,53,54 reducing a major source of potential drug-drug interactions. Patients 
receiving propranolol may have an increase in plasma rizatriptan concentration, possibly reflecting competitive 
inhibition of monoamine oxidase A.55 Rizatriptan crosses the blood-brain barrier better than other triptans.56 
Though other triptans can be administered intranasally or by or injection, rapidly absorbed oral rizatriptan is a 
logical, cost-effective choice for this first phase II study.  Rizatriptan is now available in generic formulation, 
making it a cost-effective option for future clinical care. If oral rizatriptan is effective for treating vertigo attacks 
in VM, then other routes of administration can be assessed in later studies. 
 
G. Summary of Significance 
One percent of the general population and up to 10% of treatment-seeking patients with recurrent vestibular 
attacks suffers from VM.  Little is known about its clinical course or the prevalence and severity of comorbid 
conditions, leading to diagnostic confusion and inadvertently misguided therapies.  In the absence of proven 
treatments, current clinical practice relies on anecdote and uncontrolled studies, several of which suggest good 
response to triptans.1-4 This investigation, if successful, will provide the first evidence base for any abortive or 
prophylactic therapy for VM (Specific Aim #1).  It also will lay the foundation for a definitive Phase III trial of 
rizatriptan for treating vestibular attacks and associated symptoms in patients with VM. Data on the key clinical 
features of VM and its comorbid conditions will provide the detailed information needed to write Manuals of 
Operating Procedures for future trials including guidance on subject selection and methods of handling 
potential confounds (Specific Aim #2).  More immediately, it will provide clinically useful information to improve 
diagnostic clarity of VM.  It also may provide insights into the pathophysiology of the condition. 
 
II. INNOVATION 
A. Prior Controlled Study of Triptans for Vestibular Migraine 
Neuhauser et al.8 conducted a placebo-controlled trial of oral zolmitriptan for aborting VM attacks, but the study 
did not reach statistical significance due to inadequate power.  Criteria for entry into that study included age 
between 18 and 65 years and a diagnosis of VM according to the investigators’ original 2001 definition.20 That 
definition differed from the recently published ICHD-3 diagnosis (Table 1)14 in that it required a lifetime history 
of just two, not five, attacks of vestibular symptoms.  Randomization to treatment required demonstration of 
active illness as defined by two or more moderate to severe vestibular attacks in the 12 months preceding 
study entry.  Of 73 subjects initially enrolled, only 19 (26%) were randomized to crossover treatment. Most 
subjects (N=32 or 44% of initial sample) who were not randomized failed to meet requirements for frequency 
and severity of acute attacks.  Another 14 subjects (19%) could not be randomized because they lived too far 
from the study location. Among those who were randomized, 10/19 (53%) subjects treated a total of 17 attacks 
(8 with zolmitriptan, 9 with placebo). The others had no attacks after randomization or dropped out of the study. 
Response rates were 3/8 (38%) for zolmitriptan and 2/9 (22%) for placebo, numbers too small to make any 
conclusions with regard to treatment response. Five lessons can be learned from this failed trial. First, 
investigators must enroll patients who have more frequent and severe attacks. The natural waxing and waning 
course of illness prevented nearly half of subjects in the zolmitriptan trial from being randomized. This problem 
is related to one of the fundamental questions about VM. How many attacks are needed to diagnose the 
condition with reasonable sensitivity and specificity? The new diagnostic criteria for VM, included in the 
appendix of ICHD-3, require five, rather than two, lifetime vestibular attacks in patients who meet other criteria 
for migraine headache.14  Five has already been adopted as the number of attacks required to meet criteria for 
other types of migraine in the ICHD.  The larger number was chosen to increase diagnostic specificity.14 It also 
will likely identify individuals with more active illness. The second lesson from the failed zolmitriptan trial is that 
a prospective period of observation is needed to ensure that enrolled subjects continue to be symptomatic 
before they are assigned to treatment. This will reduce the randomization of subjects whose retrospectively 
reported history of vestibular attacks is not sustained when observed prospectively. The third lesson is that a 
greater chance of success may be achieved by focusing on patients with severe, long duration attacks, 
irrespective of other migraine features during attacks. This is likely to provide clearer direction to subjects 
about which attacks qualify for study treatment. The fourth lesson is that efforts should be made to treat more 
attacks per randomized subject.  It is usually not desirable to treat many attacks in just a few subjects because 


generalizability could suffer; however, it is reasonable to gather more data from each carefully enrolled subject 
than Neuhauser and colleagues did in their failed trial.8 The fifth lesson is that a large number of potential 
subjects, recruited from more than one center, will be required to complete an adequate Phase II study. All five 
of these factors have been incorporated into the present proposal. 
 
B. Preliminary Studies: Clinical and Research Experience with VM at UCLA and Mayo Clinic 
Investigators at UCLA and Mayo Clinic have had extensive experience in research and clinical management of 
patients with VM.5,6,19,21,22,24,27,28,31,34,35 We have published two of the largest cross-sectional diagnostic studies 
of migraine and vestibular symptoms reported to date.5,19 The group at UCLA recently reviewed the clinical 
features of 208 patients who presented to the neurotology clinic over a two-year period with idiopathic 
recurrent spontaneous attacks of vestibular symptoms without associated auditory symptoms.19 Of these 208 
patients, 180 (87%) met ICHD-II criteria for migraine (112 with aura and 68 without aura). Among the patients 
with recurrent vertigo and ICHD-II migraine, 70% experienced headache, aura, photophobia, or phonophobia 
with some or all of their vestibular attacks, meeting the ICHD-3 criteria for VM.14 The age of onset of migraine 
headaches preceded the onset of vestibular attacks by an average of 14 years, and aura preceded vestibular 
attacks by 8 years. The most frequent duration of vestibular attacks was between 1 hour and 1 day.  
 
The Mayo Clinic group reviewed medical records of all patients that they evaluated for vestibular symptoms 
between April 2008 and July 2009,5 identifying 228 patients with headache disorders, including 88 with VM. As 
in the UCLA study, the most common duration of vestibular attacks was between 1 hour and 1 day. More than 
half of the patients with VM has at least one comorbid condition such as Meniere’s disease, BPPV, CSD, 
anxiety, or depression.5,6 Comorbidity affected subjects’ clinical presentations, but the characteristic features of 
VM could still be identified by careful diagnostic assessments.6 The Mayo Clinic group is halfway through a 
double-blind, parallel group comparison trial of verapamil vs. sertraline for patients with co-existing VM/CSD. 
This pharmacologic dissection (not efficacy, hence no placebo) study was designed to identify which episodic 
and chronic vestibular symptoms are more likely to respond to a medication effective for migraine (verapamil) 
versus one useful for CSD (sertraline). The interim analysis identified several factors that strongly reinforced 
our decision to proceed with an abortive, not prophylactic, trial in this Phase II proposal. Fully two-thirds of 
potentially eligible subjects were excluded from the VM/CSD study because they had active medical conditions 
or were taking medications that would confound migraine prophylaxis. That problem would apply to any other 
prophylactic medication trial for VM. Until more data on the nature and prevalence of these confounds emerge 
from the VM/CSD trial and other studies, a Phase II trial of any prophylactic medication for VM will be 
impossible to design properly and doomed to failure if attempted. These confounds are much less likely to 
affect an abortive trial as they would cause far fewer problems with comorbidity and drug-drug interactions. 
The VM/CSD interim analysis also demonstrated that we have sufficient patient volumes to support the present 
proposal (>100 patients with VM annually) and great success enrolling subjects (75% of eligible individuals).   
 
