A Herbal Medicine, Gongjindan , in Subjects with Chronic Dizziness (GOODNESS Study): Study Protocol for a Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Clinical Trial for Effectiveness, Safety, and Cost-Effectiveness

Abstract

This study protocol aims to explore the effectiveness, safety, and cost-effectiveness of a herbal medication, Gongjindan (GJD), in patients with chronic dizziness. This will be a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, clinical trial. Seventy-eight patients diagnosed with Meniere’s disease, psychogenic dizziness, or dizziness of unknown cause will be randomized and allocated to either a GJD or a placebo group in a 1 : 1 ratio. Participants will be orally given 3.75 g GJD or placebo in pill form once a day for 56 days. The primary outcome measure will be the Dizziness Handicap Inventory score. Secondary outcome measures will be as follows: severity (mean vertigo scale and visual analogue scale) and frequency of dizziness, balance function (Berg Balance Scale), fatigue (Fatigue Severity Scale) and deficiency pattern/syndrome (qi blood yin yang-deficiency questionnaire) levels, and depression (Korean version of Beck’s Depression Inventory) and anxiety (State-Trait Anxiety Inventory) levels. To assess safety, adverse events, including laboratory test results, will be monitored. Further, the incremental cost-effectiveness ratio will be calculated based on quality-adjusted life years (from the EuroQoL five dimensions’ questionnaire) and medical expenses. Data will be statistically analyzed at a significance level of 0.05 (two-sided). This trial is registered with ClinicalTrials.gov NCT03219515 , in July 2017.

Full text

Research Article
A Herbal Medicine, Gongjindan, in Subjects with
Chronic Dizziness (GOODNESS Study):
Study Protocol for a Prospective, Multicenter,
Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group, Clinical Trial for Effectiveness,
Safety, and Cost-Effectiveness
Seungwon Shin,1Jinyoung Kim,1Ami Yu,2Hyung-Sik Seo,3Mi-Ran Shin,4
Jae-Heung Cho,5Gilhee Yi,6Seung-Ug Hong,6and Euiju Lee7
1Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu,
Seoul 02447, Republic of Korea
2Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, 23 Kyungheedae-ro, Dongdaemun-gu,
Seoul 02447, Republic of Korea
3Department of Korean Medical Ophthalmology & Otolaryngology & Dermatology, School of Korean Medicine,
Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
4Department of Sasang Constitutional Medicine, College of Oriental Medicine, Semyung University, 65 Semyung-ro,
Jecheon, Chungcheongbuk-do 27136, Republic of Korea
5Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, 23 Kyungheedae-ro,
Dongdaemun-gu, Seoul 02447, Republic of Korea
6Department of Oriental Medicine Ophthalmology & Otolaryngology & Dermatology, College of Oriental Medicine,
Dongguk University, 27 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Republic of Korea
7Department of Sasang Constitutional Medicine, College of Korean Medicine, Kyung Hee University, 23 Kyungheedae-ro,
Dongdaemun-gu, Seoul 02447, Republic of Korea
Correspondence should be addressed to Seung-Ug Hong; heenthsu@hanmail.net and Euiju Lee; sasangin@daum.net
Received 16 July 2017; Accepted 19 October 2017; Published 13 December 2017
Academic Editor: Carmen Mannucci
Copyright ©  Seungwon Shin et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
is study protocol aims to explore the eectiveness, safety, and cost-eectiveness of a herbal medication, Gongjindan (GJD), in
patients with chronic dizziness. is will be a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-
group, clinical trial. Seventy-eight patients diagnosed with Meniere’s disease, psychogenic dizziness, or dizziness of unknown
cause will be randomized and allocated to either a GJD or a placebo group in a  :  ratio. Participants will be orally given .g
GJD or placebo in pill form once a day for  days. e primary outcome measure will be the Dizziness Handicap Inventory
score. Secondary outcome measures will be as follows: severity (mean vertigo scale and visual analogue scale) and frequency
of dizziness, balance function (Berg Balance Scale), fatigue (Fatigue Severity Scale) and deciency pattern/syndrome (qi blood
yin yang-deciency questionnaire) levels, and depression (Korean version of Beck’s Depression Inventory) and anxiety (State-
Trait Anxiety Inventory) levels. To assess safety, adverse events, including laboratory test results, will be monitored. Further, the
incremental cost-eectiveness ratio will be calculated based on quality-adjusted life years (from the EuroQoL ve dimensions’
questionnaire) and medical expenses. Data will be statistically analyzed at a signicance level of . (two-sided). is trial is
registered with ClinicalTrials.gov NCT, in July .
