Clinical trial NCT02158585
Conditions: Meniere's Disease Ménière's Vertigo Vertigo, Intermittent Vertigo, Aural
Keywords: Lamotrigine Lamictal Anticonvulsant Ménière's disease Vertigo attack Dizziness Vestibular disorder
Sponsor: Dent Neuroscience Research Center
Start date: 2014-06-01; Completion date: 2017-03-01
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This double-blinded study evaluates the frequency of vertigo attacks and the quality of life of patients diagnosed with Ménière's disease after being randomly assigned to take a placebo or lamotrigine.

Detailed description:

Arms: arm 1: The placebo will match the lamotrigine dosage, frequency and duration. arm 2: Lamotrigine will be taken orally for the duration of 20 weeks, consisting of a six-week titration, 12-week study period, and two-week taper. Possible doses are 25mg twice a day, 50mg twice a day, and 100 mg twice a day during titration; 150mg twice a day for the 12-week study period; 150mg once a day for Week 1 of the taper; and 75mg once a day for Week 2 of the taper. Patients who withdraw at any point of the study will have a two-week taper consisting of the current dose once a day for one week followed by half the dose once a day for another week.
Interventions: intervention 1: Lamotrigine intervention 2: Placebo
Intervention descriptions: intervention 1: Lamotrigine will be taken orally on a daily basis for the duration of 20 weeks, consisting of a six-week titration, 12-week study period, and two-week taper. Possible doses for patients are 25mg twice a day, 50mg twice a day, and 100 mg twice a day during titration; 150mg twice a day for the 12-week study period; 150mg once a day for Week 1 of the taper; and 75mg once a day for Week 2 of the taper. Each increase in dose will be maintained for two weeks before deciding to further increase or decrease based on tolerability. Patients who discontinue at any point of the study will have a two-week taper consisting of the current dose once a day for one week followed by half the dose once a day for another week. intervention 2: The placebo will match the lamotrigine dosage, frequency and duration.

Protocol documents:
Prot_SAP_000.pdf: 
 
University at Buffalo Institutional Review Board (UBIRB) 
Office of Research Compliance | Clinical and Translational Research Center Room 5018 
875 Ellicott St. | Buffalo, NY 14203 
UB Federalwide Assurance ID#: FWA00008824 
PROTOCOL TITLE: Lamotrigine for Ménière's disease: a double-blind, placebo-
controlled pilot study 
Page 1 of 55 
 
 
INSTRUCTIONS: Complete Research Protocol (HRP-503) 
 Depending on the nature of what you are doing, some sections may 
not be applicable to your research.  If so, you must provide the 
reason why the section is not applicable for the response.  For 
example, most behavioral studies would answer all questions in 
section 30 with words to the effect of “drugs and medical devices 
are not used in this study.” 
 When you write a protocol, keep an electronic copy. You will need 
to modify this copy when making changes. 
 Do not remove the italics instructions or headings. 
 If you are pasting information from other documents be sure to use 
the “Merge Formatting” paste option so that the formatting of the 
response boxes is not lost.  If information is presented outside of 
the response boxes, it will not be accepted.  
 If this study involves multiple participant groups who participate 
in different research procedures, consent processes, etc., be 
certain to provide information in each applicable section for each 
participant group and clearly label each participant group within 
a section or subsection.  
 
 
PROTOCOL TITLE: 
Include the full protocol title. 
Response:  
Lamotrigine for Ménière's disease: a double-blind, placebo-controlled 
pilot study 
PRINCIPAL INVESTIGATOR: 
Name 
Department 
Telephone Number 
Email Address 
Response:  
Lixin Zhang 
Dizziness & Balance 


 
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Revised: August 3, 2018 
716-250-2000 
lzhang@dentinstitute.com 
VERSION NUMBER: 
Include the version number of this protocol. 
Response:  
7 
DATE: 
Include the date of submission or revision. 
Response: 6/4/2015 
 
Grant Applicability: 
Describe whether or not this protocol is funded by a grant or contract and if so, 
what portions of the grant this study covers. 
Response:  
Not funded by a grant 
 


 
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Revised: August 3, 2018 
Table of Contents 
1.0 
Objectives ................................................................................................................ 4 
2.0 
Background .............................................................................................................. 4 
3.0 
Inclusion and Exclusion Criteria ............................................................................ 11 
4.0 
Study-Wide Number of Subjects (Multisite/Multicenter Only) ............................ 19 
5.0 
Study-Wide Recruitment Methods (Multisite/Multicenter Only).......................... 19 
6.0 
Multi-Site Research (Multisite/Multicenter Only)................................................. 20 
7.0 
Study Timelines ..................................................................................................... 20 
8.0 
Study Endpoints ..................................................................................................... 21 
9.0 
Procedures Involved............................................................................................... 22 
10.0 Data and Specimen Banking .................................................................................. 29 
11.0 Data Management .................................................................................................. 30 
12.0 Provisions to Monitor the Data and Ensure the Safety of Subjects ....................... 33 
13.0 Withdrawal of Subjects .......................................................................................... 35 
14.0 Risks to Subjects .................................................................................................... 36 
15.0 Potential Benefits to Subjects ................................................................................ 38 
16.0 Vulnerable Populations .......................................................................................... 38 
17.0 Community-Based Participatory Research ............................................................ 39 
18.0 Sharing of Results with Subjects ........................................................................... 39 
19.0 Setting .................................................................................................................... 40 
20.0 Resources Available............................................................................................... 42 
21.0 Prior Approvals ...................................................................................................... 44 
22.0 Recruitment Methods ............................................................................................. 44 
23.0 Local Number of Subjects ..................................................................................... 46 
24.0 Confidentiality ....................................................................................................... 46 
25.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 47 
26.0 Compensation for Research-Related Injury ........................................................... 48 
27.0 Economic Burden to Subjects ................................................................................ 48 
28.0 Consent Process ..................................................................................................... 49 
29.0 Process to Document Consent in Writing .............................................................. 54 
30.0 Drugs or Devices.................................................................................................... 54 
 


 
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1.0 
Objectives 
1.1 Describe the purpose, specific aims, or objectives. 
Response:  
The purpose of this study is: 
• 
Primary objective: To determine if lamotrigine, a sodium channel 
blocker, can reduce the frequency of Ménière's vertigo attacks greater than 
a placebo treatment 
• 
Secondary objective: To determine if lamotrigine can improve 
other Ménière's disease symptoms, like tinnitus and hearing loss, and 
improve patients’ quality of life greater than a placebo treatment 
1.2 State the hypotheses to be tested. 
Response:  
Lamotrigine, a sodium channel blocker, can reduce the frequency of 
Ménière's vertigo attacks greater than a placebo treatment and it can 
improve other Ménière's disease symptoms, like tinnitus and hearing loss, 
and improve patients’ quality of life greater than a placebo treatment 
2.0 
Background 
2.1 Describe the relevant prior experience and gaps in current 
knowledge. 
Response:  
Prosper Ménière first described an inner ear disorder that caused vertigo 
and hearing loss (Baloh, Halmagyi, & Zee, 2012; Gates, Green, Tucci, & 
Telian, 2004). Today the disorder, known as Ménière's disease (MD), is 
reported to affect 20 to 200 individuals per 100,000. MD continues to be 
characterized by the same symptoms described in 1861. The 1995 
American Academy of Otolaryngology- Head and Neck Surgery’s (AAO-
HNS) criteria include recurrent spontaneous and episodic vertigo with 
hearing loss, aural fullness and/or tinnitus. The vertigo episodes can last 
from 20 minutes up to several days (Committee on Hearing and 
Equilibrium, 1995; Gates et al., 2004). Additionally, many individuals 
develop related anxiety and depression symptoms, and a poorer quality of 
life (Balaban, Jacob, & Furman, 2011; de Moraes, Soares, Ferriolli, & 
Perracini, 2013; Van Cruijsen, Jaspers, Van de Wiel, Wite & Albers, 
2006). Those diagnosed with Ménière's disease are severely impacted and 
treatment of the vestibular disorder is challenging. The disease’s 
idiopathic nature is one hindrance to developing an efficacious therapy. 
It is commonly thought that endolymphatic hydrops (EH) causes 
Ménière's disease (Sajjadi & Paparella, 2008). The buildup of endolymph 
fluid within the cochlear and saccular ducts, from either failed absorption 
or excess production, cause the structures to expand into the 


 
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endolymphatic space (Syed & Aldren, 2012; Thai-Van, Bounaix & 
Fraysse, 2001). The subsequent increased inner ear pressure may cause 
damage to hair cells and the vestibular labyrinth, prompting vertigo 
attacks and an aural fullness sensation. These symptoms are characteristic 
of Ménière’s disease; however, hydrops may instead be an 
epiphenomenon rather than the primary cause (Lempert, 2012). EH has an 
earlier age of onset than Ménière's disease and not every patient with EH 
develops Ménière's symptoms (Foster & Breeze, 2013). Additionally, 
studies have shown that animals induced with hydrops did not develop 
vertiginous spells and did not present differences in hydrostatic pressures 
in the perilymph and endolymph (Berlinger, 2011; Kimura, 1982). This 
suggests that the mechanism of hydrops is not fully understood and that 
EH is likely a predisposing factor, but not a sufficient primary cause. 
It has been hypothesized that Ménière’s disease is an autoimmune 
disorder. Some viruses are well known for affecting the inner ear (Davis & 
Johnson, 1976) and the chemical damage caused by an immune reaction 
could cause labyrinthitis. This leads to fibrosis in the vestibular cistern and 
endolymphatic hydrops (Greco et al., 2012). Supporters of this theory cite 
the presence of lymphatic vascularization, various immunocompetent cells 
located close to the endolymphatic sac and biological signs of immune 
reactions in Ménière’s disease patients (Evans, Baldwin, Bainbridge & 
Morrison, 1988; Dornhoffer, Wagner, Arenberg, & Montague, 1993; 
Soliman, 1996). The theory’s major inconsistency is that autoimmune 
disorders are systemic and should thus affect both ears rather than the 
commonly seen unilateral MD presentation (Foster & Breeze, 2013). 
A more recent etiology theory involves ischemia. The stria vascularis 
within the inner ear is particularly sensitive to ischemia and when affected 
the ear loses endocochlear potential. This results in tinnitus and low 
frequency hearing loss. Furthermore, vertigo can occur when a significant 
amount of the calyces or boutons of sensory neurons in at least one of the 
cristae or maculae becomes ischemic. Repeat destruction of calyces and 
boutons and hair cell ischemia cause sensory neuron death and 
degeneration of hair cells, which manifests as progressive hearing loss and 
vestibular impairment (Foster & Breeze, 2013). Whether ischemia causes 
endolymphatic hydrops to occur or vice versa is disputed. One belief is 
that cerebrovascular problems cause the perfusion pressure to lower to just 
above the ischemic threshold of an ear with endolymphatic hydrops, 
causing the Ménière’s symptoms. An alternative argument is that 
cerebrovascular impairments cause altered hemodynamics, which then 
cause endolymphatic hydrops. Although the involvement of 
endolymphatic hydrops in Ménière’s disease is a shared feature among 
various theories, there is still much to be discovered. The unknown 
etiology has led to several treatment approaches with various success.  
A low salt diet is frequently recommended based on the belief that sodium 
increases inner ear fluid and causes the integral hydrops (Gates et al., 


 
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2004). Patients are instructed to avoid adding salt to food, make a habit of 
reading food labels, and avoid processed food. Increasing water intake has 
also been used to further reduce sodium levels. These restrictions can be 
very difficult to maintain long-term and compliance is often an issue 
(Gates, 2005). Even though limiting sugar, monosodium glutamate, 
caffeine, and alcohol has been reported to help decrease the frequency of 
MD attacks, there is no substantial evidence that dietary considerations 
can significantly affect the fluid composition in the inner ear or address 
Ménière’s symptoms (Berlinger, 2011; Gates, 2004; Quaranta, Aloisi, De 
Benedittis & Scaringi, 1999).  
Pharmacological treatments have routinely been symptomatic, focusing on 
eliminating dizziness with vestibular suppressants and relieving nausea, 
vomiting, and anxiety (Strupp et al., 2008). Benzodiazepines, like 
Diazepam, have a central vestibular sedative effect and can be useful in 
helping with anxiety, but can interfere with vestibular compensation and 
cause side effects of dependence, impaired memory, and incoordination 
with ataxia (Thai-Van, Bounaix, & Fraysse, 2001). Antiemetic agents are 
used to control the vertigo and anxiety associated with MD. Meclizine, a 
well-known antiemetic, is believed to decrease the excitability in the 
middle ear labyrinth and reduce the strength of the middle ear vestibular-
cerebellar pathways (Thai-Van, Bounaix, & Fraysse, 2001). However, 
negative side effects include drowsiness and increased toxicity of 
antipsychotics and anticholinergics (Quaranta et al., 1999). 
Drug therapies grounded in etiology theories of ischemia and hydrops 
include vasodilators and diuretics. Betahistine, a vasodilator, blocks H1 
and H3 receptors and increases vestibular and cochlear blood flow to 
facilitate vestibular compensation and control vertigo (Strupp et al., 2008). 
Although Betahistine is able to control vertigo, it has not been shown to 
address any other MD symptoms (Kaylie, Jackson & Gardner, 2005). The 
drug has not been US FDA approved and side effects include stomach 
fullness and discomfort, diarrhea, nausea, and headaches (Sampson, 2003; 
Monzani, 2012; Quaranta et al., 1999). Alternatively, diuretics are 
prescribed to reabsorb the endolymph fluid causing endolymphatic 
hydrops. Long term, non-blind trials showed up to a 79% improvement in 
vertiginous symptoms with some improvement in hearing, but this may 
reflect the natural history of the disease (Thai-Van, Bounaix, & Fraysse, 
2001). Other doubts about the benefits of diuretics arise from 
methodology flaws in many of the studies (Quaranta et al., 1999). 
Aminoglycosides reduce the sensitivity of the vestibular system by 
damaging the vestibular sensory hair cells. The injection treatment claims 
to preserve hearing because vestibular sensory hair cells are more sensitive 
to damage than cochlear hair cells. Gentamicin is the most commonly used 
aminoglycoside due to its availability, large therapeutic window before 
becoming cochleotoxic, and less pain experienced during injection 
(Silverstein, Wazen, Van Ess, Daugherty & Alameda, 2010). Studies have 