C. Considerations for Improved Subject Selection for the Current Proposal 
In our clinical and research experience vestibular attacks can be reliably identified and should be the easiest of 
all VM symptoms to target for treatment.  The most frequent duration of vestibular attacks with VM is hours to a 
few days. Focusing on patients with this duration of attacks is logical to maximize recruitment and ensure that 
enrolled subjects have attacks of sufficient duration to assess response to treatment. Therefore, our cohort of 
interest will be patients with a lifetime histories of five or more vestibular attacks lasting 2-72 hours with full 
interictal recovery and diagnoses of migraine. With regard to comorbidities, the requirement for at least five 
spontaneous episodes without hearing loss over more than a year will effectively exclude early cases of 
Meniere’s syndrome. Patients with previously established Meniere’s disease will be excluded from this study 
because their acute vertiginous symptoms overlap considerably with those of VM. Vertigo attacks caused by 
BPPV are of short duration (<2 minutes), making them easy to distinguish from the hours-long attacks of VM in 
our cohort of interest. CSD causes chronic non-vertiginous symptoms, not episodic symptoms. Therefore, 
patients with coexisting BPPV or CSD will not be excluded if they have vestibular attacks and meet all other 
inclusion and exclusion criteria. Coexisting anxiety or depressive disorders will be managed during the 
observation period and will not be exclusionary, if they can be stabilized within three months.  These 
considerations balance the needs for successful subject recruitment, subject safety, and focus on the target 
symptoms of interest (i.e., recurrent, spontaneous vestibular attacks in patients with VM), while retaining 
generalizability to real world clinical settings and gathering critical information about potentially confounding 
variables for future Phase III trials, all informed by our preliminary data and previous clinical experience. 


 
D. Summary of Innovation 
Two important improvements over previous work have been incorporated into this proposal.  The first 
innovation is a practical one in terms of study design. We carefully considered shortcomings in the previously 
published zolmitriptan trial8 and incorporated design elements into this proposal to overcome them, including 
enhanced subject selection criteria, a prospective observation period, and specific strategies for addressing the 
common problem of comorbidity in VM (essentially ignored in previous studies). If we are successful, then 
these elements will inform the design of future therapeutic investigations for patients with VM, including not 
only Phase III studies of rizatriptan, but also clinical trials of other abortive and prophylactic therapies. 
 
The second innovation concerns the fundamental definition of VM.  We will use the recently published ICHD-3 
diagnostic criteria14 as they represent the current consensus of international experts in the field, although they 
have not yet been formally validated.  We will focus our intervention specifically on recurrent spontaneous 
vestibular attacks lasting at least 1 hour in the absence of auditory deficits.  We will require that enrolled 
subjects have at least 2 qualifying vestibular attacks during the observational phase so that we can teach them 
when and how to treat attacks in a systematic and consistent manner before they enter the treatment phase. If 
we are successful, our results will support the concept of VM as defined by the new criteria. 
 
III. APPROACH 
We propose a two-center, randomized, double blind, placebo-controlled, parallel, three-episode, clinical trial of 
rizatriptan 10 mg oral tablets versus placebo for treating spontaneous vestibular attacks in patients with VM.  
Our primary Specific Aim is to test hypotheses 1a-1d that rizatriptan will be:  
1a. Superior to placebo in reducing the severity and duration of vestibular attacks as measured by: 
(1) Proportion of treated attacks in which subjects experience a reduction in severity rating from Grade 3/2 
to Grade 1/0 at one hour after taking study medication (see below for rating description). This is the 
main outcome measure; 1a(2)-1d(2) are secondary outcome measures. 
(2) Proportion of treated attacks in which subjects achieve sustained relief (i.e., vestibular symptom 
severity rating of Grade 1/0) for 24 hours after taking study medication, without use of non-study 
therapies. 
(3) Proportion of treated attacks in which subjects experience freedom from vestibular symptoms (i.e., 
severity rating of Grade 0) at one hour after taking study medication. 
(4) Use of fewer non-study therapies after each attack treated with study medication. 
 
1b. Superior to placebo in reducing severity of symptoms associated with vestibular attacks as measured by: 
(1) 
Proportion of treated attacks in which subjects experience relief (reduction to Grade 1/0) from 
VM-associated symptoms (e.g., nausea, vomiting, motion sensitivity, gait disturbance, headache, 
photophobia, and phonophobia) at one hour after taking study medication. 
(2) 
Proportion of treated attacks in which subjects achieve sustained relief from VM-associated 
symptoms for 24 hours after taking study medication without use of non-study therapies. 
 
1c. Superior to placebo on treatment satisfaction and health-related quality of life as measured by: 
(1) 
Scores on the Treatment Satisfaction Questionnaire for Medication (TSQM)57 at 48 hours after each 
attack treated with study medication  
(2) 
Scores on the Short Form 12 (SF-12)58 at 48 hours after each attack treated with study medication  
 
1d. Tolerated as well as placebo by patients with VM as measured by: 
(1) 
No greater rate of treatment-emergent serious adverse events reported on the NCI Common Toxicity 
Criteria Scale 4.059 obtained 48 hours after each attack treated with study medication. 
(2) 
No greater rate of treatment discontinuation for adverse events of any type or severity. 
 
Our secondary Specific Aim is to gather data that will be needed to establish rigorous inclusion and exclusion 
criteria, determine sample sizes, and prepare Manuals of Operating Procedures for future Phase III treatment 
trials of rizatriptan and other abortive and prophylactic medications for VM.  We intend to gather the following 
specific information during the Observation Phase of this study, which will last up to 12 months: 
 
2a. The natural range of frequency and severity of vestibular attacks in treatment-seeking patients with VM. 


Our goal is to identify the mean, median, and range of naturally occurring vestibular attacks in patients with 
VM, allowing future investigators to accurately estimate the sample sizes and study durations needed for 
abortive and prophylactic medication trials. 
 
2b. The type and severity of medical and psychiatric conditions that commonly coexist with VM. 
Our goal is to identify the prevalence and severity of common comorbidities of VM, allowing future investigators 
to make informed decisions about the inherent compromise between excluding subjects with potential 
confounds versus including subjects with manageable comorbidities to maintain real world generalizability. 
 
2c. 
The types, doses, and frequency of use of prescription and non-prescription medications for VM.  
Our goal is to create a compendium of usual clinical care and self-treatment of VM, giving future investigators 
naturalistic data to (1) guide selection of allowable co-treatments in future studies of prophylactic and abortive 
medications for VM and (2) determine which usual care treatments may be worthy of future controlled trials. 
 
We also intend to collect the data described in 2a-c through the treatment phase of the study.  Our goal is to 
conduct exploratory analyses of the influence of these variables on the efficacy of rizatriptan for VM, further 
enhancing the design of future Phase III trials and providing possible insights into the pathophysiology of VM 
 
A. Resources and Research Facilities 
UCLA and Mayo Clinic are well-established tertiary neurotology centers with strong referral bases regionally 
and nationally. Both centers see large volumes of patients with VM annually and maintain large databases of 
patients previously diagnosed with VM. Members of the study teams at both sites have been involved in 
neurotology research and clinical practice for many years and have recently published investigations of VM as 
detailed in Preliminary Results. Facilities needed to carry out study procedures already exist at both sites. The 
Research Pharmacy at Mayo Clinic will support both sites. 
 
B. Subject Selection and Recruitment 
New patients referred to UCLA or Mayo Clinic for recurrent vestibular symptoms during the time of the study 
will undergo diagnostic evaluations per usual clinical practice at each site.  Patients who meet the selection 
criteria below will be invited to participate in the study. Existing databases will be screened for potentially 
eligible subjects. Individuals who appear to meet selection criteria will be sent a postal invitation to contact the 
study centers. Those who are interested will be scheduled for clinical re-evaluation and to review the study 
procedures and verify eligibility. New patients and individuals identified through existing databases who agree 
to participate will be enrolled after giving written informed consent. Others will be offered usual clinical care. 
 
C. Study Plan 
The study will be conducted in accordance with the principles of Good Clinical Practice and will be approved by 
required institutional review boards and regulatory agencies. All subjects will give written informed consent 
before undergoing any study procedures.  We have received a letter from the FDA indicating that our proposal 
meets the requirements for exemption from IND registration (appendix). 
 