Hindawi
Evidence-Based Complementary and Alternative Medicine
Volume 2017, Article ID 4363716, 10 pages
https://doi.org/10.1155/2017/4363716

 Evidence-Based Complementary and Alternative Medicine
1. Introduction
Dizziness is a typical manifestation of various neurological
diseases. It is mostly related to vestibular disorders of the
inner ear, such as benign paroxysmal positional vertigo
(BPPV), vestibular neuritis, or Meniere’s disease (MD) [].
However, the symptom may also arise from some condi-
tions involving the central nervous system (e.g., cerebral
stroke, vertebrobasilar insuciency), cardiovascular diseases
(e.g., arrhythmia, orthostatic hypotension) [], or even
certain psychiatric conditions []. In some cases, chronic
and recurrent dizziness fails to receive a diagnosis and
remains as unspecied or undened dizziness in clinical rec-
ords.
According to studies investigating the etiology of recur-
rent dizziness, .% of cases were attributed to MD [],
% to psychogenic dizziness [], and –% to dizziness
of unknown cause [, ]. Public healthcare data systems also
show the incidence of dizziness has increased by approxi-
mately % in the past  years [].
Otorhinolaryngologists prescribe vasodilators or diuret-
ics to patients with MD. For example, betahistine is frequently
used as a full agonist of the H receptors located in blood ves-
sels in the inner ear, which can increase local vasodilation and
helpalleviatesymptoms[].Moreover,diureticsaresome-
times used to treat endolymphatic hydrops. However, there
is no conrmatory evidence of the utility of these treatments
[]. For psychogenic dizziness, psychiatrists administer to
patients antianxiety agents or antidepressants, accompanied
by cognitive-behavioral therapy [], which also lack clinical
verication. If the dizziness is due to unknown causes,
drugs, such as meclizine, clonazepam, or lorazepam, or reha-
bilitation therapy is prescribed, which mostly rely on anecdo-
tal evidence [].
Due to these limitations, many patients with dizziness
visit practitioners of traditional medicine in Korea. Tradi-
tional Korean Medicine (TKM) doctors prescribe various
herbal medications to these patients, based on syndrome/
pattern identication []. Gongjindan (GJD) is one of the
most preferred options. A classic Korean book of traditional
medicine, Dongeuibogam,suggeststhatGJDcanbepre-
scribed for liver-deciency syndrome/pattern with symptoms
of dizziness/vertigo, dim eyes, a pale face, and/or weak
muscles [, ]. However, the modern scientic level of the
evidence for GJD remains low.
Most studies have been in vivo or in vitro experiments that
have demonstrated the ecacy of GJD in ameliorating mem-
ory impairments [, ] or fatigue [], its antioxidant eects
[], neuroregulatory eects for transient middle cerebral
artery occlusion [] or Alzheimer’s disease [], and lipid-
lowering eect in hyperlipidemia []. Clinical studies have
been rarer. A retrospective study for Alzheimer’s disease []
and a case report for dizziness of patients with anemia []
have been published. Only one randomized controlled trial
(RCT) with GJD has so far been planned with fatigue patients
[], which has not announced its results yet. erefore,
the eectiveness of GJD should be explored clinically with
qualied RCTs using a placebo for comparison. is study
would be the rst RCT for chronic dizziness to explore the
clinical eectiveness, safety, and cost-eectiveness of a herbal
drug, GJD pills.
is study protocol is primarily aimed at exploring the
eectiveness of GJD in patients with chronic dizziness, com-
pared to placebo. Additionally, the safety and cost-effective-
ness of GJD will be investigated.
2. Materials and Methods
isstudyprotocolhasbeendesignedtoconformwith
Standard Protocol Items: Recommendations for Interven-
tional Trials (SPIRIT),  statement [], and the elaborated
Consolidated Standards of Reporting Trials (CONSORT)
statement for herbal interventions [].
2.1. Objectives and Hypothesis. e primary objective of this
study is to evaluate the eect of GJD administration for
 weeks, compared to placebo, on chronic dizziness (MD,
psychogenic dizziness, or dizziness of unknown cause). e
alternative hypothesis is that the mean dierence between
Dizziness Handicap Inventory (DHI) scores at baseline and
endpoint in the GJD group will not be equal to that in the
placebo group.
Additionally, the changes in dizziness severity and fre-
quency will be evaluated with validated scales. Further, the
levels of fatigue, depression, anxiety, and quality of life (QoL)
will be compared between the two groups posttreatment.
e safety of GJD administration will be examined based on
laboratory tests and adverse events (AEs). Finally, the cost-
eectiveness of GJD will be evaluated with quality-adjusted
life years (QALY).