 
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had success with gentamicin, including complete resolution of vertigo 
attacks (Steenerson, Hardin, & Cronin 2008), minor improvements in 
tinnitus and aural fullness (Quaranta, Aloisi, Benedittis, & Scaringi, 1999), 
reduction in disability and anxiety (Boleas-Aguirre Sanchez-Ferrandiz, 
Guillen-Grima, & Perez, 2007), and increased perceived quality of life 
(Postema, Kingma, Wit, Albers & Wan Der Laan, 2008). However, some 
patients still suffered hearing loss (Kaylee, Jackson, & Gardner, 2005; 
Posema et al., 2008). It is unclear whether this is due to the gentamicin 
therapy, natural history of the disease or inconsistent procedures (Brinson, 
Chen & Arriaga, 2007). The treatment lacks a standard dosage, number of 
treatments, and time between treatments, or indicators for ending 
treatment. Aminoglycosides therapy also excludes bilateral MD patients, 
who would experience bilateral hypofunction and induced disequilibrium 
and oscillopsia (Coelho & Lalwani, 2008). 
Corticosteroids therapeutic usage aligns with the autoimmune etiology. 
Success rates vary across literature and, similarly to gentamicin treatment, 
there is a wide variety of recommended doses and frequency of 
administration (Hamill, 2006). Complications reported include pain, short-
lasting vertigo, otitis media, perforations in the tympanic membrane, and 
hearing loss. Corticosteroids have recently had great success with treating 
sudden sensorineural hearing loss, but there is no strong evidence to 
support its use for Ménière’s disease (Gottsball, Hoffer, Moore & 
Balough, 2005). Prospective studies have shown an improvement in 
vertigo with no significant changes with hearing and tinnitus (Coelho & 
Lalwani, 2008). Since there is no effect on hearing, it is believed that the 
pathophysiology of Ménière’s is different from sudden sensorineural 
hearing loss (Gottsball, 2005). The decision to use a specific drug for MD 
is based on what the physician believes is causing the disease, whether it is 
endolymphatic hydrops, ischemia, or autoimmune disease. However, 
evidence is lacking for many of these pharmacotherapies and negative side 
effects are a major concern. 
Surgical treatment, aimed to either relieve endolymphatic hydrops or 
deafferent the affected ear, is typically used for Ménière’s disease patients 
who haven’t had success with medications (Gates et al., 2004). Observed 
improvement of MD symptoms in higher elevations or with weather 
changes proposed the idea that the relative positive pressure in the middle 
ear was responsible for the relief (Gates et al., 2004). In an attempt to 
replicate the effect, a portable low-intensity alternating pressure generator 
was created to apply pulsed pressure into the ear via a surgically implanted 
tympanostomy tube. The machine is now marketed in the United States as 
the Meniett device (Gottshall, 2008). The Meniett device is well tolerated 
and able to reduce vertigo, at least in the short term (Thai-Van, Bounaix & 
Fraysse, 2001; Shojaku et al., 2011; Boudewyns et al., 2005; Buchanan, 
2010). Researchers are cautious about its use because it is difficult to 
comprehend why pulsed pressure would benefit Ménière’s patients. It 
instead might be treating patients who have a perilymphatic fistula and are 


 
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misdiagnosed with Ménière’s (Hain, 2010). Middle and external ear 
infections have also been reported (Coehlo & Lalwani, 2008).  Acceptance 
of this treatment is especially slow because of its high cost and uncertainty 
about its long-term effectiveness (Gates et al., 2004). U.S. insurers do not 
recognize Tympanostomy tube placement for Ménière’s disease as an 
indication and few insurers have made provisions for payment. 
Conservative endolymphatic sac surgery decompresses the endolymphatic 
sac from the overlying bone and drains the endolymph to keep the 
innervation intact and restore normal endolymphatic pressure (Hamill, 
2006). Although publicized as a placebo effect 20 years ago (Thomsen, 
Bretlau, Tos & Johnsen, 1981), endolymphatic sac surgery is still the most 
commonly used initial surgical treatment for Ménière’s (Ghossaini & 
Wazen, 2006). There is very little risk involved (Hamill, 2006). And this 
treatment is especially useful for bilateral Ménière’s disease because it 
conserves hearing and does not rely on later compensation. The short-term 
rate of vertigo control is as high as 80-90% (Huang, 2002). However, the 
surgery’s long-term efficacy is unclear (Silverstein, Lewis, Jackson, 
Rosenberg, Thompson & Hoffmann, 2003; Telischi & Luxford, 1993). 
Vestibular nerve section surgery cuts the vestibular portion of the 8th 
nerve while the cochlear portion remains intact (Hamill, 2006). Ghossaini 
& Wazen (2006) reported that this surgery has comparable results to 
gentamicin when examining vertigo control rates. The surgery virtually 
eliminates vertigo and preserves hearing (Hamill, 2006). Unfortunately, 
because the intracranial cavity is opened during this surgery, it requires a 
several day hospitalization and complications during the procedure are 
higher than other surgical options. This includes risk of facial nerve 
paralysis, hearing loss, cerebrospinal fluid leak and headache (Gates, 
2006; Gates et al., 2004). This surgical option is contraindicated for 
bilateral Ménière’s disease patients, similarly to gentamicin, (Hamill, 
2004), older patients, individuals with MS and with cerebellar dysfunction 
(Gates, 2006). So, although vestibular nerve section can eliminate vertigo, 
it is still an invasive procedure that should not be used with all Ménière’s 
patients. 
Surgical labyrinthectomy is a treatment option for Ménière’s disease 
patients with very little usable hearing remaining (Hamill, 2004). The 
outpatient procedure removes the entire labyrinth to eliminate vertigo and 
allow vestibular compensation to occur. It has superior vertigo control 
rates over any other method, but also destroys all hearing function. This 
surgical treatment option is seen as a last resort for unilateral Ménière’s 
patients with virtually no usable hearing on the affected side.  
Consequently, there is an absence of effective treatments. Treatment has 
moved away from surgical procedures and more towards therapies that are 
non-invasive, such as dietary considerations and pharmacotherapy. The 
decision of which treatment to use varies and there are no strict protocols 
for many of the procedures, including aspects of treatment duration and 


 
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intensity. In addition, the majority of treatment options for MD have not 
had controlled experimental testing completed (Hamill, 2006).  An 
effective oral medical treatment of Ménière’s disease will revolutionize 
treatment options. It will be cheaper, avoid surgical treatment, and prevent 
hearing loss from cochlear damage, unlike other treatments. 
The idea to use lamotrigine to treat Ménière’s disease was a completely 
incidental finding. As a certified epileptologist, Dr. Lixin Zhang 
frequently uses antiepileptic medications. Dr. Zhang especially liked 
lamotrigine due to the favorable side effect profile, which includes fewer 
cognitive side effects and less sedation. Lamotrigine has already been 
shown to have an effect on migraines and visual auras during migraine 
attacks, a symptom believed to be caused by cortical spreading depression 
(Bogdanov et al., 2011). The Dizziness and Balance Center also observed 
that lamotrigine could effectively treat patients with Migraine-associated 
vertigo. Migraine has been frequently associated with Ménière’s disease 
and the two disorders share several likenesses. A study on the comorbidity 
of migraine and Ménière’s disease found a significantly higher lifetime 
prevalence of migraine for both men and women in the MD group 
compared to an age- and sex-matched control group (Radtke, Lempert, 
Gretsy, Brookes, Bronstein & Neuhauser, 2002). Both vestibular disorders 
have a similar non-drug treatment, including avoidance of caffeine, 
chocolate, alcohol, tobacco and salt (Sajjadi & Paparella, 2008). 
Additionally, Ménière’s disease and migraines have significant genetic 
components and it is possible that patients are inheriting a brain and inner 
ear abnormality that causes both disorders (Baloh, Halmagyi & Zee, 
2012). These commonalities suggest that MD patients with migraine may 
find relief with anti-migrainous medication. Lamotrigine was first used to 
treat a Ménière’s patient because the patient also suffered from migraine. 
During the treatment, the patient’s typical Ménière’s vertigo attacks were 
completely under control. From that point, any patient who was diagnosed 
with Ménière’s disease and had frequent attacks (three or more vertigo 
attacks over the last three months) was prescribed lamotrigine and 
monitored. 
The most popular theories for migraine are cortical spreading depression 
(CSD) or vasoconstriction and dilation. Cortical spreading depression is 
self-generated cortical neuronal depolarization, which then spreads slowly 
(Dodick & Gargus, 2008). The cortical neuronal activities may cause 
vasoconstriction and dilation of deep subcortical white matter vessels 
(Brennan, Beltran-Parrazal, Lopez-Valdes, Theriot, Toga & Charles, 
2007). If the vasoconstriction continuously lasts for longer periods of time, 
it may cause ischemic changes in the white matter and gray matter 
(Bashir, Lipton, Ashina & Ashina, 2013; Messina et al., 2013).  
If lamotrigine is an effective treatment for Migraine-associated vertigo and 
Ménière’s vertigo attacks, it suggests that Ménière’s disease may be like 
an “inner ear migraine”. We propose that similar neuronal activities found 


 
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in CSD, or self-generated neuronal depolarization, in the ear may spread 
from either the vestibular organ to the cochlear or vice versa. Spreading 
depression is a slow process and may explain why a true Ménière’s vertigo 
attack is at least 20 minutes and a migraine is usually defined as four hours 
or longer (Committee on Hearing and Equilibrium, 1995; Headache 
Classification Committee, 2004; Porooshani, Porooshani, Gannon & Kyle, 
2002). These neuronal activities may cause vasoconstriction and dilation, 
and repeated prolonged attacks may lead to ischemic damages to 
vestibular organs and the cochlear. This damage could then cause 
lymphatic hydrops, permanent vestibular imbalance and hearing loss. 
Another possibility is that a patient may have preexisting unilateral 
lymphatic hydrops, which is able to generate spreading depression and 
then leads to vertigo attacks, tinnitus and hearing loss. The preexisting 
condition may be a better explanation of the initial unilateral process in 
most Ménière’s patients (Foster & Breeze, 2013) and the spreading 
depression theory may best explain the episodic presentation, slow 
progression, and variable course of Ménière’s disease. If this theory holds 
true, it will completely revolutionize the understanding of this devastating 
vestibular disease and will open a new trajectory of research in terms of 
developing animal models and new medical treatments. Our preliminary 
data already shows promising findings to support this new theory. 
2.2 Describe any relevant preliminary data.  
Response:  
Between January 2011 and November 2013, 48 patients in the Dent 
Dizziness and Balance Center were diagnosed with Ménière’s disease and 
were prescribed lamotrigine as an off-label treatment. These patients were 
given a definitive or probable diagnosis based on the AAO-HNS 1995 
criteria and had experienced at least three attacks in the three months prior 
to treatment. Almost all patients had been previously seen by ENT or 
other specialists and had tried conventional treatments like an improved 
life style, a low-sodium diet and diuretics. Some patients even attempted 
surgical treatments. Dosages varied from 50-300mg daily; most patients 
experienced a reduction of vertigo attacks during titration, but if another 
attack occurred the dose was increased further. We found that 13 of the 48 
patients (27.1%) were also diagnosed with some form of anxiety, six 
individuals (12.5%) with only migraine and 21 individuals (43.8%) with 
an anxiety disorder and migraine. Out of these 48 individuals, ten were 
lost to follow-up and four patients had side effects like rash and had to 
discontinue the medication. After removing the above 14 patients, 94.1% 
(32/34) of remaining individuals reported improvement in symptoms, 
especially a reduction of Ménière’s vertigo attacks. Furthermore, 50% 
(16/32) of improved patients experienced complete vertigo attack 
remission. Before initiation of lamotrigine therapy, 48 patients reported a 
mean of 13.5 (SD=12.5) vertigo attacks in the preceding three months 
(Figure 1). Thirty-five of the patients completed the initial follow-up and 


 
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reported a mean of 4.9 (SD=7.2) vertigo attacks in the three months after 
starting lamotrigine, *p<0.0001 (Wilcoxon signed rank test). Twenty-eight 
patients reported a mean of 2.5 (SD=5.5) vertigo attacks after completion 
of a three-month maintenance dose, *p<0.0001 (compared to before 
lamotrigine). Vertigo attack reduction and remission was not affected by 
migraine comorbidity.  
2.3 Provide the scientific or scholarly background for, rationale for, and 
significance of the research based on the existing literature and how 
will it add to existing knowledge. 
Response:  
Please refer to 2.1 
2.4 Include complete specific citations/references.  
Response: 
Balaban, C.D., Jacob R.G. & Furman J.M. (2011). Neurologic bases for 
comorbidity of balance disorders,Anxiety disorders and migraine: 
Neurotherapeutic implications. Expert Review of Neurotherapeutics, 11(3), 379-
394. doi: 10.1586/ern.11.19. 
 
Baloh, R.W., Halmagyi G.M. & Zee D.S. (2012). The history and future of neuro-
otology. Continuum, 18(5), 1001-1015. 
 
Bashir, A., Lipton, R., Ashina, S. & Ashina, M. (2013). Migraine and structural changes 
in the brain: A systematic review and meta-analysis. Neurology, 81, 1260-1268. 
 
Berlinger, N.T. (2011, November). Meniere’s disease: New concepts, new treatments. 
Minnesota Medicine, 
http://www.minnesotamedicine.com/PastIssues/PastIssues2011/November2011/Menieres
Disease.aspx 
 
Brennan, K., Beltran-Parrazal, L., Lopez-Valdes, H., Theriot, J., Toga, A. & Charles, A. 
(2007). Distinct vascular conduction with cortical spreading depression. Journal of 
Neurophysiology, 97(6), 4143-4151. 
 
Brinson, G.M., Chen, D.A. & Arriaga, M.A. (2007). Endolymphatic mastoid shunt versus 
endolymphatic sac decompression for Meniere’s disease. Otolaryngology-Head and Neck 
Surgery, 136, 415-421. 
 
Bogdanov, V.B., Multon, S., Chauvel, V., Bogdanova, O.V., Prodanov, D., Makarchuk, 
M.Y. & Schoenen, J. (2011). Migraine preventive drugs differentially affect cortical 
spreading depression in rat. Neurobiological disease, 41(2), 430-435. 
 


 
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Boudewyns, A.N., Wuyts, F.L., Hoppenbrouwers, M., Ketelslagers, K., Vanspauwen, R., 
Forton, G. & Van De Heyning, P.H. (2005). Meniett therapy: Rescue treatment in severe 
drug-resistant Meniere’s disease. Acta Oto-Laryngologica, 125, 1283-1289.  
 
Buchanan, M.A. & Prinsley, P.R. (2010). The Journal of Laryngology & Otology, 124, 
1067-1072.  
 
Committee on Hearing and Equilibrium. (1995). Committee on Hearing and Equilibrium 
guidelines for the diagnosis and evaluation of therapy in Meniere’s disease. 
Otolaryngology - Head and Neck Surgery, 113 (3), 181-185. ISSN 0194-5998, 
10.1016/S0194-5998(95)70102-8. 
(http://www.sciencedirect.com/science/article/pii/S0194599895701028) 
 
Davis, L.E. & Johnson R.T. (1976). Experimental viral infection of the inner ear. 
Laboratory Investigation, 34(4), 349–356. 
 
de Moraes S.A., Soares W.J., Ferriolli E. & Perracini M.R. (2013). Prevalence and 
correlates of dizziness in community-dwelling older people: a cross sectional population 
based study. BMC Geriatrics, 13(4). [PubMed: 23290128] 
 
Dodick, D. & Gargus, J. (2008). Why migraines strike. Scientific American, 299(2), 56-
63. 
 
Dornhoffer, J.L., Wagner, M., Arenberg, I.K. & Montague, D. (1993). 
Immunoperoxidase study of the endolymphatic sac in Meniere’s disease. Laryngoscope, 
103(9), 1027-34. 
 
Evans, K.L., Baldwin, D.L., Bainbridge, D. & Morrison, A. W. (1988). Immune status in 
patients with Meniere’s disease. Archives of oto-rhino-laryngology, 245(5), 287-292. 
 
Foster C.A. & Breeze R.E. (2013). Endolymphatic hydrops in Meniere’s disease: Cause, 
consequence, or epiphenomenon? Otology & Neurotology, 34(7), 1210-1214. [PubMed: 
23921917] 
 
Friberg, U. & Rask-Anderson, H. (2002). Vascular occlusion in the endolymphatic sac in 
Meniere’s disease. Annals of Otology, Rhinology & Laryngology, 111, 237-245. 
 