1. Inclusion Criteria 
a) Age ≥18 years and ≤65 years (the FDA-approved age range for rizatriptan therapy in adults). 
b) History that fulfills all criteria for VM as defined in Table 1, except that attacks must last at least 2 hours. 
(Shorter attacks will not last long enough to judge treatment response.) 
c) Episodes must have a spontaneous onset and resolution without associated hearing loss or interictal 
neurotologic deficits. (Patients with uncomplicated presbycusis or fully compensated peripheral vestibular 
deficits from illnesses unrelated to current vestibular attacks may participate if they meet all other 
criteria.) 
d) Other causes of vestibular symptoms ruled out by appropriate clinical investigations. 
e) Current medication list compatible with Concomitant Medications below. 
f) Able to maintain a Vestibular Symptom Diary and complete all other study procedures. 
 
2. Exclusion Criteria 
a) Ménière’s disease by AAO-HNS criteria60  
b) Migraine with brainstem aura (formerly basilar-type migraine) by ICHD-3 criteria.14  


c) Ischemic heart disease, coronary artery vasospasm, uncontrolled hypertension. (Potential subjects with 
uncomplicated mild hypertension may be enrolled if they are willing to bring their blood pressure under 
control within the first three months of study participation and maintain treatment throughout.) 
d) History of stroke or transient ischemic attack. 
e) History of using rizatriptan specifically to treat vestibular attacks. 
f) History of adverse response to triptans. 
g) Women who are pregnant or breastfeeding. (Women of childbearing age must be willing to use medically 
acceptable methods of birth control throughout the study.) 
h) Unable or unwilling to comply with study requirements for any reason. 
 
D. Study Visits and Phases 
1. Visit 1. Prior to study entry, potential subjects will be evaluated clinically, including neurotologic history, 
examination, and laboratory testing per usual practice at each site. These steps will be part of routine clinical 
care, not study procedures. Study personnel will identify potential subjects (i.e., those diagnosed with VM) by 
contacting treating clinicians and providing information pamphlets to patients at each site. Interested patients 
will be invited to Visit 1 where the study will be reviewed with them in detail. Those who elect to participate will 
provide written informed consent. Investigators will then abstract baseline data from their medical records 
including demographics, medical history, list of allergies and current medications, family history, and results of 
neurotologic examinations and testing. Subjects will be asked to provide detailed descriptions of all symptoms 
experienced during vestibular attacks, which will be recorded verbatim. If this information fulfills all inclusion 
and exclusion criteria, subjects will be instructed in procedures for the Observation Phase, including use of the 
Vestibular Symptom Diary. Subjects also will complete the symptom self-report measures listed in Table 2. 
 
2. Observation Phase. Subjects will be followed for up to 12 months to prospectively characterize the 
frequency and severity of their vestibular attacks, associated symptoms, and comorbid conditions.  Subjects 
will record data about all vestibular attacks that they experience during this period in their Vestibular Symptom 
Diaries (see description below). Subjects will be permitted to treat their symptoms according to usual clinical 
care. They will record all interventions in their Vestibular Symptom Diaries. Study personnel will review this 
information with subjects by telephone on a monthly basis and will inquire about interval changes in subjects’ 
health and medications. This process will build rapport with subjects, ensure that they continue to meet 
inclusion/exclusion criteria, and identify comorbid conditions that could affect their safety or subsequent study 
treatment. Study personnel also will use these data to train subjects to reliably recognize attacks that will be 
appropriate for treatment with study medication when they enter the Treatment Phase of the investigation. 
Treatable comorbidities (e.g., mild hypertension, anxiety disorders) will be managed in coordination with 
subjects’ primary care clinicians or relevant specialists. Patients whose comorbidities cannot be managed and 
patients who do not have two qualifying episodes after 12 months of observation will be disenrolled. 
 
3. Visit 2. As soon as possible after subjects have their second qualifying attack, they will return to the study 
sites for re-evaluation. They will complete procedures in Table 2. Investigators will instruct subjects in the 
dosing of study medication, completion of treatment response and adverse event rating scales, and 
procedures for serious adverse events. Subjects will receive written information on adverse effects of 
rizatriptan.  Women of child bearing years will have a pregnancy test to confirm they are not pregnant. 
 
4. Treatment Phase. Subjects who qualify for randomization will enter the Treatment Phase. They will be 
randomly assigned to parallel study arms in a 2:1 ratio of rizatriptan 10 mg encapsulated tablets or look-alike 
placebo capsules. Subjects will treat three vestibular attacks that manifest with Grade 3/2 vestibular symptoms. 
Associated symptoms, including headache, need not be present and may be of lesser severity. Headaches 
without vestibular symptoms are not eligible for study treatment, but may be treated in the subjects’ usual 
manner. Subjects will be instructed to ingest one study capsule as soon as possible after onset of Grade 3/2 
vestibular symptoms. They will record treatment response in their Vestibular Symptom Diaries by rating the 
severity of vestibular and associated symptoms at the time they take study medication and at 0.5, 1, 2, 4, 24, 
and 48 hours post-dose. Subjects will record adverse effects in accordance with the Common Toxicity Criteria 
Scale 4.0, treatment satisfaction on the TSQM, and quality of life on the SF-12 at 48 hours post-dose. Then 
they will contact study personnel by phone to review the attack and treatment response. 
 


Subjects will treat one attack with study medication in a 48-hour period.  Repeat dosing of study medication 
within 48 hours will not be permitted. Subjects must have a vertigo-free period of at least 48 hours before 
treating a subsequent vestibular attack with study medication. The relatively short plasma half-life of rizatriptan 
(2-2.5 hours) justifies the 48-hour wash out period.  Subjects may use other medications to treat residual 
symptoms (see Concomitant Medications) but must wait at least 1 hour after taking the study medication. 
Additional treatments will be reported to study personnel together with other attack data. Subjects will remain in 
the Treatment Phase until they have treated three separate vestibular attacks, experience serious or 
intolerable adverse effects, withdraw for other reasons, or reach the end of the study. Study personnel will 
conduct telephone assessments on a monthly basis as they did during the Observation Phase. Extra visits to 
study clinics will be arranged as needed to re-evaluate subjects’ health and treat problematic symptoms. 
 
5. Visit 3.  Subjects will return to their study center as soon as possible after treating their third attack with 
study medication, preferably within two weeks of their last treated attack. They will complete rating scales listed 
in Table 2 and review their Vestibular Symptom Diaries with study personnel. Arrangements will be made for 
follow-up clinical care, and subjects will be discharged from the study. 
 
Table 2. Study Procedures and Rating Scales 
Procedures 
Visit 1 
Enrollment 
Observation 
Phase 
Visit 2 
Randomization 
Treatment 
Phase 
Visit 3 
End Point 
Obtain informed consent 
X 
 
 
 
 
Abstract medical record data 
X 
 
 
 
 
Verify enrollment criteria 
X 
 
 
 
 
Characterize baseline symptoms 
X 
 
 
 
 
Instruct re Vestibular Symptom Diary 
X 
 
X 
 
 
Assess & stabilize comorbidity 
 
1st 3 months 
 
 
 
Review Vestibular Symptom Diary 
 
Monthly 
X 
Monthly 
X 
Update health & medication list 
 
Monthly 
X 
Monthly 
X 
Randomize for treatment 
 
 
X 
 
 
Instruct re study treatment 
 
 
X 
 
 
Dispense drug/placebo 
 
 
X 
 
 
Treat 3 attacks  
 
 
 
X 
 
Pregnancy Test  
 
 
X 
 
 
 
 
 
 
 
 
Rating Scales 
 
 
 
 
 