2.2. Study Design. is study will be a prospective, multicen-
ter, randomized, double-blind, placebo-controlled, parallel-
group, clinical trial. Seventy-eight patients diagnosed with
MD, psychogenic dizziness, or dizziness of unknown cause,
with a DHI score ≥ at baseline, and having complained
of dizziness for more than  month will be randomized and
allocatedtoeithertheGJDorplacebogroupina:ratio.
eywillbeorallygiven.gGJDorplaceboinpillform
once a day for  weeks ( pills in total). To collect data for
the cost-eectiveness analysis, we will follow up the patients
for up to  months from randomization. e study owchart
is displayed in diagram form in Figure  and the specied
timetable is presented in Table .
2.3. Setting and Recruitment. Four TKM hospitals in the
Republic of Korea, that is, Kyung Hee University Korean
Medicine Hospital in Seoul, Dongguk University Ilsan Ori-
ental Hospital in Goyang (Gyeonggi-do), Pusan National
University Korean Medicine Hospital in Yangsan (Gyeong-
sangnam-do), and Semyung University Korean Medicine
Hospital in Chungju (Chungcheongbuk-do), will enroll
eligible participants. Participants will be recruited mostly
from the respective outpatient clinics. Moreover, study
advertisements will be posted on webpages and notice
boards.

Evidence-Based Complementary and Alternative Medicine 
T : Study timetable.
Screening Randomization Treatment Follow-up
Visits V V V3 V4 V5 V6 V7 V8 V9
Timepoint Within 1 4 D Day 0 14 D ±3D 28D±3D 42D ±3D 56D±3D 4M±1W 8M±1W 12M±1W
Enrollment:
Informed consent ×
Demographics ×
Vita l sign ××××××
Electrocardiography ××
Lab test ××
Medical history ×
Concomitant medication ××××××
Pregnancy test ×
CNS examination ×
Nystagmus examination ×
Eligibility assessment ×
Random allocation ×
Interventions:
GJD (1 pill/day)
Placebo (1 pill/day)
Assessments:
DHI ××××××
MVS ×××
VAS ×××
Frequency ×××
BBS ×××
FSS ×××
GPE ×
K-BDI ×××
STAI ×××
QBYY-Q ×××
EQ-5D ××××××
Cost information ××× × ×××
New BI ×
Adverse events ××× ×
BBS, Berg Balance Scale; BI, Blinding Index; D, day(s); DHI, Dizziness Handicap Inventory; EQ-D, EuroQoL ve dimensions’ questionnaire; FSS, Fatigue
Severity Scale; GJD, Gongjindan; GPE, global perceived eect; K-BDI, Korean version of Beck’s Depression Inventory; M, month(s); MVS, mean vertigo scale;
QBYY-Q, qi blood yin yang-deciency questionnaire; STAI, State-Trait Anxiety Inventory; VAS, visual analogue scale; W, week(s).
2.4. Ethical Review and Trial Registration. is protocol
(version .) and the informed consent forms have been peer-
reviewed and approved by the Institutional Review Board of
Kyung Hee University Korean Medicine Hospital (approval
number KOMCIRB--HRBR-) following the scien-
tic content and ethical compliance with regulations, that is,
Good Clinical Practice and relevant laws by Ministry of Food
and Drug Safety in Korea. e study has been registered at
ClinicalTrials.gov in July  (identier: NCT).
2.5. Eligibility Criteria. Participants will be included if they
satisfy all of the following criteria:
() Age between  and  years, of either sex
() Dizziness originating from MD, psychogenic cause,
or unknown cause
()Recurringsymptomofdizzinessformorethan
month
() DHI score ≥ at baseline
() Liver-deciency pattern/syndrome identied by
TKM doctors
() Willingness to provide written informed consent.