Gates, G.A. (2005). Treatment of Meniere’s disease with the low-pressure pulse 
generator (Meniett device). Expert Review of Medical Devices, 2(5), 533-537. 
 
Gates, G.A. (2006). Meniere’s disease review 2005. Journal of the American Academy of 
Audiology, 17(1), 16-26. 
 
Gates, G.A., Green, D., Tucci, D.L. & Telian, S.A. (2004). The effects of transtympanic 
micropressure treatment in people with unilateral Meniere’s disease. Archives of 
Otolaryngology Head Neck Surgery, 130(6), 718-725. 


 
Page 13 of 55 
Revised: August 3, 2018 
 
Ghossaini, S.N. & Wazen, J.J. (2006). An update on the surgical treatment of Meniere’s 
disease. Journal of the American Academy of Audiology, 17, 38-44. 
 
Greco, A., Gallo, A., Fusconi, M., Marinelli, C., Macri, G.F. & de Vincentiis, M. (2012). 
Meniere's disease might be an autoimmune condition? Autoimmunity Reviews, 11(10), 
731-738. ISSN 1568-9972, http://dx.doi.org/10.1016/j.autrev.2012.01.004. 
(http://www.sciencedirect.com/science/article/pii/S1568997212000092) 
 
Greenberg, S.L. & Nedzelski, J.M. (2010). Medical and noninvasive therapy for 
Meniere’s disease. Otolaryngologic Clinics of North America, 43(5), 1081-90. 
 
Gottshall, K.R., Hoffer, M.E., Moore, R.J., & Balough, B.J. (2005). The role of vestibular 
rehabilitation in the treatment of Meniere’s disease. Otolaryngology-Head and Neck 
Surgery, 133, 326-328. 
 
Hamill, T.A. (2006). Evaluating treatments for Meniere’s disease: Controversies 
surrounding placebo control. Journal of the American Academy of Audiology, 17, 26-37.  
 
Headache Classification Subcommittee of the International Headache Society. (2004). 
The international classification of headache disorders: 2nd edition, Cephalalgia, 24, 1-
160. 
 
Kaylie, D.M., Jackson, C.G., & Gardner, E.K. (2005). Surgical management of Meniere’s 
disease in the era of gentamicin. Otolaryngology-Head and Neck Surgery, 132(3), 443-
450. 
 
Kimura, R.S. (1982). Animal models of endolymphatic hydrops. American Journal of 
Otolaryngology, 3(6), 447-451. 
 
Lempert T. (2012). Recurrent spontaneous attacks of dizziness. Continuum, 18(5), 1086-
1101. 
 
Messina, R., Rocca, M.A., Colombo, B., Valsasina, P., Horsfield, M.A., Copetti, M.M 
Falini, A., Comi, G. & Filippi, M. (2013). Cortical abnormalities in patients with 
migraine: A surface-based analysis. Radiology, 268(1), 170-180. 
 
Monzani, D., Barillari, M.R., Ciufelli, M.A., Cavazza, E.A., Neri, V., Presiutti, L. & 
Genovese, E. (2012). Effect of a fixed combination of nimodipine and betahistine versus 
betahistine as monotherapy in the long-term treatment of Meniere’s disease: a 10-year 
experience. Acta Otorhinolaryngologica Italica, 32, 393-403. 
 
Porooshani, H., Porooshani, A.H., Gannon, L. & Kyle, G.M. (2002). Speed of 
progression of migrainous visual aura measure by sequential field assessment. Neuro-
Ophthalmology, 28(2), 101-105. 
 


 
Page 14 of 55 
Revised: August 3, 2018 
Postema, R.J., Kingma, C.M., Wit, H.P., Albers, F.W. & Van Der Laan, B.F. (2008). 
Intratympanic gentamicin therapy for control of vertigo in unilateral Meniere’s disease: a 
prospective, double-blind, randomized, placebo-controlled trial. Acta Oto-Laryngologica, 
128, 876-880. 
 
Radtke, A., Lempert, T., Gretsy, M.A., Brookes, G.B., Bronstein, A.M. & Neuhauser, H. 
(2002). Migraine and Meniere’s disease: is there a link? Neurology, 59, 1700-1704. 
 
Sajjadi, H. & Paparella M.M. (2008). Meniere’s disease. Lancet, 372, 406-14. 
 
Sampson, W.I. (2003). Homeopathic vs. conventional treatment of vertigo. Archives of 
Otolaryngology-Head & Neck Surgery, 129 (4), 497-498. 
 
Semaan, M.T. & Megerian, C.A. (2011). Meniere’s disease: A challenging and relentless 
disorder. Otolaryngologic Clinics of North America, 44, 383-403. 
 
Shojaku, H., Watanabe, Y., Mineta, H., Aoki, M., Tsubota, M., Watanabe, K. & Shigeno, 
K. (2011). Long-term effects of the Meniett device in Japanese patients with Meniere’s 
disease and delayed endolymphatic hydrops reported by the Middle Ear Pressure 
Treatment Research Group of Japan. Acta-Otolaryngologica, 131(3), 277-283.  
 
Silverstein, H., Lewis, W.B., Jackson, L.E., Rosenberg, S.I., Thompson, J.H. & 
Hoffmann, K.K. (2003). Changing trends in the surgical treatment of Meniere’s disease: 
Results of a 10-year survey. ENT-Ear, Nose & Throat Journal, 82(3), 185-194. 
 
Silverstein, H., Wazen, J., Van Ess, M.J., Daugherty, J. & Alameda, Y.A. (2010). 
Intratympanic gentamicin treatment of patients with Meniere’s disease normal hearing. 
Otolaryngology-Head and Neck Surgery, 142, 570-575.  
 
Soliman, A.M. (1996). A subpopulation of Meniere’s patients produce antibodies that 
bind to endolymphatic sac antigens. The American Journal of Otology, 17(1), 76-80. 
 
Strupp, M., Hupert, D., Frenzel, C., Wagner, J., Hahn, A., Jahn, K. & Brandt, T. (2008). 
Long-term prophylactic treatment of attacks of vertigo in Meniere’s disease-comparison 
of a high with a low dosage of betahistine in an open trial. Acta Oto-Laryngologica, 128, 
520-524.  
 
Syed I. & Aldren C. (2012).Meniere's disease: an evidence based approach to assessment 
and management. International Journal of Clinical Practice, 66, 166-170. 
 
Telischi, F.F. & Luxford, W.M. (1993). Long-term efficacy of endolymphatic sac surgery 
for vertigo in Menière's disease. Otolaryngology- Head and Neck Surgery, 109(1), 83-87. 
 
Thai-Van, H., Bounaix, M., & Fraysse, B. (2001). Meniere’s disease: Pathophysiology 
and treatment. Drugs, 61(8), 1089-1102. 
 


 
Page 15 of 55 
Revised: August 3, 2018 
Thomsen, J., Bretlau, P., Tos, M. & Johnsen, N.J. (1981). Placebo effect in surgery for 
Meniere’s disease: A double-blind, placebo-controlled study on endolymphatic sac shunt 
surgery. Archives of otolaryngology- Head & Neck Surgery, 107(5), 271-277. 
 
Van Cruijsen N., Jaspers J.P.C., Van de Wiel H.B.M., Wite H.P. & Albers F.W.J. (2006). 
Psychological assessment of patients with Meniere’s disease. International Journal of 
Audiology, 45, 496-502. 
 
Quaranta, A., Aloisi, A., De Benedittis, G. & Scaringi, A. (1999). Intratympanic therapy 
for Meniere’s disease: High-concentration gentamicin with round-window protection. 
Annals New York Academy of Sciences, 884, 410-424. 
 
3.0 
Inclusion and Exclusion Criteria 
3.1 Describe the criteria that define who will be included or excluded in 
your final study sample.  
Respons Inclusion Criteria:  
•Male and female participants aged 18 years or older 
•Diagnosed with unilateral definite Ménière's disease according to the 
AAO-HNS 1995 criteria, confirmed by an ENT 
•Active vertigo: at least two Ménière's vertigo attacks (defined as lasting 
20 minutes or longer and associated with tinnitus, ear fullness, or low 
frequency hearing loss and nausea/vomiting) every four weeks during the 
eight-week qualification period and at least two or more Ménière's vertigo 
attacks during the lead-in phase prior to randomization 
•Documented unilateral lower frequency hearing loss defined as the four-
tone average (arithmetic mean rounded to the nearest whole number) of 
the pure-tone thresholds at 0.25, 0.5, 1 and 2 kHz more than or equal to 25 
dB of the worse audiogram during the six months before screening 
•Have tried diuretics for at least one month and discontinued treatment due 
to continued vertigo attacks 
•All other co-existing medical or psychiatric conditions are stable, and no 
greater than moderate severity 
•Willing to avoid pregnancy during the entirety of the study (abstinence or 
two forms of acceptable birth control, such as condoms and oral 
contraceptives) 
 
Exclusion Criteria: 
•Bilateral Ménière's disease 
•Current or past history of migraine 


 
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•Any other neuro-otologic disease or major vestibular abnormality found 
during screening that could confound the evaluation of Ménière's 
symptoms 
•Previous intolerance or sensitivity to lamotrigine 
•On any prohibited medication within four weeks prior to the study 
•History of tympanostomy tubes with evidence of perforation or lack of 
closure 
•IT gentamicin injections or endolymphatic sac surgery within the last 
year 
•History of or current immunodeficiency disease, nephrolithiasis, 
hypertension, cardiac disease, arrhythmia, hypercholesterolemia, 
hemiplegic/basilar migraine, stroke, diabetes, vascular disease or kidney 
disease 
•Family history of unexplained deafness 
•Pregnant or breastfeeding 
•Current diseases or conditions that may be associated with an altered 
perception of processing stimuli 
•Current severe medical condition(s) that in the view of the investigator 
prohibits participation 
•Previously used the investigational drug 
•Current non-vertiginous dizziness (orthostatic or panic disorder) unless it 
could be clearly differentiated from Ménière's attacks by the participante:  
 
3.2 Describe how individuals will be screened for eligibility. 
Response:  
Dr. Zhang conducts and orders a physical exam and relevant testing to 
assure subjects meet criteria outlined. 
Participants who are diagnosed with Ménière's disease, as determined by 
clinical history,  ENT confirmation and an audiogram, will qualify if 
they also have had two or more Ménière's vertigo attacks in a four-week 
span for two consecutive four-week periods (the qualification period). 
Those who meet these criteria will then need two or more Ménière's 
vertigo attacks during a four-week lead-in period to further establish a 
baseline and verify randomization eligibility. Participants are allowed 
from the beginning of the lead-in to take their choice of a symptomatic 
abortive medication according to its package instructions for Ménière's 
vertigo attacks that last longer than 30 minutes with nausea and/or 
vomiting. Symptomatic abortive medications include, but are not limited 
to, meclizine (Antivert), Valium, diazepam, or Zofran.   
 


 
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A total of 25 participants will be enrolled for the pre-randomization 
stage. Those who do not wish to continue to the next stage or who no 
longer meet inclusion/exclusion criteria will be replaced. At screening, 
participants will be asked to undergo a urine pregnancy for women of 
reproductive age (<50yrs) to ensure that they are eligible to continue. If a 
complete blood count (CBC), comprehensive metabolic profile (CMP), 
and creatinine clearance has not been conducted within the past three 
months, the participant will have blood drawn into tubes that will be 
centrifuged and shipped to Kaleida Health’s labs to be analyzed. A urine 
sample will be obtained for the 24 hour creatinine clearance analysis as a 
screening measure for healthy kidney and liver function. As part of the 
patient’s routine medical care, the blinded PI will conduct a full 
neurological and physical exam, review prior and current medications 
and request all medical history of the participant’s Ménière's disease. 
This includes any results from vestibular testing that confirm the 
Ménière's diagnosis and rule out other causes (e.g. a basic vestibular 
exam, four calorics, rotary chair, and posturography testing). If 
participants have not undergone a comprehensive audiogram (including 
electrocochleaography and tympanometry subtests) and an 
electrocardiogram within the past three months, they will undergo all of 
the missing tests at the Dent Neurologic Institute before enrollment. 
These tests are test for other disorders that may require treatment as part 
of the patient’s standard medical care and to also function to verify 
eligibility and establish a baseline for improvement and possible adverse 
events during the study. Participants will be asked to complete a series of 
questionnaires that include the Dizziness Handicap Inventory (DHI), 
Ménière's Disease Patients-Oriented Severity Index (MDPOSI), 
Ménière's disease Self-Assessment, Tinnitus Handicap Inventory (THI), 
Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder 
(GAD-7) and the baseline Columbia-Suicide Severity Rating Scale (C-
SSRS). These assessments will provide a baseline of the participant’s 
symptom severity, frequency and duration of vertigo attacks and quality 
of life. 
 
Following the screening visit, participants will enter a four week lead-in 
period. They are responsible for recording vertigo and other symptom severity, 
and abortive medication use with the Ménière's daily survey. During this period 
any uncompleted audiogram or EKG testing can take place. This lead-in period 
will provide a more accurate representation of the Ménière's disease vertigo 
frequency and allow for screening tests to be completed at the participant’s 
convenience. If the participant is on any prohibited medication at the screening, 
the medications will be discontinued if the participant wishes to continue in the 
study and it is deemed safe by the PI and the prescribing doctor. The lead-in 
period will also be used as a wash-out.  
 
At Visit 2, after the four week lead-in, inclusion/exclusion criteria 
will be re-evaluated. This includes a review of any concomitant 


 
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medications. Participants will be asked to hand in their Ménière's survey 
if they opted for the paper document. The surveys will be reviewed to 
ensure that abortive measures were only used during the severe attacks, 
as instructed. The Principal Investigator will assess any possible adverse 
events and then staff will administer the questionnaire batch. If the 
participant is eligible for randomization, he/she will be assigned to either 
a placebo or lamotrigine treatment group. Assignment will be based on a 
randomization conducted by UBSoPPS Research pharmacists, and the 
participant will be considered “enrolled” in the study at this point, and 
from this point on, all medical services, except abortive medication(s) of 
the patient’s choice) are study-related and are not billed to the patient’s 
insurance. 
 
 
3.3 Indicate specifically whether you will include or exclude each of the 
following special populations: (You may not include members of 
these populations as subjects in your research unless you indicate 
this in your inclusion criteria.) 
 
Adults unable to consent 
 
Individuals who are not yet adults (infants, children, teenagers) 
 
Pregnant women 
 
Prisoners 
Response:  
Exclude all 
3.4 Indicate whether you will include non-English speaking individuals.  
Provide justification if you will exclude non-English speaking 
individuals.  
(In order to meet one of the primary ethical principles of equitable 
selection of subjects, non-English speaking individuals may not be 
routinely excluded from research.  In cases where the research is of 
therapeutic intent or is designed to investigate areas that would 
necessarily require certain populations who may not speak English, 
the researcher is required to make efforts to recruit and include non-
English speaking individuals.  However, there are studies in which it 
would be reasonable to limit subjects to those who speak English: 
e.g., pilot studies, small unfunded studies with validated instruments 
not available in other languages, numerous questionnaires, and 
some non-therapeutic studies which offer no direct benefit.)  
 