Dizziness Handicap Inventory61 
X 
 
X 
 
X 
Anxiety Scale (GAD-7)62 
X 
 
X 
 
X 
Depression Scale (PHQ-9)63 
X 
 
X 
 
X 
Vestibular Symptom Diary 
 
X 
 
X 
 
Common Toxicity Criteria Scale 4.059 
 
 
 
X 
 
Treatment Satisfaction (TSQM)57 
 
 
 
X 
 
Quality of Life Scale (SF-12)58  
X 
 
X 
X 
X 
NEO-PI-3 Personality Inventory78 
X 
 
 
 
 
 
E. Outcome and Safety Measures (#1-4 mirror measures used in Phase III registration trials of rizatriptan)12,13 
1. Vestibular Symptom Diary. During Observation and Treatment Phases of the study, subjects will track  the 
frequency of their headaches vestibular symptoms (unsteadiness/dizziness), and sensitivity to potential  
triggers of attacks (head/body motion, environmental stimuli, specific positions).  
2. Common Toxicity Criteria Scale 4.0 (National Cancer Institute).59 A clinician-rated, comprehensive 
measure of toxicity from study medications in all body systems.   
3. Treatment Satisfaction Questionnaire for Medication (TSQM).57 A validated self-report measure of 
treatment satisfaction in four domains: effectiveness, side effects, convenience, and global satisfaction. 
Subjects will be asked whether they think they received rizatriptan or placebo after each dosing 
4. Short Form 12 (SF-12).58 A 12-item self-report measure of health-related quality of life in six domains. 
5. Dizziness Handicap Inventory (DHI).61 A 25-item self-report of vertigo, dizziness, functional impairment, 
and emotional symptoms associated with vestibular symptoms. 


6. Generalized Anxiety Disorder Scale (GAD-7).62 A 7-item self-report rating scale for anxiety, a common 
comorbidity of VM. The GAD-7 has cut-offs for clinically significant levels of anxiety symptoms. 
7. Patient Health Questionnaire (PHQ-9).63 A 9 item self-report rating scale for depression, another common 
comorbidity of VM. The PHQ-9 has cut-offs for clinically significant levels of depressive symptoms. 
8. NEO-PI-3 Personality Inventory  (NEO-PI-3).78 A 240-item questionnaire that assesses traits of  the Five 
Factor Model of personality (neuroticism, extraversion, openness, agreeableness, conscientiousness). 
 
F. Handling of Study Drug. The Mayo Clinic Research Pharmacy will support both study sites. The research 
pharmacists will purchase rizatriptan 10 mg tablets from a commercial supplier. Unaltered rizatriptan tablets 
will be encapsulated. Look-alike lactose-containing placebo capsules will be manufactured in the Mayo Clinic 
Pharmacy Production Laboratory following Good Manufacturing Practices. For patients who are allergic to 
lactose, carboxymethyl cellulose will be used instead of lactose. All capsules will be labeled with NDC numbers 
so that active drug and placebo can be identified. Randomization codes will be entered into the Research 
Pharmacy record. When prescriptions for study drug are received from physician investigators, drug or placebo 
will be placed into prescription bottles with required labeling. Prescriptions will be verified and cross-checked 
against the Research Pharmacy record for each subject. Then the prescription will be dispensed to subjects or 
mailed to their homes. Subjects will return used and unused bottles to verify medication accuracy and 
adherence. Should any questions arise after study drug is dispensed, the research pharmacists will be able to 
identify study drug for each subject by cross referencing the NDC numbers and randomization codes.  
Research pharmacists will maintain drug logs and all other applicable regulatory paperwork.   
 
G. Concomitant Medications. Subjects may use medications for migraine prophylaxis and comorbid medical 
conditions, although medication doses must be stabilized during the Observation Phase and remain 
unchanged for the entire Treatment Phase. Those who take triptans for migraine headaches can continue to 
use them but not within 48 hours of taking study medication for vertigo attacks during the Treatment Phase. 
Subjects may use symptomatic medications for relief of vertigo attacks during the Observation Phase and for 
relief of symptoms that remain after taking study medication during the Treatment Phase (starting 1 hour after 
taking the study medication so that the primary outcome measure is not affected). Subjects must discontinue 
monoamine oxidase inhibitors at least 3 months before randomization. Use of other antidepressants is 
permitted. Theoretical concerns about serotonin syndrome arising from concomitant use of SSRI or SNRI 
antidepressants and triptans have not been observed in investigations of concomitant medication use.64-67 
These antidepressants will not be excluded, but subjects will be advised of potential adverse interactions. 
 
H. Safety Procedures. Study personnel will be available during working hours and 24-hour emergency 
coverage will be provided at each site. Subjects who develop serious adverse events or medical conditions 
incompatible with safe use of rizatriptan will be withdrawn from the study.  See Human Subjects for additional 
details. 
 
I. Data Management. All data entry, data quality checking, data management, and statistical analyses will be 
conducted at the Data & Statistical Coordinating Center (DSCC) at UCLA under the direction of Dr. Honghu 
Liu, who has extensive experience running DSCCs for clinical trials. The PI, Co-PI, and co-investigators will 
work with Dr. Liu to program questionnaires and data input forms (paper and electronic) as needed for the 
study. All members of the study staff will be trained in data collection and entry techniques prior to the start of 
the study. Strict rules and regulations for patient security and confidentiality will be implemented by the DSCC. 
All data transferred from each of the sites will be carefully checked and maintained, and the DSCC will ensure 
that both sites follow the data security procedures. These procedures will be incorporated into data handling 
protocols, and auditing principles and periodically checking will be used to ensure compliance. 
 
We will use a reliable and secure system for data transfer.  All survey and abstraction data will be transferred 
from each data sources to the DSCC through secured mechanisms (e.g., secured website, FTP or password 
protected files).  All data sets will be stored in password protected folders on network server or password 
protected computers designated for use by the DSCC. We will monitor the data through serial evaluation of the 
databases and analytic products throughout the process. Any discrepancy and/or inconsistency in the data will 
be evaluated and corrected in a timely manner.  
 


An analytical ID generated through a scramble function will be created for each individual patient to protect 
patient confidentiality. Data analyses conducted at the DSCC will use analytical files that contain only the 
encrypted analytical IDs; no other patient identifying information will be available. Standard labels and format 
libraries will be created to facilitate analysis. A codebook that contains the information about the standard 
variable names and coding system will be created. 
 
J. Statistical Methods 
1. Power Analysis.  The primary goal of this Phase II study is to demonstrate sufficient superiority of 
rizatriptan over placebo in the main outcome measure, 1a(1), to warrant a future Phase III trial. In the previous 
triptan study for VM8 (see Prior Controlled Study of Triptans for VM), the response rate for active drug was 3/8 
(38%) versus 2/9 (22%) for placebo. If the small sample from that failed trial reflected a true response, then the 
odds ratio favoring the triptan for VM would be 2.1. To improve our estimate, we examined the results of two 
large registration trials that used a simple randomization design similar to the present proposal to test 
rizatriptan for conventional migraine.12,13 Those studies had response rates of 74% and 77% for rizatriptan 
versus 28% and 37% for placebo giving odds ratios of 7.4 and 5.7 favoring rizatriptan.  The lower response 
rates in the VM trial most likely reflected the inadequate sample size, but could suggest that triptans are less 
effective for VM than conventional migraine.  To account for this possibility, we took the limited results of 
Neuhauser, et al.8 as a worst-case scenario for our sample size calculation.  Focusing on the main outcome 
measure, 1a(1), in this double-blind, randomized trial, with PASS 68 simple randomization design69 and using a 
type I error of 0.05, type II error of 0.2 (equivalent to power of 80%), two-sided tests, then treating 120 subjects 
(with 2:1 ratio for treatment and placebo) will allow us to detect an odds ratio as small as 3.2. Thus, the plan to 
enroll 200 subjects in the Observation Phase and select 120 for the Treatment Phase will be sufficient, even if 
the response of VM to rizatriptan proves to be only half that of conventional migraine.  Phase II trials typically 
gather data on secondary outcomes (e.g., 1a(2)-1d(2)) and other variables (2a-c) to inform the design of Phase 
III trials, but sample sizes need not be planned to demonstrate significant differences in these variables.  
 