e targeted scope of chronic dizziness has been estab-
lished based on a preceding acupuncture trial []. e liver-
deciency syndrome is dened as having all of the main
symptoms and at least two of the secondary symptoms [,
]. e main symptoms include dizziness, dim eyes, and pale
face. e secondary symptoms include lack or a momentary
loss of vision, numbness at extremities, muscular spasm,
twitching and/or cramping, hypochondriac pain, dry or pale

 Evidence-Based Complementary and Alternative Medicine
Eligibility assessment
Exclusion of participants
(i) Not meeting inclusion/exclusion
criteria
(ii) Declined to participate
(i) Endpoint assessment
(DHI, MVS, VAS, frequency score, BBS,
FSS, GPE, K-BDI, STAI, QBYY-Q, EQ-
5D, new BI)
(ii) Adverse events evaluation
GJD group (n = 39)
(i) Baseline assessment
(DHI, MVS, VAS, frequency score, BBS,
FSS, GPE, K-BDI, STAI, QBYY-Q, EQ-
5D)
Placebo group (n = 39)
(i) Baseline assessment
(DHI, MVS, VAS, frequency score, BBS,
MVS FSS, GPE, K-BDI, STAI, QBYY-Q,
EQ-5D)
Allocation
Follow-up
Intervention & assessment
Randomization
Statistical analysis Statistical analysis
Closeout & analysis
(EQ-5D, cost-eectiveness)
(i) Follow-up assessment (i) Follow-up assessment
(EQ-5D, cost-eectiveness)
Placebo group (1yr) (n = 39)
GJD group (1 yr) (n = 39)
(i) Endpoint assessment
(DHI, MVS, VAS, frequency score,
BBS, FSS, GPE, K-BDI, STAI,
QBYY-Q, EQ-5D, new BI)
(ii) Adverse events evaluation
Placebo (pill/day, 8 wks) (n = 39)
GJD (pill/day, 8wks) (n = 39)
F : Study owchart. BBS, Berg Balance Scale; BI, Blinding Index; CNS, central nervous system; DHI, Dizziness Handicap Inventory;
EQ-D, EuroQoL ve dimensions’ questionnaire; FSS, Fatigue Severity Scale; GJD, Gongjindan; GPE, Global perceived eect; K-BDI, Korean
version of Beck’s Depression Inventory; MVS, mean vertigo scale; QBYY-Q, qi blood yin yang-deciency questionnaire; STAI, State-Trait
Anxiety Inventory; VAS, visual analogue scale; wks, weeks; yr, year.
ngernails, toenails, or lips, tinnitus, and scant menstruation.
Two TKM doctors who have  year or more of clinical experi-
ence will independently identify the pattern/syndrome, and
only the patients diagnosed with consistent liver-deciency
pattern/syndrome will be enrolled in the study.
Participants will be excluded if any of the following crite-
ria is applicable:
() Dizziness attributable to vestibular disorders (e.g.,
benign paroxysmal positional vertigo, peripheral ves-
tibulopathy,labyrinthitis,andvestibularneuronitis)
() Dizziness attributable to central nervous system
(CNS) disorders (e.g., cerebellar ataxia, stroke, de-
myelination, vertebrobasilar insuciency, seizure,
increased intracranial pressure, Parkinson’s disease,
and migraines)
() Cervicogenic dizziness
() Dizziness attributable to cardiovascular disorders
(e.g., arrhythmia, heart valvular disease, anemia,
orthostatic hypotension, and coronary artery disease)
() Any active or uncontrolled disease that might cause
dizziness (e.g., uncontrolled diabetes mellitus, hyper-
tension, and respiratory or endocrinological disor-
ders)
() Dizziness attributable to medication side eects
() Severe chronic or terminal diseases (malignant can-
cer, tuberculosis, etc.)
() Intake of antivertiginous drugs that cannot be discon-
tinued

Evidence-Based Complementary and Alternative Medicine 
() Following physiotherapy, manual therapy (e.g., ves-
tibular rehabilitation), and/or cognitive-behavioral
therapy for the treatment of dizziness
() Aspartate aminotransferase (AST), alanine amino-
transferase (ALT), blood urea nitrogen (BUN), or
creatinine >×upper limit of normal range at
baseline
() Women of (suspected) pregnancy or breast-feeding
() Allergic reactions to the study medications
() Suspicion of alcohol and/or drug abuse
() Enrollment in another clinical study presently or
within  days prior to the initial administration of
the study medications
() Diculty in reliably communicating with the investi-
gators or likelihood of inability to follow instructions
() Reasons for ineligibility of participation judged by
investigators.
2.6. Dropout Criteria. Already enrolled participants will be
dropped out if they withdraw their consent for participation,
are lost to follow-up, cannot continue participation due to
adverse events or complications, consume disallowed med-
ications, or markedly deviate from the study protocol.
2.7. Randomization, Allocation, and Blinding. An indepen-
dent statistician (A. Yu) will generate random sequence
numbers via SAS. soware (SAS Institute Inc., Cary, NC).