Response:  
N/A- no non-English speaking subjects 


 
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4.0 
Study-Wide Number of Subjects (Multisite/Multicenter Only) 
4.1 If this is a multicenter study, indicate the total number of subjects to 
be accrued across all sites. 
Response:  
N/A – not a multicenter study 
5.0 
Study-Wide Recruitment Methods (Multisite/Multicenter Only) 
If this is a multicenter study and subjects will be recruited by methods not under 
the control of the local site (e.g., call centers, national advertisements) describe 
those methods.  Local recruitment methods are described later in the protocol. 
5.1 Describe when, where, and how potential subjects will be recruited. 
Response:  
N/A – not a multicenter study 
5.2 Describe the methods that will be used to identify potential subjects. 
Response:  
N/A – not a multicenter study 
5.3 Describe materials that will be used to recruit subjects. (Attach 
copies of these documents with the application. For advertisements, 
attach the final copy of printed advertisements. When advertisements 
are taped for broadcast, attach the final audio/video tape. You may 
submit the wording of the advertisement prior to taping to preclude 
re-taping because of inappropriate wording, provided the IRB 
reviews the final audio/video tape.) 
Response:  
The study hopes to recruit from the patient population at the Dent 
Dizziness and Balance Center and Buffalo ENT Specialists, LLP. In doing 
so, the PI and staff will have to access medical charts/records to verify 
eligibility and diagnosis of Meniere's disease prior to obtaining consent of 
potential participants. A referral letter will also be sent to area physicians 
and ENT specialists informing them of the study design and 
inclusion/exclusion criteria. Those receiving the letter are encouraged to 
notify eligible patients of the opportunity to participate and how to contact 
the study staff if they are interested. If enrollment numbers are not met, 
another letter will be sent out to remind the physicians and specialists. If 
enrollment numbers are still not met through this method, recruitment 
strategies will include an advertisement in the once monthly issue of an 
After 50 free newspaper, Buffalo Healthy Living magazine, 32 sixty-
second radio advertisements and 50 sixty-second streaming commercials 
for two weeks. The study has requested funds for this purpose, but is 
hoping to exhaust all other potential participants within the Dizziness and 


 
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Revised: August 3, 2018 
Balance Center and Buffalo ENT Specialists first. Therefore, the 
additional newspaper and radio advertisement recruitment materials will 
be submitted as an addendum at a later date. 
6.0 
Multi-Site Research (Multisite/Multicenter Only) 
6.1 If this is a multi-site study where you are the lead investigator, 
describe the processes to ensure communication among sites, such 
as: 
 
All sites have the most current version of the protocol, consent 
document, and HIPAA authorization. 
 
All required approvals have been obtained at each site 
(including approval by the site’s IRB of record). 
 
All modifications have been communicated to sites, and 
approved (including approval by the site’s IRB of record) 
before the modification is implemented. 
 
All engaged participating sites will safeguard data as required 
by local information security policies. 
 
All local site investigators conduct the study appropriately. 
 
All non-compliance with the study protocol or applicable 
requirements will reported in accordance with local policy. 
Response:  
N/A – not a multicenter study 
6.2 Describe the method for communicating to engaged participating 
sites: 
 
Problems. 
 
Interim results. 
 
The closure of a study 
Response:  
N/A – not a multicenter study 
7.0 
Study Timelines 
7.1 Describe the duration of an individual subject’s participation in the 
study. 
Response:  
The study is composed of five phases: medical history qualification (eight 
weeks), lead-in (four weeks), titration (six weeks), study period (12 
weeks), and taper (two weeks). 
7.2 Describe the duration anticipated to enroll all study subjects. 
Response:  
1-2 years 


 
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7.3 Describe the estimated date for the investigators to complete this 
study (complete primary analyses) 
Response:  
06/2016 
8.0 
Study Endpoints 
8.1 Describe the primary and secondary study endpoints. 
Response:  
The endpoints of this study are: 
Primary Efficacy Endpoint: 
 Comparison between lamotrigine and placebo groups of the 
reduction of Ménière's vertigo attacks from baseline  
 
Secondary Efficacy Endpoints: 
 Comparison between lamotrigine and placebo groups of 
vertigo attacks: 
 Responder rate: Percentage of patients with > 50% 
reduction in vertigo attack frequency during treatment vs. 
baseline 
 Vertigo attack free rate analysis: Length of vertigo attack-
free intervals, number and percentage of vertigo attack-free 
days per 28 days period, number and percentage of patients 
who are vertigo attack-free during the double blind phase 
 Comparison between lamotrigine and placebo groups of 
hearing loss: 
 Analysis of audiograms between baseline and end of the 
study 
 Comparison between lamotrigine and placebo groups of 
symptom severity: 
 Ménière's Disease Patients-Oriented Severity Index 
(MDPOSI) 
 Tinnitus Handicap Inventory (THI) questionnaire 
 Clinical Global Impression-Severity & Change 
 Comparison between lamotrigine and placebo groups of quality of 
life: 
 Dizziness Handicap Inventory (DHI) questionnaire 
 AAO-HNS Ménière's disease self-assessment 


 
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 Patient Health Questionnaire-9 (PHQ-9) 
 Generalized Anxiety Disorder 7-item scale (GAD-7) 
8.2 Describe any primary or secondary safety endpoints. 
Response:  
N/A – no such endpoints 
9.0 
Procedures Involved 
9.1 Describe and explain the study design. 
Response:  
This is a randomized double-blind pilot proof-of-concept clinical trial. The 
principal investigator and all staff involved in clinic visits will remain 
blinded until the blind is scheduled to be broken or there is an emergency.  
Participants who are diagnosed with Ménière's disease, as determined by 
clinical history,  ENT confirmation and an audiogram, will qualify if they 
also have had two or more Ménière's vertigo attacks in a four-week span 
for two consecutive four-week periods (the qualification period). Those 
who meet these criteria will then need two or more Ménière's vertigo 
attacks during a four-week lead-in period to further establish a baseline 
and verify randomization eligibility. Participants are allowed from the 
beginning of the lead-in to take their choice of a symptomatic abortive 
medication according to its package instructions for Ménière's vertigo 
attacks that last longer than 30 minutes with nausea and/or vomiting. 
Symptomatic abortive medications include, but are not limited to, 
meclizine (Antivert), Valium, diazepam, or Zofran. The abortive 
medication can be used throughout the study regardless of treatment 
assignment and its use will be recorded. Twelve eligible participants, with 
a minimum total of six attacks during the qualification and lead-in periods, 
will be randomly assigned to either a placebo or lamotrigine treatment 
group. Randomization will be conducted by UBSoPPS Research 
Pharmacy. The study drug and matching placebo will be titrated from 
25mg twice a day (BID) up to 150mg BID over a six week period. During 
titration, clinic visits are scheduled every two weeks to assess any adverse 
events, symptoms, quality of life, and compliance. Those who cannot 
tolerate the 150mg BID dose may return to a 100mg BID dose during an 
unplanned visit. However, if a participant is unable to tolerate the 100mg 
BID dose they will be withdrawn from the study. Participants will 
maintain the 150mg BID or 100mg BID dose for a 12-week period with 
clinic visits every four weeks to assess their progress. Between all study 
visits, participants are asked to complete a daily survey describing their 
symptoms. This survey is hosted by polleverywhere.com and can be 
completed through text message, an online website, or with a paper 
document- whatever method is preferred by the participant. At the 
conclusion of the 12-week study period, a study staff will be un-blinded 


 
Page 23 of 55 
Revised: August 3, 2018 
and will give participants assigned to the lamotrigine group the option to 
continue the study medication as a long-term open-label use outside of the 
study or to begin a two-week taper off. The number of participants who 
decide to continue the study medication will be noted, but the participant 
will be terminated from the study and thus responsible for all following 
costs. Those assigned to the placebo treatment will be informed of their 
treatment assignment and terminated from the study. 
9.2 Provide a description of all research procedures being performed 
and when they are performed, including procedures being performed 
to monitor subjects for safety or minimize risks. 
Response:  
Please note: these procedures are a continuation from section 3.2, where section 3.2 
outlines the screening procedures that are also part of standard medical care, and this 
section, section 9.2, is specific to research-only procedures. 
 
At Visit 2, after the four week lead-in, inclusion/exclusion criteria will be re-evaluated. 
This includes a review of any concomitant medications. Participants will be asked to 
hand in their Ménière's survey if they opted for the paper document. The surveys will be 
reviewed to ensure that abortive measures were only used during the severe attacks, as 
instructed. The Principal Investigator will assess any possible adverse events and then 
staff will administer the questionnaire batch. If the participant is eligible for 
randomization, he/she will be assigned to either a placebo or lamotrigine treatment group. 
Assignment will be based on a randomization conducted by UBSoPPS Research 
pharmacists, and the participant will be considered “enrolled” in the study at this point, 
and from this point on, all medical services, except abortive medication(s) of the patient’s 
choice) are study-related and are not billed to the patient’s insurance. Both groups will 
receive an amber vial of 28 pills with instructions to take one pill twice a day. Those in 
the lamotrigine group will be taking 25mg BID while those in the placebo group will be 
taking encapsulated microcrystalline cellulose. A drug dosage log will also be given to 
participants and they will be asked to write down the number of pills taken. Participants 
will be advised to notify the Principal Investigator or study staff if they develop rashes or 
other side effects. If the principal investigator decides that the rash is medication related, 
the participant will immediately stop the medication, return for an early termination visit 
and be terminated early from the study. Serious adverse events requiring withdrawal and 
unrelated to rash will return for an early termination visit and begin a two-week taper. If 
at any visit a participant is found to be non-compliant with dosing instructions, the 
Principal Investigator will assess the situation and determine if early termination is 
required. If the participant is terminated, they will follow the same taper schedule and 
early termination visit required for those withdrawing due to adverse events other than 
rash.  Staff members will also remind participants to complete the daily survey and how 
to do so. 
Two weeks later at Visit 3, current medications and adverse events will be 
reviewed by the Principal Investigator. A staff member will collect the medication 
containers, conduct a pill count and collect and review the dosage log and daily Ménière's 
survey responses. If the participant is determined to be compliant the staff member will 


 
Page 24 of 55 
Revised: August 3, 2018 
administer the questionnaire batch. Continuing participants will receive an amber vial of 
28 pills with instructions to take one pill twice a day. The medication will either be 
lamotrigine 50mg BID or the matching placebo. Staff members will then hand out 
another dosage log and remind participants to complete the daily survey. Participants are 
asked to return in two weeks. 
At Visit 4, current medications and adverse events will be reviewed by the 
Principal Investigator. A staff member will collect the medication containers, conduct a 
pill count and collect and review the dosage log and daily Ménière's survey responses. If 
the participant is determined to be compliant the staff member will administer the 
questionnaire batch. Continuing participants will receive an amber vial of 28 pills with 
instructions to take one pill twice a day. The medication will either be lamotrigine 100mg 
BID or the matching placebo. Staff members will then hand out another dosage log and 
remind participants to complete the daily survey. Participants are asked to return in two 
weeks. 
At Visit 5, current medications and adverse events will be reviewed by the 
Principal Investigator. Participants will complete another physical and neurological 
exam, a comprehensive audiogram with tympanometry, and a urine pregnancy test for 
females of reproductive age (<50yrs). Blood will be drawn, centrifuged and shipped to 
Kaleida Health’s labs to analyze study drug levels. Additionally, a urine sample will be 
obtained for 24 hour creatinine clearance analysis as a screening measure for healthy 
kidney and liver function, to verify participants’ ability to continue in the study. Study 
drug level results will be separated from other testing results and sent to UBSoPP 
Research Pharmacy to hold until the blind is broken and compliance can be reviewed. A 
staff member will collect the medication containers, conduct a pill count and collect and 
review the dosage log and daily Ménière's survey responses. If the participant is 
determined to be compliant, the staff member will administer the questionnaire batch. 
Continuing participants will receive an amber vial of 56 pills with instructions to take one 
pill twice a day. Participants’ clinical response and tolerability will be assessed and if a 
participant reports no serious side effects from medications, the study drug will be further 
titrated to 150 mg BID or the matching placebo. If the participant finds that they cannot 
tolerate the 150mg BID dose, they are able to come into the clinic for an unscheduled 
visit and decrease to 100mg BID. Staff members will then hand out another dosage log 
and remind participants to complete the daily survey. Participants are asked to return in 
four weeks. 
At Visit 6, current medications and adverse events will be reviewed by the 
Principal Investigator. A staff member will collect medication containers, conduct a pill 
count and collect and review the dosage log and daily Ménière's survey responses. If the 
participant is determined to be compliant the staff member will administer the 
questionnaire batch. Continuing participants will receive an amber vial of 56 pills of the 
same dosage, either 150mg BID or 100mg BID, with instructions to take one pill twice a 
day. Staff members will then hand out another dosage log and remind participants to 
complete the daily survey. Participants are asked to return in four weeks. 
At Visit 7, current medications and adverse events will be reviewed by the 
Principal Investigator. A staff member will collect medication containers, conduct a pill 
count and collect and review the dosage log and daily Ménière's survey responses. If the 
participant is determined to be compliant the staff member will administer the 


 
Page 25 of 55 
Revised: August 3, 2018 
questionnaire batch. Continuing participants will receive an amber vial of 56 pills of the 
same dosage, either 150mg BID or 100mg BID, with instructions to take one pill twice a 
day. Staff members will then hand out another dosage log and remind participants to 
complete the daily survey. 
Four weeks later participants return to the clinic for Visit 8, current medications 
and adverse events will be reviewed by the Principal Investigator. The Principal 
Investigator will also administer a neurological and physical exam and complete the 
Clinical Global Impression-Severity and Change assessment. A staff member will collect 
medication containers, conduct a pill count and collect and review the dosage log and 
daily Ménière's survey responses. Participants will complete the questionnaire batch, and 
undergo a comprehensive audiogram with tympanometry. Blood will be drawn, 
centrifuged and shipped to Kaleida Health’s labs to analyze study drug levels, CMP, 
CBC, and a urine pregnancy test will be conducted for female participants of 
reproductive age (<50yrs). Additionally, a urine sample will be obtained for 24 hour 
creatinine clearance analysis as a screening measure for healthy kidney and liver 
function. At the conclusion of the visit a staff member will be un-blinded by unsealing an 
envelope that contains treatment code and participant number. Those in the lamotrigine 
group will be given the option to be terminated from the study, but to continue the study 
medication at their own cost. Alternatively, they can continue in the study and begin to 
taper off the study drug. Those who decide to continue the study medication will be 
noted, but no further study participation is required. Participants continuing lamotrigine 
will be free to follow up on their treatment through the Dizziness and Balance Clinic or 
through a physician of their choice. Participants who decide to discontinue the study drug 
will begin a two-week taper consisting of one week at their current dosage QD and then 
one week of half the current dosage QD, and be paid for these 2 remaining study visits 9 
and 10. Those assigned to the placebo group will be terminated from the study and are 
informed that they are allowed to seek treatment for their Ménière's disease at the 
Dizziness and Balance Clinic or elsewhere. 
At both of the taper visits, participants will be given the tapered dose and asked to 
continue their dosage log. Staff will collect medication containers, conduct a pill count 
and review the dosage log to verify that participants are stopping the study drug in a safe 
manner. Any adverse events will continue to be reviewed by the Principal Investigator. 
At the last visit, participants will undergo one last physical and neurological exam and be 
notified of their termination from the study. At this point participants are informed that 
they are allowed to seek treatment for their Ménière's disease at the Dizziness and 
Balance Clinic or elsewhere. 
9.3 Describe procedures performed to lessen the probability or 
magnitude of risks. 
Response: Procedures to minimize risk of adverse events due to the drug are 
outlined in sections 9.2 and 12.7.  
To provide detail sufficient detail on study procedures in reducing risk associated 
with the blood draws, I will copy Dent Neurologic Institute’s official Blood Draw 
Policy here, which is adhered to by all employees of Dent who draw blood, 
including the research staff member assigned on our study team to draw blood. 
POLICY & PROCEDURE 