2. Randomization. A randomization scheme will be developed to assign the 120 patients expected to be 
included in the Treatment Phase to parallel treatment arms in a 2:1 ratio of active drug:placebo.    
 
3. Statistical Analysis and Modeling. We will use SAS and R70 statistical software, creating ad hoc 
algorithms and macro procedures to solve analytical questions for which no marketed algorithms exist.  
1.  As a first step to understanding the nature of our data, we will conduct univariate analysis of demographics, 
primary and secondary outcome measures, illness-related variables (e.g., frequency, severity, and duration of 
vertigo attacks), associated symptoms, comorbid conditions, and self-report rating scales. The marginal 
distribution of each measure will be calculated at each time point and across time.  The time trends of outcome 
measures will be evaluated by graphical analyses. For example, parallel plots for each of the outcome 
measures will be created to examine the patterns of change over time. 
 
2.  We will test the four hypotheses of Specific Aim #1 using bivariate methods and multivariate modeling. First, 
we will analyze differences between rizatriptan and placebo on all outcome measures at each time point using 
chi-squares to cross-tabulate categorical variables, and t-tests, analyses of variance (ANOVAs), or marginal 
regressions to compare continuous variables.  
 
3.  After testing bivariate differences, we will use repeated measures mixed effects models71,72 to compare 
outcome measures between rizatriptan and placebo over time, and examine the effects of covariates on 
treatment response.  As an example, for the special case of binary outcome vertigo severity (Grade 3/2 versus 
Grade 1/0) and the more general case of ordinal outcome vertigo severity (Grade 3, 2, 1, 0), we will use SAS 
PROC GLIMMIX73 to model the logits of cumulative probabilities including vectors for study drug, illness related 
variables, associated symptoms, rating scales, random effects, and time. The estimates on the linear scale will 
represent log cumulative odds. The cumulative logits are formed as log {Pr(ϒi≤ j) / Pr(ϒi > j)} = Χiα + ΖiγI + εI  for 
i=1, …, n, where ϒi is the ni x 1 vector of the outcome measure for the ith patient, j=0,1,2,3, ni is the number of 
measurements for the ith subject in the period, Χi is ni x p known predictors (indicator signifying rizatriptan and 
placebo, and time variable.) The fixed effects parameter vector of α is p x 1. Ζi is ni x k known predictors, which 
are associated with the random part of the model, including time-varying and time factors. γI is the k x 1 
random effect parameter vector and γI  ~ Ν(0,D), εI is ni x 1  and εI ~ Ν(0,σ2Ι), which is independent of γI . Let 


Σi(θ) = Ζi DΖiT + σ2Ι  with θ being the parameter of covariance vector. Integrating out γI in the above random 
effect model, we can write ϒi ~ Ν(Χiα , Σi(θ) ).  
  
4.  We will use this 3-step analysis procedure to test all outcome measures for hypotheses 1a-1d. However, 
the principal result of the study will be determined by the findings of bivariate analyses and multivariate 
modeling of the main outcome measure, 1.a.(1), plus favorable findings on tolerability measures, 1d(1)-1d(2). 
We will include all subjects who treat at least one vertigo attack with study drug (i.e., intent-to-treat analysis). A 
statistically significant result favoring rizatriptan over placebo on 1a(1) and absence of statistically significant 
differences on 1d(1)-1d(2) will support development of a Phase III clinical trial of rizatriptan for treating 
vestibular attacks in patients with VM. The design of future trials will also be informed by results of tests of 
secondary measures 1a(2)-1c(2).  We did not hypothesize equal tolerability for rizatriptan and placebo, but 
rather an absence of significantly higher rates of serious adverse effects and drug-related treatment 
discontinuation, so our statistical analyses of measures 1d(1)-1d(2) will not include equivalence tests. 
 
5.  Analyses of Specific Aim #2 (a-c) will be descriptive and exploratory. As a Phase II trial, this proposed study 
is not powered for a thorough examination of covariates and confounds.  We will start by reviewing univariate 
analyses of data collected during the Observation Phase of the study to identify results that will be critical for 
designing future Phase III trials.  First, we will examine the distribution of VM attack frequency and severity (2a) 
to determine if these variables have normal, skewed, bimodal, or other distributions.  This will allow future 
investigators to estimate recruitment patterns for Phase III studies.  Second, we will establish a rank order of 
comorbid conditions (2b) by prevalence and likelihood of affecting the clinical course or treatment of VM. This 
will allow future Phase III investigators to understand trade-offs between strictness of subject selection criteria 
and generalizability of results. Third, we will establish a rank order of usual care and self-medication therapies 
for VM (2c).  This will allow future investigators to establish criteria for allowable co-treatments in Phase III 
trials.  Finally, we will repeat the multivariate modeling of step 3 above, including variables representing data 
2a-c collected during the Treatment Phase of the study. Variables found to have significant or trend level 
effects on rizatriptan versus placebo treatment will mark design considerations for Phase III trials and 
potentially generate hypotheses for epidemiologic, mechanistic, or other lines of investigation of VM. 
 
6.  Missing Data: We do not anticipate a major problem with missing data from subjects who complete this 
study. Furthermore, repeated measures mixed effects models allow unbalanced data (e.g., missing follow-up 
data).  Nevertheless, we will use the following approach to missing data.  We will calculate the frequency and 
pattern of missingness of each measure as missing completely at random (MCAR), missing at random (MAR) 
or missing not at random (MNAR).74,75 Based on the nature of missingness, we will determine which imputation 
approach would be appropriate. For complex situations, we will use EM algorithm, fully Bayesian, maximum 
likelihood procedures, and parametric multiple imputation (MI) methods, which are appropriate under general 
MAR conditions. ML and MI tend to yield similar results when implemented in comparable ways. Nonrandom 
dropout may be a problem because subjects having the most severe attacks may object to taking placebo pills 
or seek alternative treatment. Subject demographics and illness characteristics can be used to test the MAR 
assumption. To reduce the possible impact of non-random dropout or MNAR missingness, subject 
characteristics variables will be used in the missing data model with MI/ML, which can reduce estimation bias 
due to MNAR missingness, and partially restore lost power due to missingness.76,77 We will examine the 
distribution of the outcome of interest (treated attacks in which subjects experience a reduction in severity 
rating) and the auxiliary variable, and apply joint modeling and MI methods to utilize the auxiliary information 
(e.g., subject characteristics). We will apply MNAR methods (e.g., selection models, pattern mixture models, 
and shared parameter models) to perform sensitivity analysis to evaluate model robustness.75 
 
7. Interim analysis: We will conduct an interim analysis at study midpoint without breaking the blind to assess 
(1) recruitment, (2) safety, and (3) efficacy. Plans for shortfalls in recruitment are noted below. We will 
terminate the study for insufficient safety if there is a statistically significant difference between arms in adverse 
events of greater than minor severity, or for lack of efficacy if response rates are <25% in both arms, i.e., no 
better than placebo rates in previous triptan trials. We will continue the study if the primary outcome, 1(a)1, is 
>25% in at least one arm, but not statistically different between arms. If the primary outcome is statistically 
different, then we will terminate the study because the primary aim will be met.  We will break the blind and 
identify the results as positive (rizatriptan superior to placebo) or negative (rizatriptan inferior to placebo).  
 