Stratied randomization will be performed in blocks in order
to keep the sizes of both arms similar with the strata of the
study sites. e random number table will be delivered from
the statistician to a pharmaceutical company, where GJD and
placebo pills will be produced.
e investigational products labeled with random codes
will be provided to a pharmacist, who will dispense them to
the enrolled participants. According to the order of enroll-
ment, participants will be allocated to either the GJD group
ortheplacebogroupina:ratio.Asonlythestatisticianand
the pharmaceutical company will have access to the random
table throughout the study, allocation will stay concealed.
Sincewearegoingtouseplacebopillsthatlook,taste,
and smell similar to GJD pills, both investigators and patients
will stay blinded until the completion of the study. Only
clinical emergency due to serious AEs will break the code and
blinding.
2.8. Gongjindan (GJD). e GJD group will be orally given
. g of GJD in pill form (product name: Iksu Gongjindan),
on an empty stomach every morning for  weeks ( days).
is has been determined based on clinical experience within
the dose regimen ( to  oral administrations per day) of
GJDpillsapprovedbytheMinistryofFoodandDrugSafety
in Korea. e manufacturer, Iksu Pharmaceutical Co. Ltd.
(Gwangju, Republic of Korea). obtained Good Manufactur-
ing Practice authorization from the Ministry of Food and
Drug Safety in Korea. e GJD pill and its ingredients have
also been registered with the same governmental authority.
GJD is composed of six herbs (with country of origin
and material standard; KHP, Korean Herbal Pharmacopoeia;
KP, Korean Pharmacopoeia): Cervi Parvum (Cervus elaphus
Linn´
e, family Cervidae, Russia, KHP) . mg, Angelica
Gigas Root (Angelica gigas Nakai, family Umbelliferae, Korea,
KP) . mg, Cornus Fruit (Cornus ocinalis Siebold et
Zuccarini, family Cornaceae, China, KP) . mg, Ginseng
(Panax ginseng C. A. Meyer, family Araliaceae, Korea, KP)
. mg, Steamed Rehmannia Root (Rehmannia glutinosa
Liboschitz ex Steudel, family Scrophulariaceae, China, KP)
. mg, and Musk (Moschus moschiferus Linn´
e, family
Moschidae, Russia, KHP)  mg.
Aer the herbs are weighed, they are pulverized, steril-
ized, and mixed with the excipient (corn starch . mg),
binders (glycerin  mg and suitable amount of honey), and
preservative (sodium benzoate . mg). e mixture is
formed into a pill (. g/pill) and covered with gilt paper.
Separately packaged and labeled GJD will be directly deliv-
eredtothepharmacistsofeachstudysitefromthepharma-
ceutical company. A voucher specimen will be retained and
kept with the manufacturer.
2.9. Placebo. Since there have been no clinical trials to show
the eectiveness and/or safety of GJD pills over placebo,
we have decided to adopt placebo control for this dizziness
trial. Placebo pills will be made by the same pharmaceutical
company as the GJD pills. ey will be made similar in
appearance, taste, and odor to the GJD pills, containing excip-
ients (corn starch . mg, sodium carboxymethyl cellulose
 mg, lactose hydrate . mg, and citric acid hydrate
 mg), coloring agents (sepia color  mg and caramel
color  mg), binders (glycerin  mg and honey  mg),
avoring agents, and preservative (sodium benzoate . mg)
with gilt-paper covering. e entire manufacturing process
will follow the relevant guidelines of the Korean Ministry of
Food and Drug Safety.
e placebo group will be orally given . g of placebo
pill on an empty stomach every morning for  weeks (
days).
2.10. Concomitant Medications. All of the concomitant med-
ications will be recorded throughout the trial. No other drugs
(betahistine, difenidol, unarizine, cinnarizine, dimenhydri-
nate, gingko, meclizine, metoclopramide, scopolamine, pen-
toxifylline, perphenazine, ergoloid mesylate, droperidol, phe-
nobarbital, prochlorperazine, promethazine, trimethobenza-
mide, or vertigoheel, etc.) or herbal drugs to manage the
symptomofdizzinesswillnotbeallowed.Moreover,other
therapiesfordizziness,likephysicaltherapy,rehabilita-
tion, acupuncture, electroacupuncture, pharmacoacupunc-
ture, moxibustion, cupping, and cognitive-behavioral thera-
pies, will be disallowed during the study.
e following drugs, which can induce drug-related diz-
ziness, will be closely monitored: 𝛼-adrenergic antagonist s,
alcohol, aminoglycosides, anticonvulsants, antidepressants,
anti-Parkinson medication, antipsychotics, 𝛽-blockers, cal-
cium channel blockers, class a antiarrhythmics, digitalis gly-
cosides, diuretics, narcotics, oral sulfonylurea, vasodilators,

 Evidence-Based Complementary and Alternative Medicine
anticoagulants, antidementia agents, antihistamines (sedat-
ing), antirheumatic agents, anti-infectives (anti-inuenza
agents, oral antifungals, quinolones), antithyroid agents,
anxiolytics, attention-decit/hyperactivity disorder agents,
cholesterol-lowering agents, bronchodilators, skeletal muscle
relaxants, urinary and gastrointestinal antispasmodics, and
so on.