 
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Title: Blood Draws Policy Number: CLN - 037 
Category: Clinic Reference Statute, If one exists: 
Standard: Approved By: CEO: Joseph V. Fritz, PhD, CEO 
PURPOSE: 
To provide accurate and complete instructions for safe blood drawing technique. 
POLICY: 
It is the policy of the DNI to provide DENT staff with complete and accurate instructions 
for drawing blood. 
RESPONSIBILITY: 
It is the responsibility of the Clinic Managers to create and maintain the procedure. The 
DNI Clinic Staff need to be trained on this procedure. 
PROCEDURE: 
1.) Gather all necessary equipment; 
a.) Alcohol prep pads 
b.) Clean tourniquet 
c.) Clean disposal gloves – sized appropriately 
d.) 4x4 gauze 
e.) Band-Aid or tape 
f.) Tubes 
g.) Vacuum holder or syringe 
h.) Appropriate size blood draw needle or butterfly 
i.) Specimen labels 
j.) Plastic specimen bag 
2.) Meet and greet patient 
Blood Draws 
Page 1 of 3 
3.) Escort patient into phlebotomy room 
4.) Identify patient by three identifiers – name, DOB, address 
5.) Explain procedure to patient 
6.) Check with patient regarding possible allergy to latex .( If positive – see additional 
information) 
7.) Wash your hands 
8.) Inspect both arms of the patient for possible venipunture site. 
9.) Apply tourniquet to arm as per instructions 
10.) Prep skin with one alcohol prep 
11.) Don clean gloves 
12.) Palpate possible venipunture sites as per instructions 
13.) Place needle to vacuum holder or attach butterfly to syringe. 
14.) With bevel up insert needle into vein at 15 degree angle. Gently push appropriate 
vial 
onto needle hub or draw back on syringe. 
15.) Allow blood to flow into blood collection tube 
a.) Lavender tubes drawn prior to blue tubes due to additive and air in tubing. 
b.) Invert each tube a total of at least three times to insure proper mixing of blood 
and additive. 
16.) When blood has reached the appropriate level, gently remove tube and place 
second 
tube on to needle hub. Continue to do this until all blood specimens have been collected. 
Draw enough blood in syringe if using butterfly to fill tubes. 
17.) As last specimen is being obtained, remove tourniquet and complete the blood 
collection. 


 
Page 27 of 55 
Revised: August 3, 2018 
18.) Gently remove tube from needle setup. Remove needle and secure puncture site 
with 
gauze or cotton ball. 
19.) Secure all specimens. 
20.) Place Band-Aid over site. 
21.) With patient still in the room: Label all specimens with correct label. Verbally verify 
patient’s name and DOB as labels are attached to specimens. 
22.) Complete appropriate paperwork, initials, time drawn. 
Blood Draws 
Page 2 of 3 
23.) Discharge patient 
24.) Place completed specimens and paperwork into to outgoing pickup and call Quest 
or 
LabCorp for pick up. 
25.) Clean area 
26.) Wash your hands 
27.) Only three attempts are to be done. If unable to secure specimens after three 
attempts, 
must have another professional attempt. 
Blood Draws 
Page 3 of 3 
 
 
9.4 Describe all drugs and devices used in the research and the purpose 
of their use, and their regulatory approval status. 
Response:  
Lamotrigine is a FDA approved drug for treating epilepsy and bipolar disorder, 
indicated as “schedule: N” – not subject to the Controlled Substances Act. The present 
study is exploring a new indication for Lamotrigine. The FDA has concluded that the 
study meets all of the requirements for exemption from the IND regulations and, 
therefore, an IND is not required to conduct the investigation (proof of this indication has 
been previously submitted to IRB) 
The drug supply will be sent to the University of Buffalo's School of Pharmacy 
and Pharmaceutical Sciences (UBSoPPS) Research Pharmacy. Once it arrives the 
packing slip will be checked for completeness and then the study staff will be notified of 
its arrival. The invoice and inventory taken will be faxed over to the study site. The drugs 
will then be stored in their original containers in a room-temperature, dry and dark area of 
the UBSoPPS Research Pharmacy's lab, which has very limited access since it is a 
pharmacy. Temperature and humidity will be monitored by a UBSoPPS Research 
Pharmacist. 
UBSoPPS Research Pharmacy will take the manufacture supplied tablet and place 
it inside a capsule. The capsule will be filled with methylcellulose until the entire content 
of the capsule is filled, decreasing the chance for un-blinding, and the capsule then 
closed. The encapsulated lamotrigine will then be packaged in an amber vial with a study 
label. Repackaging will follow NYS regulation. Repacking will be conducted by a 
pharmacist or under his/her immediate and personal supervision. A repacking record shall 


 
Page 28 of 55 
Revised: August 3, 2018 
be maintained for five years, including the name, strength, lot number, quantity and name 
of the manufacturer and/or distributor of the drug repacked, the date of repacking, the 
number of packages prepared, the number of dosage units in each package, the signature 
of the person performing the repacking operation, the signature of the pharmacist who 
supervised the repacking, and such other identifying marks added by the pharmacy for 
internal recordkeeping purposes. Drugs repacked shall have an expiration date 12 
months, or 50 percent of the time remaining to the manufacturer's expiration date, 
whichever is less, from the date of repacking. 
SUNY at Buffalo School of Pharmacy and Pharmaceutical Sciences (UBSoPPS) 
Research Pharmacy will randomize eligible participants through www.randomizer.org. 
An UBSoPPS pharmacist will generate 12 random sets of numbers, ranging from 1-2 for 
the two assignment groups, with one unique number per set. UBSoPPS Research 
Pharmacy will use this randomization to compile a master log with the participant 
number and treatment code. 
Those assigned to the lamotrigine treatment will take encapsulated lamotrigine 
daily for the duration of 20 weeks, consisting of a six-week titration, 12-week study 
period, and two-week taper. Possible doses for patients are 25mg BID, 50mg BID, 100 
mg BID and 150mg BID during titration; 150mg BID or 100mg BID for the 12-week 
study period; 150mg QD or 100mg QD for Week 1 of the taper; and 75mg QD, or 50mg 
QD for Week 2 of the taper. Each increase in dose will be maintained for two weeks 
before deciding to further increase or decrease based on tolerability. Patients who 
discontinue at any point of the study will have a two-week taper consisting of the current 
dose QD for one week followed by half the dose QD for another week. 
9.5 Describe the source records that will be used to collect data about 
subjects. (Attach all surveys, scripts, and data collection forms.) 
Response:  
 Ménière's Disease Patients-Oriented Severity Index (MDPOSI) 
 Tinnitus Handicap Inventory (THI) questionnaire 
 Clinical Global Impression-Severity & Change 
 Dizziness Handicap Inventory (DHI) questionnaire 
 AAO-HNS Ménière's disease self-assessment 
 Patient Health Questionnaire-9 (PHQ-9) 
 Generalized Anxiety Disorder 7-item scale (GAD-7) 
 Dosing Log 
 Meniere’s daily survey 
9.6 What data will be collected including long-term follow-up. 
Response:  
Please see 9.5, plus:  
 Results of physical and neurological exams 


 
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 Audiogram 
 Drug dosing 
 CBC, CMP blood tests 
 Lamotrigine blood levels (received from lab only after unblinding 
occurs) 
 Urine pregnancy test results and creatinine levels 
 Drug adherence information 
 Medications list 
 Medical history 
9.7 For HUD uses provide a description of the device, a summary of 
how you propose to use the device, including a description of any 
screening procedures, the HUD procedure, and any patient follow-
up visits, tests or procedures. 
Response: N/A 
 
10.0 Data and Specimen Banking 
10.1 If data or specimens will be banked for future use, describe where 
the data/specimens will be stored, how long they will be stored, how 
the data/specimens will be accessed, and who will have access to the 
data/specimens. 
Response: Blood samples will be collected, centrifuged and packed before 
being shipped for analysis in the Dent Neurologic Institute Infusion Clinic 
located within the Dent Neurologic Institute. Kaleida Health Laboratory is 
located only a four-minute drive away from Dent Neurologic, making the 
shipping and processing of blood samples simple and easy. All biologic 
products will be disposed of properly as biologically hazardous waste after 
the described testing is complete, so there will be no storage of materials 
for further use.  
 
10.2 List the data to be stored or associated with each specimen. 
Response: There will be no storage of materials for further use.  
 
10.3 Describe the procedures to release data or specimens, including: the 
process to request a release, approvals required for release, who 
can obtain data or specimens, and the data to be provided with 
specimens. 
Response: N/A 


 
Page 30 of 55 
Revised: August 3, 2018 
 
11.0 Data Management 
11.1 Describe the data analysis plan, including any statistical 
procedures. 
Response: The primary response will be the number of vertigo attacks as 
measured at baseline and at the end of the study period. The secondary 
responses will include the percentage of vertigo free patients, audiograms, 
symptom severity scales and quality of life scales (listed in the Approach 
section). The analysis set will include all subjects who are randomized and 
receive at least one dose of the study medication or the placebo. Integer or 
continuous variables will be presented by their mean and median and their 
SD and IQR. Categorical variables will be summarized using counts and 
percentages. Demographic and baseline characteristics of the enrolled 
subjects will be summarized through descriptive statistics for continuous 
variables and through frequencies for categorical variables. Demographic 
and baseline characteristics of the intervention and placebo groups will be 
compared to assess for comparability. Continuous variables will be 
compared using Wilcoxon rank-sum test and categorical variables will be 
compared through Fisher’s exact test. We will test for reduction in the 
Ménière's vertigo attacks from baseline through Wilcoxon’s sign rank test 
and will compare the reduction between the two treatment groups using 
Wilcoxon rank-sum test. The tests will be two-tailed and the significance 
level will be set to 0.05. Additionally, we will perform statistical modeling 
of the number of vertigo attacks longitudinally through generalized linear 
mixed effects model using Poisson or Negative Binomial distribution as 
appropriate. Data analysis will be conducted using SAS (SAS Institute 
Inc., Cary, NC, USA) and R (http://www.r-project.org/). All data analyses 
will be performed by Dr. Terry Mashtare of the SUNY UB Statistical 
Consultant Laboratory. 
 
11.2 Provide a power analysis. 
Response: According to our preliminary data, the mean number of vertigo 
attacks after 3 months of treatment with Lamotrigine was 4.91 (SD=7.24), 
and we expect the mean number of vertigo attacks in the placebo group to 
be approximately 13.  We assumed Negative Binomial distribution for the 
response, two-sided tests, level of significance 0.05 and considered 
various sample sizes, mean and variance of the number of attacks in the 
two groups. We calculated the associated power for comparison of the 
mean response between the two groups by utilizing Monte Carlo 
simulations and using Negative Binomial regression model with log link. 
Each simulation consisted of 1000 iterations and was conducted in R 
(http://www.r-project.org/). This analysis showed that a power above 80% 
can be obtained with a sample of 12 participants.  


 
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Revised: August 3, 2018 
Table: Associated Power for Comparison of the Mean Response between 
Treatment Groups Calculated with Monte Carlo Simulations and Negative 
Binomial Regression Model with Log Link 
Total N 
Mean Number 
of Attacks in 
Lamotrigine 
group at the end 
of the study 
Standard 
Deviation of 
the number of 
attacks 
Mean Number 
of Attacks in 
Placebo group 
at the end of 
the study 
α 
level 
Power 
12 
5 
7.24 
13 
0.05 
57.6 
12 
5 
6 
13 
0.05 
60.6 
12 
5 
4 
13 
0.05 
86.6 
12 
6 
6 
13 
0.05 
58.2 
12 
6 
4 
13 
0.05 
83.5 
14 
5 
7.24 
13 
0.05 
60.7 
14 
5 
6 
13 
0.05 
70.1 
14 
5 
4 
13 
0.05 
92.8 
20 
5 
7.24 
13 
0.05 
67.6 
20 
5 
4 
13 
0.05 
97.6 
20 
5 
7.24 
12 
0.05 
60.4 
20 
5 
4 
12 
0.05 
94.5 
20 
6 
7.24 
12 
0.05 
48.8 
20 
6 
4 
12 
0.05 
91.9 
34 
5 
7.24 
13 
0.05 
82.2 
34 
5 
6 
13 
0.05 
92.5 
Update on 6/4/2015:  
As of 6/4/2015 
# 
Expected N complete 
12 
Complete 
8 
Currently enrolled 
3 
Potentially eligible, not enrolled 
6 
Screened & eligible but declined participation in study 
1 
Screened and ineligible 
5 
Started study but dropped out 
2 
TOTAL  
25 
We engage in a multi-step process to reduce drop-outs, however, this is a 
very long study (6 months), and some drop-outs are to be expected. Thus 
far, we’ve had 2 participants drop out of the study and 8 have completed. 
Therefore, our dropout rate is 25%. To compensate for drop-outs, we 
request to increase our enrollment by 25%, rounded to the nearest whole 
number attain equal numbers in each group, for a total N of 16.  
 


 
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11.3 Describe the steps that will be taken secure the data (e.g., training, 
authorization of access, password protection, encryption, physical 
controls, certificates of confidentiality, and separation of identifiers 
and data) during storage, use, and transmission. 
Response:  Data will be password protected and participant identity will be coded 
to ensure confidentiality of information. The participant code number and identifying 
information will be kept in a locked office in the Dent Neurologic Institute and the 
UBSoPPS Research Pharmacy. At the conclusion of the study only the PI, Co-
Investigator, Statistician, or Research Assistant at Dent Neurologic Institute will have 
access to the data and participant information.  
11.4 Describe any procedures that will be used for quality control of 
collected data. 
Response: The data will be accurately entered twice in a password 
protected Excel Spreadsheet and checked automatically by an Excel 
program for accuracy. Data will only be viewed and analyzed by the 
research personnel. 
 
11.5 Describe how data and specimens will be handled study-wide: 
Response: Please see 11.3 and 11.4 
 
11.6 What information will be included in that data or associated with the 
specimens? 
 Response: Ménière's Disease Patients-Oriented Severity Index 
(MDPOSI) 
 Tinnitus Handicap Inventory (THI) questionnaire 
 Clinical Global Impression-Severity & Change 
 Dizziness Handicap Inventory (DHI) questionnaire 
 AAO-HNS Ménière's disease self-assessment 
 Patient Health Questionnaire-9 (PHQ-9) 
 Generalized Anxiety Disorder 7-item scale (GAD-7) 
 Dosing Log 
 Meniere’s daily survey 
 Pertinent results of neurological or physical exams 
 Drug dosing 
 CBC, CMP blood tests 
 Lamotrigine blood levels 


 
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Revised: August 3, 2018 
 De-identified demographics information 
11.7 Where and how data or specimens will be stored? 
Response: Please see 11.4. Password-protected files are located at Dent 
Neurologic Insititute, and study data are separate from personally 
identifiable information.  
 
11.8 How long the data or specimens will be stored? 
Response: Data will be stored for the duration of the study. Then, any 
documents or files that acted as personal identifiers for the study will be 
destroyed at the earliest opportunity. All documents will be placed in one 
of the HIPAA/Confidential Document bins which are located throughout 
the Dent Neurologic Institute. These secure bins are then emptied and the 
documents are destroyed by Cintas. Cintas is certified by the National 
Association for Information Destruction and also compliant with HIPAA 
and PCI standards. 
 