K. Timeline of Study 
 
 
 
 
 
 
 
During the first three months of the study, we expect to finalize data entry methods and train study personnel.  
Then we will begin recruitment into the Observation Phase.  Patients will remain in the Observational Phase 
until they have two qualifying attacks or for a maximum of 12 months. These phases will continue for a total of 
four years.  Subjects who are active in the Treatment Phase at month 57 will be scheduled for a Final Visit 
(Visit 3) regardless of how many attacks they have treated.  We will conduct reviews every 3 months to 
evaluate enrollment and the flow of subjects through all parts of the study to determine whether recruitment 
efforts have to be extended and to examine safety data with the DSMB. Analysis of data from the Observation 
Phase will begin as soon as that portion of the study is closed. Interim analysis will occur at month 33. Analysis 
of treatment outcome data will commence after the last subject has a Final Visit. 
 
L. Feasibility and Limitations  
The primary hindrance to successful completion of this study will be patient recruitment and retention.  
Rizatriptan has a proven track record of safety in thousands of patients over more than a decade of clinical 
use, so we do not expect significant problems with medication intolerance.  The study of zolmitriptan by 
Neuhauser, et al.,8 demonstrated the pitfalls of a triptan trial for patients with VM. Just 26% of enrolled subjects 
were randomized to treatment because they did not continue to have active verstibular attacks. We believe that 
we will substantially increase that randomization rate by enrolling only subjects with more active illness, as 
described in “Considerations for Improved Subject Selection for the Current Proposal.” The previous 
investigators excluded 12% of subjects for coexisting medical problems. We expect to stabilize coexisting 
medical problems such as uncontrolled hypertension or anxiety disorders during our 12 month Observation 
Phase, allowing us to retain a higher percentage of enrolled subjects.  Neuhauser, et al.,8 also excluded 14% 
of subjects from randomization because they lived too far from the study center. Geographic barriers are much 
less of a problem for medical care in 2013 than they were in 2003. Both of our centers have expanded the 
reach of patient care through electronic communications and other secure technologies, eliminating the need 
for a geographic exclusion. These factors and the improvements in study design based on the five-point 
examination of shortcomings in the zolmitriptan trial (see “Prior Controlled Study of Triptans for Migraine-
Associated Vertigo”) should allow us to successfully randomize 50% of enrolled subjects into the Treatment 
Phase of this study. Keeping in mind that the sample size calculation reflected the worst-case scenario (100 
subjects for the Treatment Phase), then we will have to recruit a maximum of 200 subjects into the Observation 
Phase. Our recently published studies5,19 indicate that we see approximately 200 new patients with VM at our 
two centers annually. A record review suggests that half of those would likely meet study inclusion criteria.  
Therefore, we expect to examine 400 potential subjects during the 4 years of active enrollment. Study success 
would require us to recruit 50% of those patients. The Mayo Clinic team has enrolled 79.3% of eligible patients 
into a currently active trial of sertraline versus verapamil for patients with VM/CSD, which demonstrates our 
ability to achieve needed enrollment.  Subjects entering the current Mayo study have almost no experience 
with triptans.  Most have been prescribed vestibular suppressants (e.g., meclizine) for acute attacks, meaning 
that we will lose almost no subjects due to prior rizatriptan treatment. (N.B. – The current Mayo study will not 
compete with this proposal. Its inclusion criteria target chronic, not acute, symptoms).  
 
Start 
Up 
Enrollment and Observation Phase (48 months) 
Data 
Analysis 
0 
3 
15 
27 
39 
9 
57 
60 
51 
Study timeline (months) 
Randomization and Treatment Phase (48 months) 
Quarterly Reviews 
Interim Analysis 


M. Plans to Address Limitations 
The patient flow just reviewed suggests that we will be able to meet study recruitment and retention targets. 
However, we intend to examine rates of enrollment into the Observation Phase and randomization into the 
Treatment Phase every quarter. If we fall short of targets for enrollment or randomization at any point, we will 
take three steps, as needed. (1) Contact patients with VM who were previously examined at our institutions. 
Both centers maintain databases of patients who participated in previous diagnostic studies (N>400), many of 
whom expressed interest in treatment trials. (2) The Mayo Clinic site will expand recruitment to the Mayo Clinic 
Health System of hospitals and clinics across a three-state area of the upper Midwest, and UCLA will expand 
recruitment to affiliated hospitals and clinics across Southern California. (3) Both sites will advertise selectively 
to regional and local professional organizations, patient advocacy groups, and the general public. 
 
A negative treatment result (i.e., finding that rizatriptan is not superior to placebo) will not be a study failure. 
Rather, it will be evidence that rizatriptan lacks the efficacy needed to pursue a Phase III trial in patients with 
VM. A negative result will prompt a search for other abortive and prophylactic therapies for VM and might 
nudge researchers to re-evaluate the concept of VM as a migrainous phenomenon. Data collected for Specific 
Aim #2 should be helpful in considering alternative medications and different potential pathophysiologic 
processes for VM regardless of the efficacy of rizatriptan. 
 
 
IV. HUMAN SUBJECTS  
 
The proposed study will take place at UCLA and Mayo Clinic. In accordance with NIH policy, both sites have 
implemented mandatory educational programs for all study personnel on the protection of subjects in human 
research. Procedures are in place at both institutions to track the compliance of investigators with these 
programs. All key personnel will maintain current training certificates throughout the duration of this study. 
Certificates of training completion will be kept on file at both sites.   
The study protocol will be submitted to the Institutional Review Boards (IRB) at each site for full review. This 
study is a randomized clinical trial that meets the federal definition of moderate risk. Subject enrollment will 
not begin until IRB approval is obtained.  Written consent will be obtained from all subjects using IRB 
approved consent forms.  All patient recruitment materials and announcements will be approved by the IRBs.   
A. Involvement of human subjects  
1. Number of subjects - We plan to recruit 240 subjects during the 5-year grant period, equally divided 
between the two study sites.  
2. Inclusion/exclusion criteria.  
Patients who meet all inclusion and exclusion criteria listed in the “Study Plan” and agree to take part in the 
study will be enrolled after providing written informed consent.  Adults >65 years of age will be excluded from 
the study because FDA registration trials for rizatriptan did not include adults in this age group.  Children <18 
years of age will be excluded because the safety and efficacy of rizatriptan for VM has not been established 
and VM is a condition affecting adults more than children. Subjects must be mentally and physically capable 
of participating in all aspects of the study. Based on our prior experience and the known demographics of 
vestibular migraine (VM), we expect to enroll more women than men. The majority of subjects will be non-
Hispanic white, but we will actively recruit patients from diverse racial/ethnic backgrounds.   
Determination of eligibility.  The PIs and Co-investigators will make final determinations of potential subject 
eligibility after reviewing clinical history, physical examination and test results, and final clinical diagnoses.  
Special inclusion or exclusion criteria. None.  
3. Vulnerable subjects.  
We will exclude children (<18 years of age) from this study.  We also will exclude older adults (>65 years of 
age) from this study (See IV.A.2).  No members of other vulnerable groups will be targeted for recruitment.  
B. Procedures  