2.11. Screening Process. Aer a TKM doctor obtains informed
consent from a patient, he/she will go through an extensive
screening process for the eligibility decision. Height, weight,
body mass index, vital signs (blood pressure, pulse, and
body temperature), and electrocardiogram will be measured.
Furthermore, blood and urine laboratory tests will be per-
formed, including pregnancy testing. History of medical
diseases and drugs will be recorded. If the patient was
under administration of any of the drugs disallowed in
this study, he/she will be able to participate aer a -week
wash-out period. To rule out untargeted diseases related to
chronicdizziness,aslistedintheexclusioncriteria,weare
going to test for CNS abnormalities (deep tendon reex,
Homan sign, Babinski sign, ankle clonus, nger to nose,
nger to nger, rapid alternating movement, heel to shin,
Romberg’s test, Brudzinski sign, Kernig sign, Naziger test,
etc.). Additionally, spontaneous, gaze-evoked, positional, and
positioning (Dix-Hallpike) nystagmus will be tested for, too.
Finally, two TKM doctors will judge if the patient has liver-
deciency pattern/syndrome or not, and those that will
receive a consistent diagnosis will be considered to be eligible.
e whole process is depicted in Table .
2.12. Outcomes
2.12.1. Primary Outcome
Dizziness Handicap Inventory (DHI).DHIwasdeveloped
to evaluate functional, emotional, and physical impairments
due to dizziness []. is widely used scale for patients with
dizziness is a patient-rated outcome (PRO) and has been
validatedinKorean[].escaleconsistsofitems(,,
or  scores/item, – scores). e primary endpoint is the
mean dierence of DHI total score between the baseline and
the endpoint of the treatment period. Secondarily, the before-
and-aer eect of GJD between the baseline and every visit
will also be investigated.
2.12.2. Secondary Outcomes. e following outcomes will be
evaluated at baseline, mid-term point, and the endpoint of
thetreatment.emeandierencesofeachscalescorefrom
thebaselineandeachmeasurementpointwillbecompared
between the GJD and the placebo groups.
Mean Vertigo Score (MVS).MVSisaPROassessingthe
intensity of dizziness and has been employed in various
clinical trials [–]. It includes six items for symptom types
and six items for symptom provoking conditions. Patients
answer on a scale from  (none) to  (very strong) and the
nal score is calculated as the sum divided by  (– scores).
Visual Analogue Scale (VAS).eVASwasusedinthe
previous studies on dizziness [–]. is scale consists of
a  cm line, where  represents “not dizzy at all” and 
“dizziest I can imagine being.”
Dizziness Frequency.Patientswillbeaskedhowmany
episodes of dizziness they experience. e frequency will be
scored as  (none),  (less than once a month),  (– episodes/
month),  (– episodes/week),  (once a day), or  (more
than twice a day), as per the notation used in the previous
studies [–].
Berg Balance Scale (BBS). e BBS was originally developed
for elderly patients with balance impairment; however, it has
been used to assess overall balance ability regardless of age. Its
reliability[,],validity[],andsensitivity[]havebeen
veried and it has been validated in Korean []. Patients will
be asked to perform  tasks and each task will be evaluated
separately.
Fatigue Severity Scale (FSS). GJD is widely administered to
patients with chronic fatigue. In this study, we are going to
assess the patients’ fatigue level with the FSS. is -point
Likert scale (nine items, – score range) is a PRO and it
has been validated [].
Global Perceived Eect (GPE). GPE is a validated scale
evaluating a patient’s perception of symptom worsening or
improvement around a specic timepoint []. is scale has
also been used in clinical studies on dizziness [, , ], and
it consists of seven options ( for completely recovered to  for
worst ever).
Based on the previous study showing that the patients
with dizziness can become markedly depressed and anxious
[], the following scales will also be included.
KoreanVersionofBeck’sDepressionInventory(K-BDI).eK-
BDI is a PRO evaluating the severity of depression with 
items ( to /points,  points in total). e Korean version
of this scale has been validated [, ].