11.9 Who will have access to the data or specimens? 
Response: Only the PI, Co-Investigator, Statistician, or Research Assistant at Dent 
Neurologic Institute will have access to the data and participant information.   
11.10Who is responsible for receipt or transmission of the data or 
specimens? 
Response: Lizin Zhang, MD PhD 
 
11.11How data and specimens will be transported? 
Response: Data are stored in password-protected files, and will be 
transferred electronically to the statistician if needed. 
 
12.0 Provisions to Monitor the Data and Ensure the Safety of Subjects 
12.1 Describe the plan to periodically evaluate the data collected 
regarding both harms and benefits to determine whether subjects 
remain safe.   
Response: Please also see section 12.7 pertaining to this question. 
 
Adverse events (AE) will be reported to, evaluated and monitored by the PI, Dr. 
Zhang. Any severe adverse event (SAE) will be reported to both the PI and the HSIRB 
within 24 hours of the research personnel becoming aware of the event. The PI will also 
evaluate and monitor any severe adverse event. In the event that 20% of the participants 
should experience an SAE the study will be terminated. In addition to terminating the 
study due to the previously specified criteria, at any point if the PI should decide to 


 
Page 34 of 55 
Revised: August 3, 2018 
terminate the study for other reasons, such as no clear evidence of benefit from the study 
or arising safety concerns, all participants will receive a phone call informing them of the 
new findings and they will be asked to come in for an early termination visit. Their safety 
will be assessed, the remaining drug will be collected, and new AEs or SAEs will be 
recorded. Each participant will also be informed that they will be reimbursed for travel 
for each visit that they had completed thus far. Reports of adverse events will be 
continually monitored by co-investigators in order to monitor subject response, ensure 
subject safety, and determine the necessity for an early termination. 
After signing the informed consent, each participant will be assigned a participant 
number that will be used as coded identification for the entire study. The study’s research 
personnel will compile and analyze incoming data, which will be reviewed on a bi-
weekly basis to minimize the risks pertaining to the study. Dr. Zhang will be responsible 
for data and safety oversight for the study. Data will be entered by the research personnel 
and verified at 100%. Data will be password protected, participant identity will be coded 
and access to identifying information will be limited to ensure confidentiality. 
12.2 Describe what data are reviewed, including safety data, untoward 
events, and efficacy data. 
Response: Please see 12.1. Also, the ratio of side effects vs. improvements 
in symptoms will be specifically evaluated.  
 
12.3 Describe how the safety information will be collected (e.g., with case 
report forms, at study visits, by telephone calls with participants). 
Response: Safety information is collected at every visit; participants are 
asked about adverse events and complete questionnaires providing 
feedback on symptoms every visit throughout the duration of the study. 
Additionally, participants are encouraged to contact study personnel with 
any concerns, and are required to agree to report any degree of adverse 
health or psychological complaints regardless of whether or not they 
believe it is related to the study for the duration of the study including up 
to 28 days after their participation has concluded.  
 
12.4 Describe the frequency of data collection, including when safety 
data collection starts. 
Response: Data are collected at every visit; every 2 weeks for the first 10 
weeks, then every 4 weeks from weeks 10 through 22, then two more 
visits separated by 1 week each. As previously stated, safety data are 
collected at every visit.  
 
12.5 Describe who will review the data. 
Response: Only the PI, Co-Investigator, Statistician, or Research Assistant 
at Dent Neurologic Institute will have access to the data and participant 
information. 


 
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Revised: August 3, 2018 
 
12.6 Describe the frequency or periodicity of review of cumulative data. 
Response: Data will be reviewed bi-weekly. 
 
12.7 Describe the statistical tests for analyzing the safety data to 
determine whether harm is occurring. 
Response: I called IRB on 3/20/2015 to inquire about this and received 
verbal confirmation that the following procedures pertain to our study: 
This is a small (n=12), single location pilot study on the use of 
Lamotrigine to treat Meniere’s disease. The study employs procedures that 
do not provide sufficient information to conduct statistical testing for 
potential harm. The main reason for this is because the way in which harm 
is determined is through probing participants about any side effects, 
adverse events, or complains at every study visit, as well as providing 
them with a means of contacting us M-F 8am-4:30pm  if they experience 
any side effects between study visits. Additionally, the consent form 
outlines specific side effects to watch for that can be associated with the 
drug, including the course of medical action they should take if they 
develop the most common allergic reaction (rash). Finally, participants are 
explicitly asked at the time of consent whether or not they agree to report 
all adverse effects to the PI or research staff throughout the duration of the 
study, regardless of whether they believe it is related to the drug or not. 
All participants must agree to this in order to be in the study. While we 
have not encountered any adverse events or side effects, if we did, the PI 
would be informed and we would complete an adverse event report and 
submit to IRB immediately.    
 
12.8 Describe any conditions that trigger an immediate suspension of the 
research. 
Response: The research will be immediately suspended if the study drug is 
found to be unsafe due to a drug recall or similar event, or if the safety, 
security, or functionality of the facilities at which the study takes place 
become compromised in any way.  
 
13.0 Withdrawal of Subjects 
13.1 Describe anticipated circumstances under which subjects will be 
withdrawn from the research without their consent. 
Response: Participants may be withdrawn early without their consent if 
they develop a rash at any point during the study and Dr. Zhang decides 
that it is caused by the treatment, if they develop a serious adverse event 


 
Page 36 of 55 
Revised: August 3, 2018 
other than rash that requires discontinuing involvement in the study, if at 
any visit they are found to not be following dosing instructions. 
13.2 Describe any procedures for orderly termination. 
Response: For rash, participants are asked to immediately stop the 
medication, take an antihistamine, like Benadryl, return for an early 
termination visit and will be removed early from the study. If a different 
adverse event is experienced other than a rash, the participant will be 
asked to return for a visit (for which they are paid as per study 
compensation guidelines) and begin a two-week decrease of the current 
study drug dose. This decrease is the current study drug dose once a day 
for one week followed by half of the study drug dose once a week for 
another week. If a participant is found to not be following dosing 
instructions at any visit, Dr. Zhang will review the situation and determine 
whether they need to be removed from the study, and if so, the participant 
will follow the same taper schedule and early termination visit required for 
those withdrawing due to adverse events other than rash. 
 
13.3 Describe procedures that will be followed when subjects withdraw 
from the research, including partial withdrawal from procedures 
with continued data collection. 
Response: Participants are informed in the consent form that if they 
choose to withdraw from the study, there will be no further information 
collected from them or about them. There isn’t an instance of “partial 
withdrawal” in this study. 
 
14.0 Risks to Subjects 
14.1 List the reasonably foreseeable risks, discomforts, hazards, or 
inconveniences to the subjects related the subjects’ participation in 
the research. Include as may be useful for the IRB’s consideration, a 
description of the probability, magnitude, duration, and reversibility 
of the risks. Consider physical, psychological, social, legal, and 
economic risks. 
There will be blood draws that are required for this study. Possible side effects 
from blood drawing include anxiety, faintness, vein inflammation, pain, bruising, or 
bleeding at the site of puncture. There is also a slight possibility of infection. Experienced 
medical personnel will be responsible for blood draws to minimize these risks. 
There will be an electrocardiogram test. Skin irritation is rare but could occur 
during this test from the electrodes or gel that is used. 
Participants may feel discomfort regarding questions asked in study 
questionnaires. 
Participants will also be taking medications during the length of the study. All 
medications are FDA approved for use in patients. While lamotrigine is approved for use 


 
Page 37 of 55 
Revised: August 3, 2018 
in people who have a seizure disorder, the indication investigated during this study has 
not been approved. 
Those assigned to the Lamotrigine treatment are at risk for rash, including 
Stevens-Johnson syndrome and toxic epidermal necrolysis, aseptic meningitis, hepatic 
and renal failure, DIC, arthritis, diplopia, sedation, dizziness, ataxia, headache, nausea 
and vomiting. Psychosis and depression are associated with epilepsy and occur in open 
label studies with all new AED’s, but it is difficult to ascertain whether these 
relationships are causal. Incidence of rash was approximately 0.8% in adults receiving it 
as initial monotherapy for epilepsy and 0.08% in adults receiving it as initial 
monotherapy for bipolar and other mood disorders. This risk increases with concomitant 
valproate/divalproex use and reduces with slow titration. In order to prevent a rash, the 
daily dosage of lamotrigine will be slowly titrated by 50mg every two weeks. 
Valproate/divalproex, an anti-epileptic medication, is also prohibited from the study. If a 
study related rash does occur, the participant will be instructed to immediately 
discontinue the medication and to take an antihistamine drug. If the rash occurs with 
other serious symptoms associated with Stevens-Johnson syndrome and/or toxic 
epidermal necrolysis, such as fever, fatigue, sore throat, conjunctivitis or sores and/or 
ulcers in the mouth, lips or genital areas, participants are instructed to go to the 
emergency room. Hepatic and renal failure will be monitored with CBC andCMP blood 
analysis and a urine sample will be obtained for 24 hour creatinine clearance analysis as a 
screening, after titration and after the maintained dose period. Beginning with Visit 2, the 
C-SSRS will be conducted by a certified study staff to determine if there are any positive 
responses since last visit and whether it is safe for the participant to continue to 
participate in the trial. Any suicidal risk should be managed appropriately by the PI, who 
is a qualified mental health practitioner (MHP). 
During the washout period and with placebo assignment, MD symptoms may 
become worse, stay the same, or improve. However, all participants are allowed to 
mitigate their symptoms with their choice of an abortive medication throughout the study. 
Common side effects from abortive medications include drowsiness, blurred vision, dry 
mouth, constipation or dizziness. Common serious side effects include an allergic 
reaction involving rash, difficulty breathing, and/or swelling of the face, lips, tongue or 
throat. Participants should read their specific abortive medication’s package insert for a 
full list of side effects. 
Hearing loss is another symptom of Ménière's disease currently without a 
treatment. During the study, participants’ MD may worsen or stay the same and 
participants may experience fluctuating hearing loss or develop permanent hearing loss in 
the affected ear as a natural progression of the disorder. 
All participants will be counseled on the definition of adverse events so that they 
may monitor for them. Additionally, participants will be asked for the presence of any 
adverse/serious events (specifically including those side effects associated with 
lamotrigine) at each visit. Dr. Zhang, as the PI, is directly responsible for assessing and 
monitoring all possible side effects and/or adverse events 
Social risk is minimal; all measures will be taken to keep personal identifiable 
data confidential. Economical risk is small, but participants may have to take time off of 
work or find transportation in order to get to a required visit. Participants will be 
reimbursed for their travel up to 11 completed visits. 


 
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14.2 If applicable, indicate which procedures may have risks to the 
subjects that are currently unforeseeable. 
N/A 
14.3 If applicable, indicate which procedures may have risks to an 
embryo or fetus should the subject be or become pregnant. 
Response: Lamotrigine is a Category C medication, meaning that animal 
reproduction studies have shown an adverse effect on the fetus and there are no adequate 
and well-controlled studies in humans. To avoid the potential risk to the fetus, pregnant 
and breastfeeding women are excluded from the study and all female participants must be 
willing to avoid pregnancy during the entirety of the study. 
14.4 If applicable, describe risks to others who are not subjects. 
Response: N/A 
 
15.0 Potential Benefits to Subjects 
15.1 Describe the potential benefits that individual subjects may 
experience from taking part in the research. Include as may be 
useful for the IRB’s consideration, the probability, magnitude, and 
duration of the potential benefits. 
Participants receiving the study drug may see improvement in their MD 
symptoms and quality of life. It is possible, however, that participants will receive no 
direct health benefit from being in this study. Others may benefit from the information 
learned. The results of this study could support a minimally invasive, tolerable and 
efficacious treatment for those who suffer from Ménière's disease. Risks to the current 
study’s participants are reasonable in relation to the importance of the knowledge gained. 
Many of the current alternative treatments for Ménière's disease are much higher in risk 
than the treatment proposed by this study. The improvement of symptoms and quality of 
life could also be greater than available treatments. Although this is just a pilot-of-proof 
study, the evidence could argue for larger clinical studies in the future that then support 
FDA review of the new indication and, eventually, approval of the new indication. 
Subsequently, the efficient and low-risk medication would be made available to MD 
patients at affordable costs shared with insurance companies. Additionally, the results of 
the study would support research into a new etiology theory of Ménière's disease. 
15.2 Indicate if there is no direct benefit. Do not include benefits to 
society or others. 
Response: N/A 
 
16.0 Vulnerable Populations 
16.1 If the research involves individuals who are vulnerable to coercion 
or undue influence, describe additional safeguards included to 
protect their rights and welfare. 


 
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 
If the research involves pregnant women, review 
“CHECKLIST: Pregnant Women (HRP-412)” to ensure that 
you have provided sufficient information. 
 
If the research involves neonates of uncertain viability or non-
viable neonates, review “CHECKLIST: Neonates (HRP-413)” 
or “HRP-414 – CHECKLIST: Neonates of Uncertain Viability 
(HRP-414)” to ensure that you have provided sufficient 
information. 
 
If the research involves prisoners, review “CHECKLIST: 
Prisoners (HRP-415)” to ensure that you have provided 
sufficient information. 
 
If the research involves persons who have not attained the 
legal age for consent to treatments or procedures involved in 
the research (“children”), review the “CHECKLIST: Children 
(HRP-416)” to ensure that you have provided sufficient 
information. 
 
If the research involves cognitively impaired adults, review 
“CHECKLIST: Cognitively Impaired Adults (HRP-417)” to 
ensure that you have provided sufficient information. 
 
Consider if other specifically targeted populations such as 
students, employees of a specific firm or 
educationally/economically disadvantaged persons are 
vulnerable to coercion or undue influence.  The checklists 
listed above for other populations should be used as a guide to 
ensure that you have provided sufficient information.  
Response: N/A 
 
17.0 Community-Based Participatory Research 
17.1 Describe involvement of the community in the design and conduct of 
the research. 
Response: N/A 
 
Note: “Community-based Participatory Research” is a collaborative 
approach to research that equitably involves all partners in the 
research process and recognizes the unique strengths that each 
brings. Community-based Participatory Research begins with a 
research topic of importance to the community, has the aim of 
combining knowledge with action and achieving social change to 
improve health outcomes and eliminate health disparities. 
18.0 Sharing of Results with Subjects 
18.1 Describe whether or not results (study results or individual subject 
results, such as results of investigational diagnostic tests, genetic 


 
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tests, or incidental findings) will be shared with subjects or others 
(e.g., the subject’s primary care physicians) and if so, describe how 
it will be shared. 
Response:  
Results of screening tests that are relevant to the patient’s routine medical 
care will be shared with the patient as they are conducted. All testing that 
is part of routine medical care (prior to randomization), and not specific to 
study-related testing, is automatically copied to the patient’s primary 
doctor, unless the patient requests additional or alternative CCs. No study-
specific testing or outcomes are communicated to the patient, their 
primary doctor, or anybody who is not on the protocol. The only exception 
to this is in the extremely unlikely event that study-specific tests reveal a 
risk to the participants’ health, such as abnormal blood or urine test 
results, in which case the participant will be informed immediately. 
The participant will be informed in a timely manner by the investigator or 
research personnel when new information becomes available that may be 
relevant to the participant's willingness to continue participation in the 
trial. This may be done in writing by letter, revised ICF or in any manner 
approved by the reviewing IRB. The communication of this information 
should be documented in the medical record along with a copy of the 
information provided. 
 