Study procedures are summarized Table 2 of the study protocol. The study involves three visits to the study 
sites, an Observation Phase and a Treatment Phase.  At the Enrollment Visit, investigators will verify eligibility, 
obtain written informed consent, and gather initial data.  Subjects will complete the self-report measures listed 
in Table 2. This visit is expected to last 2-3 hours.  After the Enrollment Visit, subjects will enter up to a 12 
month Observation Phase during which they will record descriptive data and ratings for each vertigo attack that 
they suffer, along with associated symptoms and treatments.  The research coordinator will contact subjects on 
a monthly basis to review these data. Phone interviews are expected to last less than 30 minutes.  During the 
Observation Phase, investigators will prospectively evaluate patients for comorbid medical and psychiatric 
conditions.  Investigators will treat these conditions themselves or enlist the care of relevant medical specialists 
as indicated.  Subjects may return to the study centers for ad hoc visits, if needed for additional evaluations. 
Subjects will continue in the observation period until they have two vestibular attacks that meet the inclusion 
criteria or until the 12 months are up.    
Once they have experienced two qualifying vestibular attacks or at the end of the Observation Phase, subjects 
will return to their study center for a second visit.  Investigators will collect interval history and subjects will 
complete the self-report measures listed in Table 2.  This visit is expected to last 2 hours. Subjects who 
experience at least two vestibular attacks of moderate or greater severity during the Observation Phase and 
demonstrate acceptable adherence with data gathering and reporting procedures will be randomized to treat 
three subsequent vestibular attacks with either rizatriptan or placebo (ratio 2:1) in randomized and double-blind 
fashion. Subjects will rate treatment response and adverse effects. They will contact study personnel to review 
these data at 48 hours after each vestibular attack treated with study medications. The research coordinator 
will contact subjects on a monthly basis by phone to review progress, assess adherence, and gather data on 
any interval change that might affect treatment response or safety. The Treatment Phase may last as short as 
6 days for subjects who have three vertigo attacks in quick succession after randomization to as long as 4 
years for subjects who enroll at the start of the study and do not have 3 treatable attacks before the end of the 
study. Subjects will return to the study site for an End Point Visit (visit 3) as soon as possible after treating 
three attacks or sooner if they will be withdrawn from the study for any reason. The End Point Visit is expected 
to last 2 hours.  
C. Recruitment and consent  
Patients diagnosed with VM after completing clinical evaluations for episodic vertigo at UCLA or Mayo Clinic 
will be invited to participate in the study.  Investigators will recruit patients that they see personally in their 
practices and patients seen by clinical colleagues at the study sites.  Investigators will explain the study to 
potential subjects, answer questions, and provide subjects ample opportunity to read an IRB-approved written 
consent form describing the study. Subject who consent will be enrolled and begin study procedures.  No study 
procedures will be performed before written informed consent is obtained.  Potential subjects who decline to 
participate will be offered routine clinical care.  
D. Potential Risks  
1. Adverse Effects of Medication: The primary risk to subjects will be the potential for adverse effects of 
study medication. There is a wealth of data documenting the safety and efficacy of rizatriptan in treating 
patients with migraine.  In this randomized trial, we will use a dose of rizatriptan that is generally well tolerated 
by patients with migraine (10 mg). Common adverse events include: drowsiness (4-10%), dizziness (4-10%), 
nausea (4-8%), fatigue (1-7%), tingling or numb feeling (4%), dry mouth (3%), muscle pain or cramps (2%), 
and tightness in the neck or jaw (2%), tremors, chills, and flushing (feeling of warmth). Serious adverse events 
include chest pain (3%), hypertension, coronary artery spasm, myocardial infarction, peripheral ischemia, 
ventricular arrhythmia, ischemic colitis, anaphylaxis, angioedema, analgesic overuse headache, 
cerebrovascular accident, and serotonin syndrome.   
2. Loss of Confidentiality: There is also a risk of loss of confidentiality if identifying information and data from 
medical records or study forms are inadvertently released.  
3. Time Demands: This study places demands on subjects’ time for completion of the Vertigo Symptom Diary 
and self-report instruments as well as monthly telephone appointments with investigators or research 
coordinators. The Vertigo Symptom Diary will have to be completed during and after each attack.  Subjects will 


track vertigo, headache, and associated symptoms in their diaries.  They will rate each symptom using a single 
number from 0-3 at 0.5, 1, 2, 4, 12, 24, and 48 hours after the onset of each vertigo attack, which is expected 
to take 10-20 seconds at each time point or less than 3 minutes total per attack.  Over the course of the study, 
subjects also will be required to complete 20 rating scales ranging in length from 7 to 36 questions. Each of 
these will take 1-5 minutes to complete for a total of about 80 minutes over the entire study.  Telephone 
appointments are expected to be less than 30 minutes long on a monthly basis. During study Visit 1 only, 
subjects will complete a personality questionnaire that will take 30-40 minutes. 
 
4. Special circumstances involving studies assessing depression:  This investigation is not designed 
specifically to treat depression, but depression is more common in patients with vestibular disorders than in the 
general population. For that reason, all patients at Mayo Clinic in Rochester are screened for depression as 
part of clinical testing in the Vestibular Laboratory.  Those who screen positive are examined by a Mayo Clinic 
psychiatrist or psychologist familiar with mood symptoms in patients with vestibular disorders. This has been 
part of routine clinical practice for 6 years.  The presence of depression, per se, will not disqualify potential 
participants from study entry.  Only those whose depression is judged unlikely to be brought under control 
within 3 months of study entry (e.g., treatment resistant depression, depression with suicidality or psychosis) 
will be ineligible to enroll.  For others, treatment of depression will be part of the overall plan to manage 
common VM comorbidities during the Observation Phase, as described above (Section III.D.2).   
 
Depression may affect the clinical course and treatment of VM.  Therefore, depressive symptoms will be 
measured in all subjects at Visits 1, 2, and 3 using the PHQ-9 to gather data to control for this confound.  Any 
subject whose PHQ-9 scores suggest clinically significant depression (PHQ-9 >9) or suicidal thoughts (PHQ-9 
question 9 >0) will be examined by a study physician at the time of the visit to ensure that treatment for 
depression is initiated or updated and that the level of depressive symptoms is compatible with continued study 
participation.  Patients judged ineligible will be disenrolled and provided or referred for appropriate treatment. 
 
E. Risk Minimization  
1. Adverse Effects of Medication: Subjects with ischemic heart disease, uncontrolled hypertension, or 
coronary artery vasospasm will be excluded from the study because of the known cardiac complications of 
triptans. Those who are allergic or unable to tolerate triptans in the past will also be excluded from the study. 
(See “Exclusion Criteria”).  
Subjects will be closely monitored.  The research coordinator will inquire about adverse events and changes in 
health status during monthly telephone interviews.  Subjects will be instructed to contact a member of the 
research staff regarding adverse events at any time during the study.  They will be instructed to report cardiac 
symptoms or allergic reactions immediately.  Subjects who develop treatment-related serious adverse events 
or new onset exclusionary medical conditions will be withdrawn immediately from the study.  
2. Loss of Confidentiality: Confidentiality will maintained to the extent legally permissible by the appropriate 
handling of patient records and study data. Data obtained from source documents, interviews and 
questionnaires will be captured on research forms, entered online, and stored at DSCC. The information will 
be kept confidential in a secure electronic database with restricted and monitored access. A unique subject 
ID number will be used for each subject’s research case report forms and all communications, in accordance 
with the Health Insurance Portability and Accountability Act. No identifying information will be entered into the 
database.  
3. Time Demands: The Clinical Trials Subcommittee of the International Headache Society published 
guidelines for data collection during clinical trials of migraine treatments.15  The data collection instruments 
selected for this proposed study – a symptom diary and validated measures of functional impairment and 
quality of life – follow those recommendations.  The specific diary method for rating symptoms during and 
after attacks was adopted from two major registration trials for rizatriptan,12,13 
which included several hundred 
subjects each.  The self-reports of dizziness handicap, quality of life, depression and anxiety have been used 
by thousands of patients in clinical and research settings around the world for many years.  Specific scales 
were chosen to achieve the goals of the study, while keeping demands on subjects’ time to a minimum.  
F. Risk/Benefit Analysis: A potential benefit to subjects who participate in this study will be the possibility of a 


reduction in vestibular attack duration and/or severity and interference with daily activities as well as possibly 
improved quality of life. It is also possible that there would be no benefit to the study participants. A benefit to 
society may be greater understanding of treatment options for vestibular attacks in patients with VM.  
 
G. Gender/minority recruitment: Men and women of all racial and ethnic backgrounds will have an 
opportunity to participate in this study.  White women have been heavily over-represented in large pre-
registration and post-marketing trials of rizatriptan, with most studies including about 90% white patients and 
90% women.  Our published research in VM included a 2:1 female:male ratio, in keeping with the known sex 
distribution of VM.  We anticipate a similar sex ratio for subjects in this study.  We project that 20% of our 
sample will be from minority groups.   
 