State-Trait Anxiety Inventory (STAI).eSTAIassessesthe
level of anxiety in the subdomains of state and trait. Each
subdomain includes  items and each item has the options
of – points (– scores/subdomain). Its reliability and
validity have been shown [].
Qi Blood Yin Yang-Deciency Questionnaire (QBYY-Q).GJD
is a herbal medication prescribed to patients with liver-
deciency pattern/syndrome in TKM. erefore, we assumed
that the level of deciency pattern/syndrome could vary
between groups at the end of the intervention. QBYY-Q is a
PRO to evaluate the severity of qi-, blood-, yin-, and yang-
deciency pattern/syndrome [, ]. A previous clinical
study on chronic fatigue demonstrated the reliability and
validity of this scale []. e scale consists of  items and
each item is rated from  to  points.
2.12.3. Blinding Assessment. isisadouble-blindclinical
trial with placebo control. Both study participants and TKM

Evidence-Based Complementary and Alternative Medicine 
doctors will remain blind until the end of the trial. At the
end of treatment of each participant, they will be asked in
which group they think they belonged to, the GJD group,
placebo group, or unknown, and the new Blinding Index
(BI) will be calculated following []. e index score varies
within  (complete lack of blinding),  (consistent with perfect
blinding), or − (guessed they were in the opposite group).
2.12.4. Safety Assessment. e AEs will be monitored during
the whole treatment period. e following adverse reactions
are expected: anorexia, discomfort feeling of stomach area,
nausea, vomiting, diarrhea, or rash on skins. e intensity
and frequency of each episode will be recorded. Moreover,
laboratory tests will be performed at baseline and the end-
point. Complete blood cell tests (red blood cell, hemoglobin,
hematocrit, platelet, and white blood cell), serum biochem-
icaltests(creatinine,BUN,ALT,AST,andglucose),and
urinalysis (pH, specic gravity, glucose, ketone, red blood
cell, nitrate, total protein, bilirubin, urobilinogen, and white
blood cell) will be performed. If serious AEs occur, postman-
agement will be properly conducted.
2.12.5. Cost-Eectiveness Assessment. e EuroQoL ve di-
mensions’ questionnaire (EQ-D), consisting of two parts,
that is, EQ-D-L and EQ VAS, will be used to assess quality
of life, based on which QALY will be calculated. e Korean
versionofEQ-Dscalehasbeenstudiedonitsvalidityand
reliability []. Also, direct costs (medical and nonmedical
expenses) incurred in treating dizziness during the treatment
( weeks) and follow-up (up to  months from random-
ization) periods will be investigated (Table ). Medical fee
signies the cost paid in hospitals or clinics. Nonmedical fee
signies transportation and time costs that patients would
incur for dizziness treatment. Based on the calculated QALY
and fees, the incremental cost-eectiveness ratio (ICER) will
be estimated (ICER = Δcost/Δ eectiveness). e ICER
signies the amount of cost necessary to improve by  unit
of eectiveness.
2.13. Sample Size Calculation. To c a lcul ate t h e e  e c t size, we
usedaprecedingRCTonacupuncturetherapyforMDwith
DHI assessment, as there have been no clinical studies for
GJD eectiveness in chronic dizziness []. e null hypoth-
esis is that 𝜇GJD =𝜇placebo,while the alternative hypothesis
is 𝜇GJD ̸=𝜇
placebo,where𝜇denotes the mean dierence of
DHIscorebetweenthebaselineandendpoint.Withthemean
dierence (−.) and the standard deviation (.), under
the assumption of correlation coecient (.), the sample size
was calculated as  per group (two-sided, 𝛼 = 0.05 and 1−𝛽
= .). erefore, we are going to recruit  participants for
both groups ( per group) under a % anticipated dropout
rate.
2.14. Statistical Analysis. e primary and secondary vari-
ables for the eect assessments will be statistically analyzed
by analysis of covariance (ANCOVA) or rank ANCOVA with
group and site as covariates. If any demographic charac-
teristics show signicant dierence between groups, those
variableswillalsobeusedascovariates.Whenthereisa
signicant interaction between diagnosis (MD, psychogenic
dizziness, or dizziness of unknown cause) and group, sub-
group analysis will be performed.
e condence interval (CI) of BI will be addressed and
blinding will be deemed successful when the CI includes
the zero value. For safety assessment, the chi-squared test or
Fisher’s exact test will be performed with the proportions of
AEs, while lab results will be compared between groups by
chi-squared test (proportions of abnormal results) or McNe-
mar’s test (before-and-aer comparison within a group). An
independent statistician (A. Yu) will analyze any data with a
signicance level of . (two-sided) with SAS . soware
(SAS Institute Inc.).
e primary analysis will be performed with the full
analysis set, which is dened as the group of participants who
were prescribed at least once or more the GJD or placebo
pillsandforwhomDHIwasevaluatedmorethanonce.e
missingdatawillbeimputedwiththelastobservationcarried
forward method. e per protocol set will be additionally
analyzed, which includes only the participants who complete
all the scheduled visits. We are going to include any partic-
ipantswhotookatleastonepillofthestudydrugsforthe
safety assessment.