19.0 Setting 
19.1 Describe the sites or locations where your research team will 
conduct the research.  
All site visits will be conducted at the Dent Neurologic Institute. The Dizziness 
and Balance Center (DBC) is well outfitted with the necessary audio testing equipment. 
This equipment is regularly maintained for clinical use. The space within the DBC will 
provide private exam rooms and check out areas for informed consent, questionnaires and 
other study procedures. The Dizziness and Balance Center will also provide access to a 
patient population for recruitment purposes. Blood samples will be collected, centrifuged 
and packed before being shipped for analysis in the Dent Neurologic Institute Infusion 
Clinic located within the Dent Neurologic Institute. In addition to the study space and 
equipment available at Dent, the organization serves as a resource for research design and 
implementation. Research staff has insured that all study personnel have undergone the 
appropriate training for human subjects research. The Dent Neuroscience Research 
Center, also located within the same building, is composed of experts with years of 
research experience that can guide and assist the study team. Other personnel at Dent 
include experienced pharmacists, audiologists and psychiatrists, all of whom the PI has 
built consultation relationships with over several years. Lastly, the Dent is funding one of 
the staff members to work on the execution of the study full-time. 
Kaleida Health Laboratory is located only a four-minute drive away from Dent 
Neurologic, making the shipping and processing of blood samples simple and easy. The 


 
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clinical laboratory leads Western New York in quick and accurate testing, performing 
more than 4 million tests each year. Kaleida Health’s experienced laboratory scientists, 
couriers and computer system will ensure that the blood analysis for the study is done in 
an exceptional manner. Although a contract will only be created once the study receives 
IRB and funding approval, the Dent Neurologic Institute has successfully worked with 
Kaleida Health in the past. 
UBSoPPS Research Pharmacy is a licensed pharmacy that provides the expertise 
of a licensed pharmacist to assist clinicians in conducting clinical studies. The Pharmacy 
allows the investigating clinician to conduct blinded studies involving placebos and 
encapsulates drug preparations in various design patterns. The facility can compound 
specific drug strengths that may not be available commercially, thereby giving the 
clinician more control over the strengths of the drug they wish to investigate. All research 
is conducted in an ethical manner with its focus on protecting the human subjects and 
complying with all HIPAA regulations. Budget planning is provided and assistance in 
statistical design is available. 
The UB Statistical Consulting Laboratory provides doctorate level expertise in 
biostatistics and clinical research. This collaboration will strengthen the design of the 
study and the subsequent conclusions made from the study’s results. 
19.2 Identify where your research team will identify and recruit potential 
subjects. 
Response: The study hopes to recruit from the patient population at the 
Dent Dizziness and Balance Center and Dr. Diaz-Ordaz’s patients at Buffalo 
ENT Specialists. In doing so, the PI and staff will have to access medical 
charts/records to verify eligibility and diagnosis of Meniere's disease prior to 
obtaining consent of potential participants. The study needs information from 
preexisting medical records to identify a candidate pool based on specific 
criteria applied to those records. Obtaining a signed authorization prior to 
recruitment is not practicable. If an authorization form was given to every 
patient seen in the Dizziness and Balance Center and every one of Dr. Diaz-
Ordaz’s patients, the time needed for recruitment would be dramatically 
increased and potential eligible participants could be overlooked due to their 
next appointment being scheduled for months later. Additionally, the 
information we are looking to capture was not collected for research purposes. 
This information already exists within patients’ charts and patients have already 
consented to Dr. Zhang and the staff of the Dizziness and Balance Center or Dr. 
Diaz-Ordaz to have access to this information as part of their standard care. 
Once eligible potential participants are identified they will be sent a letter, which 
gives an overview of the study and contact information if they are interested in 
enrolling. 
A referral letter will also be sent to area physicians and ENT specialists 
informing them of the study design and inclusion/exclusion criteria. Those 
receiving the letter are encouraged to notify eligible patients of the opportunity 
to participate and how to contact the study staff if they are interested. 
If enrollment numbers are not met through this method, recruitment 
strategies will include an advertisement in the once monthly issue of an 


 
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After 50 free newspaper, 32 sixty-second radio advertisements and 50 
sixty-second streaming commercials for two weeks. The study has 
requested funds for this purpose, but is hoping to exhaust all other 
potential participants within the Dizziness and Balance Center and Dr. 
Diaz-Ordaz’s patients first. Therefore, the additional newspaper and 
radio advertisement recruitment materials will be submitted as an 
amendment at a later date. 
 
19.3 Identify where research procedures will be performed. 
Response: Research Procedures with participants will be performed at 
Dent Neurologic Institute, within the Dizziness and Balance Center 
(DBC). 
 
19.4 Describe the composition and involvement of any community 
advisory board. 
Response: N/A 
 
19.5 For research conducted outside of the organization and its affiliates 
describe: 
 Site-specific regulations or customs affecting the research for 
research outside the organization. 
 Local scientific and ethical review structure outside the 
organization. 
Response: Please see section 19.0 for site specific 
procedures/policies/regulations for the pharmacy, laboratory, and 
statistical computing sites. 
 
20.0 Resources Available 
20.1 Describe the qualifications (e.g., training, experience, oversight) of 
you and your staff as required to perform their role. When 
applicable describe their knowledge of the local study sites, culture, 
and society. Provide enough information to convince the IRB that 
you have qualified staff for the proposed research. Note- If you 
specify a person by name, a change to that person will require prior 
approval by the IRB. If you specify people by role (e.g., coordinator, 
research assistant, co-investigator, or pharmacist), a change to that 
person will not usually require prior approval by the IRB, provided 
that person meets the qualifications described to fulfill their roles. 
Response:  


 
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Study coordinator: College degree or applicable technical training, 
Mathematics/statistics skills, prior research experience, proficiency in 
Microsoft Office, CITI and HIPAA training, strong interpersonal and 
communication skills, excellent organizational skills, problem-solving 
skills, high level of communication through written form.  
Co-PIs: College degree or applicable technical training, proficiency in 
Microsoft Office, CITI and HIPAA training, strong interpersonal and 
communication skills, excellent organizational skills. 
Other research staff: Excellent oral and written communication skills, 
including listening skills for participant concerns and communications, 
some basic knowledge of the research protocol and related literature, CITI 
and HIPAA training 
 
Describe other resources available to conduct the research: For example, 
as appropriate: 
20.2 Justify the feasibility of recruiting the required number of suitable 
subjects within the agreed recruitment period. For example, how 
many potential subjects do you have access to? What percentage of 
those potential subjects do you need to recruit? 
Response: While Meniere’s Disease affects approximately 20-200 out of 
every 100,000 people, at this specialized institute, Dr. Zhang sees 
approximately 70-100 Meniere’s Disease patients per year. Therefore, we 
believe it is reasonable to obtain the 12 participants (or approximately 5-
10% of these patients) who meet eligibility criteria over the next 1-2 years. 
 
20.3 Describe the time that you will devote to conducting and completing 
the research. 
Response: The study coordinator will work on the study full time at 40 
hours per week. The remaining research staff will spend, on average, 
approximately 3-5 hours per week each on the research study. The 
pharmacy has allocated 21 pharmacist hours, and the statistician has 
allocated 20 towards this pilot study. 
 
20.4 Describe your facilities. 
Response: The Dizziness and Balance Center (DBC) is well outfitted with 
the necessary audio testing equipment. This equipment is regularly 
maintained for clinical use. The space within the DBC will provide private 
exam rooms and check out areas for informed consent, questionnaires and 
other study procedures. The Dizziness and Balance Center will also 
provide access to a patient population for recruitment purposes. Blood 
samples will be collected, centrifuged and packed before being shipped for 


 
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analysis in the Dent Neurologic Institute Infusion Clinic located within the 
Dent Neurologic Institute. In addition to the study space and equipment 
available at Dent, the organization serves as a resource for research design 
and implementation. Research staff has insured that all study personnel 
have undergone the appropriate training for human subjects research. The 
Dent Neuroscience Research Center, also located within the same 
building, is composed of experts with years of research experience that 
can guide and assist the study team. Other personnel at Dent include 
experienced pharmacists, audiologists and psychiatrists, all of whom the 
PI has built consultation relationships with over several years. 
 
20.5 Describe the availability of medical or psychological resources that 
subjects might need as a result of an anticipated consequences of the 
human research. 
Response: Routinely, the Buffalo General Hospital, Erie County Medical 
Center, Millard Fillmore Hospital and/or the University at Buffalo, State 
University of New York, Dent Neurologic Institute, their agents 
employees do not compensate for or provide free medical care for human 
subjects/participants in the event that any injury results from participation 
in a human research project.  In the unlikely event that a participant 
become ill, injured, or requires psychological services as a direct result of 
participating in this study, they may receive the appropriate medical care 
at the location of their choosing.  
20.6 Describe your process to ensure that all persons assisting with the 
research are adequately informed about the protocol, the research 
procedures, and their duties and functions. 
Response: All study personnel undergo CITI, HIPAA, and other HSIRB-
required training. Additionally, study personnel are required to read 
through the protocol and develop a good understanding of the study 
procedures. Additionally, study personnel work together in a collaborative 
environment to maintain awareness of the study procedures and any 
learning opportunities that may arise. Additionally, members of the 
research team meet weekly to discuss study progress, and clear roles as 
well as individual projects are defined in these meetings. 
21.0 Prior Approvals 
21.1 Describe any approvals that will be obtained prior to commencing 
the research. (E.g., school, external site. funding agency, laboratory, 
radiation safety, or biosafety approval.) 
Response: Approval from our funding body, Dent Family Foundation, was 
required. 
 
22.0 Recruitment Methods 


 
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22.1 Describe when, where, and how potential subjects will be recruited. 
Response: Recruitment strategies include an advertisement in the once monthly issue of 
an After 50 free newspaper. If needed, the study will also be investing in 32 sixty-second 
radio advertisements and 50 sixty-second streaming commercials for two weeks. 
Additionally, the study hopes to recruit from the current patient population at the Dent 
Dizziness and Balance Center. However, we will avoid infringing on the privacy rights of 
both former and current patients by only allowing the principal investigator, who is the 
clinic doctor, and other study staff involved with the Dent Dizziness and Balance Center 
to reach out to patients. We believe this is ethical because Dr. Zhang and the clinic staff 
already have access to any potential participants’ medical history and it would prevent 
other study staff from gaining access to medical information before the start of the study 
and without the participant’s direct consent. 
22.2 Describe the source of subjects. 
Response: Individuals who read After 50 or are in the WNY area, already 
within the existing database, or in any way comes into contact with Dent 
or our advertisements, has Meniere’s Disease and is eligible and wants to 
participate. 
22.3 Describe the methods that will be used to identify potential subjects. 
Response: Potential subjects will be identified first by Dr. Zhang if they 
meet criteria for a Meniere’s disease diagnosis and meet basic eligibility 
criteria. Participants who indicate interest in participating in the study will 
then review the consent form and additional eligibility criteria with either 
the study coordinator or another member of the research team. The 
participant is given the option to take the form home to think about it or 
sign it at that time if they are certain they want to participate.   
 
22.4 Describe materials that will be used to recruit subjects. (Attach 
copies of these documents with the application. For advertisements, 
attach the final copy of printed advertisements. When advertisements 
are taped for broadcast, attach the final audio/video tape. You may 
submit the wording of the advertisement prior to taping to preclude 
re-taping because of inappropriate wording, provided the IRB 
reviews the final audio/video tape.) 
Response: Please see 22.1 
 
22.5 Describe the amount and timing of any payments to subjects. 
Response: Participants will be reimbursed $35 per visit, up to $315 total 
(6-8 visits for placebo & Lamotrigine groups, respectively, plus 1 extra 
visit if needed for a maximum of 9 visits). Payment will be made by check 
and mailed to the participant’s address as written on their signed 
Declaration of Participation form. Should the participant choose to drop 
out of the study or the study is terminated, a check will be mailed after 


 
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completion of the early termination visit or after completion of the most 
recent visit prior to dropping out. 
 
23.0 Local Number of Subjects 
23.1 Indicate the total number of subjects to be accrued locally. 
Response: 12 (all) 
 
23.2 If applicable, distinguish between the number of subjects who are 
expected to be enrolled and screened, and the number of subjects 
needed to complete the research procedures (i.e., numbers of 
subjects excluding screen failures.) 
Response: 12 subjects are needed to complete research procedures. 
Because of the long duration of the study, and based on previous 
experience with patient follow-up, we anticipate approximately 2-5 
dropouts. Additionally, we anticipate approximately 20 people will be 
consented but not enroll in the study, either due to success with other types 
of treatment (e.g., water pills) employed by Dr. Zhang or another provider, 
changing their minds or seeking treatment elsewhere, or for other 
unknown reasons. 
 
24.0 Confidentiality 
Describe the local procedures for maintenance of confidentiality. 
24.1 Where and how data or specimens will be stored locally? 
Response:  Data will be password protected and participant identity will be coded to 
ensure confidentiality of information. The participant code number and identifying 
information will be kept in a locked filing cabinet in the Dent Neurologic Institute and in 
a locked office at the UBSoPPS Research Pharmacy. Study data are separate from 
personally identifiable information. Any documents or files that acted as personal 
identifiers for the study will be destroyed at the earliest opportunity. All documents will 
be placed in one of the HIPAA/Confidential Document bins which are located throughout 
the Dent Neurologic Institute. These secure bins are then emptied and the documents are 
destroyed by Cintas. Cintas is certified by the National Association for Information 
Destruction and also compliant with HIPAA and PCI standards. 
24.2 How long the data or specimens will be stored locally? 
Response: Data will be stored for the duration of the study. Then, any 
documents or files that acted as personal identifiers for the study will be 
destroyed at the earliest opportunity. All documents will be placed in one 
of the HIPAA/Confidential Document 
24.3 Who will have access to the data or specimens locally? 


 
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Response: Only the PI, Co-Investigator, Statistician, or Research Assistant 
at Dent Neurologic Institute will have access to the data and participant 
information. 
24.4 Who is responsible for receipt or transmission of the data or 
specimens locally? 
Response: Dr. Zhang and the study coordinator share this responsibility. 
 
24.5 How data and specimens will be transported locally? 
Response: Dr. Zhang, the study coordinator and the research staff team 
share this responsibility. 
 
25.0 Provisions to Protect the Privacy Interests of Subjects 
25.1 Describe the steps that will be taken to protect subjects’ privacy 
interests. “Privacy interest” refers to a person’s desire to place 
limits on whom they interact or whom they provide personal 
information. 
Response: Only the PI, Co-Investigator, Statistician, or Research Assistant at 
Dent Neurologic Institute will have access to study-related data and participant 
information. The participant code number and identifying information will be kept in a 
locked office in the Dent Neurologic Institute and the UBSoPPS Research Pharmacy. At 
the conclusion of the study only the PI, Co-Investigator, or Research Assistant at Dent 
Neurologic Institute will have access to the data and participant information. All 
personnel have completed CITI human research training, various clinical trial trainings 
and have an educational background in human subjects research and HIPAA regulations. 
Any documents or files that acted as personal identifiers for the study will be destroyed at 
the earliest opportunity. All documents will be placed in one of the HIPAA/Confidential 
Document bins which are located throughout the Dent Neurologic Institute. These secure 
bins are then emptied and the documents are destroyed by Cintas. Cintas is certified by 
the National Association for Information Destruction and also compliant with HIPAA 
and PCI standards. 
25.2 Describe what steps you will take to make the subjects feel at ease 
with the research situation in terms of the questions being asked and 
the procedures being performed. “At ease” does not refer to 
physical discomfort, but the sense of intrusiveness a subject might 
experience in response to questions, examinations, and procedures. 
Response:  
Participants are greeted in a friendly manner, and maximal effort is made 
to build a courteous, respectful, and pleasant rapport with all study 
participants. At the consent visit, participants are encouraged to ask any 
questions as the research staff member reviews the form with them. 