V. STUDY OVERSIGHT  
The PI and Co-PI will have primary responsibility for the conduct of this clinical trial. A Data Safety Monitoring 
Board (DSMB) with oversight responsibility will be appointed by NIDCD. The DSMB will review subject accrual, 
frequencies and patterns of all adverse events, and protocol compliance on a quarterly basis and will make 
recommendations to the NIH regarding the continuation status of the protocol.  Co-Investigator Dr. Liu will 
compile clinical data to prepare the reports for DSMB reviews.    
The Principal Investigator, Co-PI and their research teams (co-investigators, research nurses, research 
coordinators, and others) will be responsible for identifying adverse events. Aggregate reports detailed by 
severity, attribution (expected or unexpected), and relationship to the study drug/study procedures will be 
made available by the DSCC for site review. A separate report detailing protocol compliance will also be 
available from the DSCC for site review monthly.  The research team will review these reports monthly and 
determine whether the protocol or informed consent document requires revision based on the reports.  
A. Definitions/Standards  
An adverse event is defined as an unfavorable and unintended sign, symptom or disease associated with a 
participant’s participation in the current study.  
Serious adverse events include those events that result in death, are life-threatening, require inpatient 
hospitalization or prolongation of existing hospitalization, create persistent or significant disability/incapacity, or 
cause a congenital anomaly or birth defects.    
An unexpected adverse event is defined as any adverse experience, the specificity or severity of which is not 
consistent with the risks or information described in the protocol. Expected adverse events are those that are 
identified in the research protocol as having been previously associated with or having the potential to arise 
as a consequence of participation in the study.  
All reported adverse events will be classified using the Common Terminology Criteria for Adverse Events 
(CTCAE), version 4, developed and maintained by CTEP at National Cancer Institute.  
B. Study Intervention and Procedures: Definition of Expected Adverse Events  
Treatment Study Drug – Rizatriptan (10mg within a 48-hour period).  Common adverse events include 
drowsiness (410%), dizziness (4-10%), nausea (4-8%), fatigue (1-7%), tingling or numb feeling (4%), dry 
mouth (3%), muscle pain or cramps (2%), tightness in the neck or jaw (2%), tremors, chills, and flushing 
(feeling of warmth).  Allergic reactions include rash or redness, swelling, or itching of the eyelids, face, or lips.  
Serious adverse events include chest pain (3%), hypertension, coronary artery spasm, myocardial infarction, 
peripheral ischemia, ventricular arrhythmia, ischemic colitis, anaphylaxis, angioedema, analgesic overuse 
headache, cerebrovascular accident, and serotonin syndrome.   
C. Reporting Timeline  
Local institutional reporting requirements to IRBs and DSMB remain the responsibility of the treating physician 


and the PI and Co-PI.  
1. Investigators must report any Serious Adverse Event (SAE) that is considered life-threatening/disabling or 
results in death of subject or is unexpected or unanticipated, within 24 hours of learning of an event.  
2. Investigators must report all other SAEs within 5 working days of learning of the event.  
3. Investigators must report all other suspected AEs within 20 working days of the notification of the event or 
of becoming aware of the event.  
4. All serious adverse events (SAEs) must be reported to the FDA.  
 
a) Fatal or life-threatening AEs, regardless of causal relationship to study medication, must be reported to 
FDA on a MedWatch Form within 7 days of the event.   
b) Serious, but not fatal or life threatening events, which are related and unexpected, must be reported to 
FDA on a MedWatch Form within 15 days of the event.  
c) Other suspected AEs will be reported to FDA every quarter after the start of the study.  
 
D. Adverse Event Data Management System (AEDAMS)  
Upon entry of a serious or unexpected adverse event, the DSCC created Adverse Event Data 
Management System (AEDAMS) will immediately notify the PI and Co-PI and any additional agencies of 
any reported adverse events per study protocol.   
Serious adverse events: Causality (definitely not related, probably not related, possibly related, probably 
related, definitely related) of the adverse event will be determined by a thorough review. A determination of the 
causal relationship of all AEs will be made based upon the package insert (Sections 6.1 and 6.2)
22
. The 
Adverse Event Data Management System (AEDAMS) maintains audit trails and stores data (and data updated) 
and communication related to any adverse event in the study.   
Non-serious expected adverse events: Except those listed above as immediately reportable, non-serious 
expected adverse events that are reported to or observed by the investigator or a member of his research 
team will be submitted to the DSCC in a timely fashion (within 20 working days). Local site investigators 
are also required to fulfill all reporting requirements of their local institutions.  
E. Study Discontinuation  
NIH and local IRBs have the authority to stop or suspend this trial at any time. This study may be suspended or 
closed if:  
• 
Accrual has been met  
• 
The study objectives have been met  
• 
The PI or Co-PI believe it is not safe for the study to continue  
• 
The DSMB recommends to the NIDCD and it suspends or closes the trial  
• 
The FDA suspends or closes the trial  
 
F. Subject Discontinuation  
An intent to treat approach will be used. All data acquired prior to termination for the reasons outlined below 
will be included in the primary analysis unless the subject withdraws consent. Every effort will be made to 
conduct a final study visit with subject upon withdrawal and subjects will be followed clinically until, if 
applicable, all adverse events resolve. The following events will result in subject discontinuation:  
• 
Withdrawal of consent  
• 
Withdrawal by the participant  
• 
Withdrawal by the investigator  Intercurrent illness or event that precludes further visits to the study site or 
ability to evaluate disease  
 
G. Clinical Trials.gov  


 
Dr. Baloh will register the trial on ClinicalTrials.gov as soon as IRB approvals are obtained.  


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BACKGROUND 
Vestibular migraine (VM) was defined by the International Headache Society and Bárány Society as a disorder 
producing recurrent episodes of vertigo or dizziness accompanied at least 50% of the time by migrainous 
features in patients with histories of migraine.  This randomized controlled trial tested the efficacy of rizatriptan 
as an abortive treatment for attacks of VM.  
METHODS 
Patients with VM (N=225) were observed prospectively to confirm the diagnosis.  Those who experienced two 
verified VM attacks within 12 months (N=114) were randomized 2:1 to treat up to three subsequent attacks with 
rizatriptan 10 mg or placebo orally.  The primary outcome was the proportion of attacks with vestibular 
symptoms (vertigo or unsteadiness/dizziness) reduced from moderate/severe to none/mild at 1 hour after 
administration of study drug.  Secondary outcomes were: (1) proportion of attacks with symptoms resolved at 1 
hour, (2) proportion of attacks with symptoms reduced from moderate/severe to none/mild at 24 hours, (3) 
treatment satisfaction at 48 hours, (4) quality of life at 48 hours, and (5) rates of adverse effects.  
RESULTS 
Of 308 treated attacks, 245(79.5%) with moderate/severe vestibular symptoms were used to test study 
outcomes.  On the primary outcome, rizatriptan did not differ from placebo in reducing vertigo [73/153(47.7%) 
vs. 53/92(57.6%) attacks, p<0.28] or unsteadiness/dizziness [29/153 (18.9%) vs. 11/92 (12%) attacks, p<0.24].  
On secondary outcomes, rizatriptan was superior to placebo in reducing unsteadiness/dizziness [120/149 
(80.5%) vs. 52/88 (59.1%) attacks, p<0.008] at 24 hours and in treatment satisfaction [regression estimate 
11.92, 95% CI (2.33, 21.62), p<0.016] and physical well-being [regression estimate 4.55, 95% CI (1.14, 7.97), 
p<0.009] at 48 hours.  Rizatriptan caused more mild/moderate fatigue and drowsiness than placebo but 
otherwise did not differ in side effect burden. 
CONCLUSIONS 
Rizatriptan was tolerated well but provided limited benefits for attacks of VM. (Funded by National Institute of 
Deafness and Other Communication Disorders, DC13256.)