3. Results and Discussion
is study is a prospective, multicenter, randomized, double-
blind, placebo-controlled, parallel-group, clinical trial to
explore the eectiveness, safety, and cost-eectiveness of
a herbal drug, GJD, for patients with chronic dizziness
attributable to MD, psychogenic dizziness, or dizziness of
unknown cause. We are going to administer to patients GJD
or placebo pills for  weeks and follow them up for  months.
Four TKM hospitals in Korea will enroll  participants.
Dizziness may ensue from a variety of central or periph-
eral diseases and in some cases as a drug complication.
is may complicate the diagnostic process. is study will
include patients diagnosed with MD, psychogenic dizziness,
or dizziness of unknown cause, which may create an issue
with homogeneity. However, there were previous clinical
studies which also focused on the symptom of dizziness with
varied origin to demonstrate new ecacy [, ], including
an acupuncture study for chronic dizziness [], which has
meaningfully been referred for this trial.
GJD is a widely prescribed herbal pill in Korea, but
it is mostly used for patients with severe deciency pat-
tern/syndrome, especially those complaining of marked
fatigue[,].However,basedontheseminalworkDongeui-
bogam [], we expect GJD to also manage chronic dizziness.
is RCT included various diseases (MD, psychogenic
dizziness, or dizziness of unknown cause) inducing dizziness,
which might reduce the level of homogeneity of patient pop-
ulation. e investigators discussed this issue, which might
aect signicantly the study results in the future. However,
it was taken into consideration that this trial should reex
the real clinical practices as much as possible, which means
that GJD is a herbal drug and it has been described based
on pattern/syndrome identication in TKM. So, we think

 Evidence-Based Complementary and Alternative Medicine
the screening process is one of the key parts for this trial to
include eligible participants. Investigators and coordinators
should be trained with written standard operating procedures
for the trial before enrolling the rst participants, since
this study is a multicenter trial, to control the high quality
throughout the whole process. Also, an independent monitor
willregularlyvisitallthehospitalsforauditingethicaland
scientic issues.
4. Conclusions
We are going to conduct a prospective, multicenter, ran-
domized, double-blind, placebo-controlled, parallel-group,
clinical trial on patients with chronic dizziness to evaluate
the eectiveness, safety, and cost-eectiveness of a herbal
drug, GJD. is study has been approved by an ethics
committeeandregisteredintheWHOinternationalclinical
trials registry platform (CRIS), in the Republic of Korea.
Abbreviations
AST: Aspartate aminotransferase
AE: Adverse event
ALT: Alanine aminotransferase
ANCOVA: Analysis of covariance
BBS: Berg Balance Scale
BI: Blinding Index
BPPV: Benign paroxysmal positional vertigo
BUN: Blood urea nitrogen
CI: Condence interval
CONSORT: Consolidated Standards of Reporting Trials
CRIS: Clinical Research Information Service
DHI: Dizziness Handicap Inventory
e: Central nervous system
EQ-D: EuroQoL ve dimensions’ questionnaire
FSS: Fatigue Severity Scale
GJD: Gongjindan
GPE: Global perceived eect
K-BDI: Korean version of the Beck’s Depression
Inventory
KHP: Korean Herbal Pharmacopoeia
KP: Korean Pharmacopoeia
MD: Meniere’s disease
MVS: Mean vertigo score
PRO: Patient-rated outcome
QALY: Quality-adjusted life year
QBYY-Q: Qi blood yin yang-deciency questionnaire
QoL: Quality of life
RCT: Randomized controlled trial
SPIRIT: Standard Protocol Items: Recommendations
for Interventional Trials
STAI: State-Trait Anxiety Inventory
TKM: Traditional Korean Medicine
VAS: Visual analogue scale.
Conflicts of Interest
e authors declare that there are no conicts of interest
regarding the publication of this article.
Acknowledgments
is research is supported by the Korea Health Technology
R&D Project through the Korea Health Industry Develop-
ment Institute (KHIDI), funded by the Ministry of Health &
Welfare, Republic of Korea (Grant no. HBC).
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