 
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Participants are explicitly told they are welcome to take the form home to 
think about and discuss with family members.  
To reduce pressure on participants at each visit, they are given time alone 
to complete the questionnaires. Additionally, appointments are scheduled 
at the participants’ convenience to the best of the study personnel’s 
availability.  
When the urine container is given to participants for visits 1, 5, and 8, it is 
placed in a large bag for privacy as they leave the building. 
 
25.3 Indicate how the research team is permitted to access any sources of 
information about the subjects. 
Response: Please see 25.1 
 
26.0 Compensation for Research-Related Injury 
26.1 If the research involves more than Minimal Risk to subjects, describe 
the available compensation in the event of research related injury. 
Response: No available compensation (please see 26.2) 
 
26.2 Provide a copy of contract language, if any, relevant to 
compensation for research-related injury. 
Response:  
REIMBURSEMENT FOR MEDICAL TREATMENT  
Routinely, the Buffalo General Hospital, Erie County Medical Center, Millard Fillmore 
Hospital and/or the University at Buffalo, State University of New York, its agents, or its 
employees do not compensate for or provide free medical care for human 
subjects/participants in the event that any injury results from participation in a human 
research project.  In the unlikely event that you become ill or injured as a direct result of 
participating in this study, you may receive medical care, but it will not be free of charge 
even if the injury is a direct result of your participation. 
27.0 Economic Burden to Subjects 
27.1 Describe any costs that subjects may be responsible for because of 
participation in the research. 
Response:  Participants may take time off work to attend the 
appointments, which last approximately 20-60 minutes. In the unlikely 
event of a medical or psychological complication from the research, 
participants will seek treatment from a provider of their choice, which is 
not paid for by the PI or study funds. Participants are paid $35 per visit to 
cover travel (and related) costs.  


 
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28.0 Consent Process 
28.1 Indicate whether you will be obtaining consent 
Response: Written consent will be obtained for all participants. The 
consent form is enclosed in this package submission. 
 
28.2 Describe where  the consent process take place 
Response: Consents will be obtained from all individuals in private exam rooms 
or private check-out areas. The exam room and the check-out desk are designed as 
a private space to ensure confidentiality during day-to-day clinical practice and 
will provide the same confidentiality and privacy for consenting participants. 
The PI or designee will fully inform the participant of all pertinent aspects of the 
study including the written information as approved by the IRB. The process includes: 
giving the participant adequate information concerning the study; providing ample time 
and opportunity for the participant to inquire about the details and to decide whether or 
not to participate; responding to participant's questions to the satisfaction of the 
participant. Participants also have the choice to sign the form at the initial visit or to take 
the form home to review independently or with their primary physician and return to sign 
it. The Principal Investigator is not the subjects’ primary care physician. It will be 
stressed that a patient’s participation is completely voluntary, that they may withdraw at 
any time and that their decision to participate or not to participate will not affect their 
standard of care at the Dent Dizziness and Balance Center or Buffalo ENT Specialists. 
Before signatures are obtained, the staff member obtaining consent will confirm that the 
patient has no further questions and understands fully. Each person’s signature and date 
must be in his / her own handwriting; no other person may fill in missing dates or times. 
All Informed consent signatures must be obtained on the same date, beginning with the 
participant’s signature. The investigator or designee will file the original signed consent 
form with the study records and a copy of the signed consent form will be provided to the 
participant at the time of consent. Any alternative treatments will be discussed before the 
participant signs the informed consent. The participant will be informed in a timely 
manner by the investigator or research personnel when new information becomes 
available that may be relevant to the participant's willingness to continue participation in 
the trial. This may be done in writing by letter, revised ICF or in any manner approved by 
the reviewing IRB. The communication of this information should be documented in the 
medical record along with a copy of the information provided. If the written consent form 
is revised during the course of a participant's duration in the study, then the participant 
shall be re consented by the principal investigator or designee with the revised IRB 
approved consent form. The investigator or designee will file the newly obtained original 
signed consent form with the participant's study record. 
28.3 Describe any waiting period available between informing the 
prospective subject and obtaining the consent. 


 
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Response: Participants are allowed to take as much or as little time as they 
would like to decide if they want to participate in the study. Subjects may 
decide to sign the consent form immediately after reviewing it with the 
research staff member or they may take it home with them to think about 
it. Participants decide how long they would like to wait. 
 
28.4 Describe any process to ensure ongoing consent. 
Response: Only a current IRB-approved and stamped form may be used to 
consent a research participant. If/when the consent document is revised or 
updated, a the most recent copy of the consent form is provided and 
explained to all current participants.  
 
28.5 Describe whether you will be following “SOP: Informed Consent 
Process for Research (HRP-090).” If not, describe: 
 
The role of the individuals listed in the application as being 
involved in the consent process. 
 
The time that will be devoted to the consent discussion. 
 
Steps that will be taken to minimize the possibility of coercion 
or undue influence. 
 
Steps that will be taken to ensure the subjects’ understanding. 
Response: The consent form enclosed in this package adheres to 
guidelines in the HRP090 form. The research staff member invites and 
encourages questions from the participant, explicitly gives them the option 
to decline participation, sign the consent, or take it home to think about it 
with friends and family. Potential participants are given the phone number 
of the study coordinator and Dr. Zhang to discuss any further questions 
they might have after leaving. Additionally, potential participants are 
given as much time as they need to read through the consent form either in 
a private exam room or at home. 
 
Non-English Speaking Subjects  
28.6 Indicate what language(s) other than English are likely to be 
spoken/understood by your prospective study population or their 
legally authorized representatives. 
Response: N/A 
 
28.7 If subjects who do not speak English will be enrolled, describe the 
process to ensure that the oral and written information provided to 
those subjects will be in that language. Indicate the language that 
will be used by those obtaining consent. 


 
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Response: N/A 
 
Waiver or Alteration of Consent Process (consent will not be obtained, 
required information will not be disclosed, or the research involves 
deception) 
28.8 Review the “CHECKLIST: Waiver or Alteration of Consent Process 
(HRP-410)” to ensure you have provided sufficient information for 
the IRB to make these determinations. Provide any additional 
information necessary here: 
Response: N/A 
 
28.9 If the research involves a waiver the consent process for planned 
emergency research, please review the “CHECKLIST: Waiver of 
Consent for Emergency Research (HRP-419)” to ensure you have 
provided sufficient information for the IRB to make these 
determinations. Provide any additional information necessary here: 
Response: N/A 
 
Subjects who are not yet adults (infants, children, teenagers) 
28.10Describe the criteria that will be used to determine whether a 
prospective subject has not attained the legal age for consent to 
treatments or procedures involved in the research under the 
applicable law of the jurisdiction in which the research will be 
conducted. (E.g., individuals under the age of 18 years.) For 
research conducted in NY state, review “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013)” to be aware 
of which individuals in the state meet the definition of “children.” 
Response: N/A 
 
28.11For research conducted outside of NY state, provide information that 
describes which persons have not attained the legal age for consent 
to treatments or procedures involved the research, under the 
applicable law of the jurisdiction in which research will be 
conducted. One method of obtaining this information is to have a 
legal counsel or authority review your protocol along the definition 
of “children” in “SOP: Legally Authorized Representatives, 
Children, and Guardians (HRP-013).” 
Response: N/A 
 
28.12Describe whether parental permission will be obtained from: 


 
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 
Both parents unless one parent is deceased, unknown, 
incompetent, or not reasonably available, or when only one 
parent has legal responsibility for the care and custody of the 
child. 
 
One parent even if the other parent is alive, known, competent, 
reasonably available, and shares legal responsibility for the 
care and custody of the child. 
Response: N/A 
 
28.13Describe whether permission will be obtained from individuals other 
than parents, and if so, who will be allowed to provide permission. 
Describe the process used to determine these individuals’ authority 
to consent to each child’s general medical care. 
Response: N/A 
 
28.14Indicate whether assent will be obtained from all, some, or none of 
the children. If assent will be obtained from some children, indicate 
which children will be required to assent. 
Response: N/A 
 
28.15When assent of children is obtained describe whether and how it will 
be documented. 
Response: N/A 
 
Cognitively Impaired Adults 
28.16Describe the process to determine whether an individual is capable 
of consent. The IRB sometimes allows the person obtaining assent to 
document assent on the consent document and does not 
automatically require assent documents to be used. 
Response: As per phone conversation with Alyssa at  IRB 4/10/2015: We 
are unsure why this question was flagged for editing. This study does not 
recruit or enroll cognitively impaired adults and Meniere’s Disease is not a 
cognitively degenerative disease. It’s an inner ear disorder that can cause 
vertigo, tinnitus/hearing loss, nausea and headaches. 
 
Adults Unable to Consent 


 
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When a person is not capable of consent due to cognitive impairment, a 
legally authorized representative should be used to provide consent and, 
where possible, assent of the individual should also be solicited. 
28.17List the individuals from whom permission will be obtained in order 
of priority. (e.g., durable power of attorney for health care, court 
appointed guardian for health care decisions, spouse, and adult 
child.)  For research conducted in NY state, review “SOP: Legally 
Authorized Representatives, Children, and Guardians (HRP-013)” 
to be aware of which individuals in the state meet the definition of 
“legally authorized representative.”  The list in the consent template 
signature section corresponds to the priority list for NYS.   
Response: N/A 
 
28.18For research conducted outside of NY state, provide information that 
describes which individuals are authorized under applicable law to 
consent on behalf of a prospective subject to their participation in 
the procedure(s) involved in this research. One method of obtaining 
this information is to have a legal counsel or authority review your 
protocol along the definition of “legally authorized representative” 
in “SOP: Legally Authorized Representatives, Children, and 
Guardians (HRP-013).” 
Response: N/A 
 
28.19Describe the process for assent of the subjects. Indicate whether: 
 
Assent will be required of all, some, or none of the subjects. If 
some, indicated, which subjects will be required to assent and 
which will not. 
 
If assent will not be obtained from some or all subjects, an 
explanation of why not. 
 
Describe whether assent of the subjects will be documented 
and the process to document assent. The IRB allows the person 
obtaining assent to document assent on the consent document 
and does not routinely require assent documents and does not 
routinely require subjects to sign assent documents. 
Response: N/A 
 
28.20For HUD uses provide a description of how the patient will be 
informed of the potential risks and benefits of the HUD and any 
procedures associated with its use. 
Response: N/A 


 
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29.0 Process to Document Consent in Writing 
 
If your research presents no more than minimal risk of harm to subjects and 
involves no procedures for which written documentation of consent is normally 
required outside of the research context, the IRB will generally waive the 
requirement to obtain written documentation of consent. 
(If you will document consent in writing, attach a consent document. If you will 
obtain consent, but not document consent in writing, attach a consent script. 
Review “CHECKLIST: Waiver of Written Documentation of Consent (HRP-411)” 
to ensure that you have provided sufficient information. You may use 
“TEMPLATE CONSENT DOCUMENT (HRP-502)”to create the consent 
document or script.) 
29.1 Describe whether you will be following “SOP: Written 
Documentation of Consent (HRP-091).” If not, describe whether and 
how consent of the subject will be obtained including whether or not 
it will be documented in writing. 
Response: The consent form for this study adheres to guidelines in form 
HRP091, and is enclosed in this package. 
 
30.0 Drugs or Devices 
30.1 If the research involves drugs or device, describe your plans to store, 
handle, and administer those drugs or devices so that they will be 
used only on subjects and be used only by authorized investigators. 
Response: Lamotrigine is a FDA approved drug, but the study is exploring a new 
indication. The FDA has concluded that the study meets all of the requirements for 
exemption from the IND regulations and, therefore, an IND is not required to conduct the 
investigation. 
The drug supply will be sent to the University of Buffalo's School of Pharmacy 
and Pharmaceutical Sciences (UBSoPPS) Research Pharmacy. Once it arrives the 
packing slip will be checked for completeness and then the study staff will be notified of 
its arrival. The invoice and inventory taken will be faxed over to the study site. The drugs 
will then be stored in their original containers in a room-temperature, dry and dark area of 
the UBSoPPS Research Pharmacy's lab, which has very limited access since it is a 
pharmacy. Temperature and humidity will be monitored by a UBSoPPS Research 
Pharmacist. 
UBSoPPS Research Pharmacy will take the manufacture supplied tablet and place 
it inside a capsule. The capsule will be filled with methylcellulose until the entire content 
of the capsule is filled, decreasing the chance for un-blinding, and the capsule then 
closed. The encapsulated lamotrigine will then be packaged in an amber vial with a study 
label. Repackaging will follow NYS regulation. Repacking will be conducted by a 
pharmacist or under his/her immediate and personal supervision. A repacking record shall 


 
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be maintained for five years, including the name, strength, lot number, quantity and name 
of the manufacturer and/or distributor of the drug repacked, the date of repacking, the 
number of packages prepared, the number of dosage units in each package, the signature 
of the person performing the repacking operation, the signature of the pharmacist who 
supervised the repacking, and such other identifying marks added by the pharmacy for 
internal recordkeeping purposes. Drugs repacked shall have an expiration date 12 
months, or 50 percent of the time remaining to the manufacturer's expiration date, 
whichever is less, from the date of repacking. 
SUNY at Buffalo School of Pharmacy and Pharmaceutical Sciences (UBSoPPS) 
Research Pharmacy will randomize eligible participants through www.randomizer.org. 
An UBSoPPS pharmacist will generate 12 random sets of numbers, ranging from 1-2 for 
the two assignment groups, with one unique number per set. UBSoPPS Research 
Pharmacy will use this randomization to compile a master log with the participant 
number and treatment code. 
Those assigned to the lamotrigine treatment will take encapsulated lamotrigine 
daily for the duration of 20 weeks, consisting of a six-week titration, 12-week study 
period, and two-week taper. Possible doses for patients are 25mg BID, 50mg BID, 100 
mg BID and 150mg BID during titration; 150mg BID or 100mg BID for the 12-week 
study period; 150mg QD or 100mg QD for Week 1 of the taper; and 75mg QD, or 50mg 
QD for Week 2 of the taper. Each increase in dose will be maintained for two weeks 
before deciding to further increase or decrease based on tolerability. Patients who 
discontinue at any point of the study will have a two-week taper consisting of the current 
dose QD for one week followed by half the dose QD for another week. 
If the drug is investigational (has an IND) or the device has an IDE or a 
claim of abbreviated IDE (non-significant risk device), include the 
following information: 
30.2 Identify the holder of the IND/IDE/Abbreviated IDE. 
Response: N/A 
 
30.3 Explain procedures followed to comply with FDA sponsor 
requirements for the following: 
 
Applicable to: 
FDA Regulation 
IND Studies 
IDE studies 
Abbreviated 
IDE studies 
21 CFR 11 
X 
X 
 
21 CFR 54 
X 
X 
 
21 CFR 210 
X 
 
 
21 CFR 211 
X 
 
 
21 CFR 312 
X 
 
 
21 CFR 812 
 
X 
X 
21 CFR 820 
 
X 
 
Response: N/A