the bmj | BMJ 2016;352:h6816 | doi: XXXXXXXXXX
mj.h6816
RESEARCH
1
OPEN ACCESS
1German Center for Vertigo and
Balance Disorders, University
Hospital Munich, Campus
Grosshadern, Munich, Germany
2Institute for Medical
Informatics, Biometry, and
Epidemiology, University of
Munich, Campus Grosshadern
3Department of Neurology,
University Hospital Munich,
81377 Munich
4Department of
Otorhinolaryngology, Head and
Neck Surgery, University
Hospital Munich
Co
espondence to: M Strupp
Michael.Strupp@med.
uni-muenchen.de
Additional material is published
online only. To view please visit
the journal online (http:
dx.doi.
org/10.1136
mj.h6816)
Cite this as: BMJ 2016;352:h6816
http:
dx.doi.org/10.1136
mj.h6816
Accepted: 02 November 2015
E!cacy and safety of betahistine treatment in patients with
Meniere’s disease: primary results of a long term, multicentre,
double blind, randomised, placebo controlled, dose de"ning
trial (BEMED trial)
Christine Adrion,1,2 Carolin Simone Fischer,1 Judith Wagner,3 Robert Gürkov,4 Ulrich Mansmann,2
Michael Strupp1,3 On behalf of the BEMED study group
ABSTRACT
STUDY QUESTION
What is the long term e!cacy of betahistine
dihydrochloride on the incidence of vertigo attacks in
patients with Meniere’s disease, compared with
placebo?
METHODS
The BEMED trial is a multicentre, double blind,
andomised, placebo controlled, three arm, parallel
group, phase III, dose de"ning superiority trial
conducted in 14 German tertiary refe
al centres (for
neurology or ear, nose, and throat). Adults aged 21-80
years (mean age 56 years) with de"nite unilateral or
ilateral Meniere’s disease were recruited from March
2008 to November 2012. Participants received placebo
(n=74), low dose betahistine (2×24 mg daily, (n=73)),
or high dose betahistine (3×48 mg daily, (n=74)) over
nine months. The primary outcome was the number of
attacks per 30 days, based on patients’ diaries during
a three month assessment period at months seven to
nine. An internet based randomisation schedule
performed a concealed 1:1:1 allocation, strati"ed by
study site. Secondary outcomes included the duration
and severity of attacks, change in quality of life scores,
and several observer-reported parameters to assess
changes in audiological and vestibular function.
STUDY ANSWER AND LIMITATIONS
Incidence of attacks related to Meniere’s disease did
not di,er between the three treatment groups
(P= XXXXXXXXXXCompared with placebo, attack rate ratios
were XXXXXXXXXX% con"dence interval 0.942 to 1.140)
and XXXXXXXXXXto XXXXXXXXXXfor low dose and high dose
etahistine, respectively. The overall monthly attack
ate fell signi"cantly by the factor XXXXXXXXXXto
0.816; P< XXXXXXXXXXThe population based, mean monthly
incidence averaged over the assessment period was
XXXXXXXXXXto 6.309), XXXXXXXXXXto 7.929), and
XXXXXXXXXXto XXXXXXXXXXfor the placebo, low dose
etahistine, and high dose betahistine groups,
espectively. Results were consistent for all secondary
outcomes. Treatment was well tolerated with no
unexpected safety "ndings. Without a control group of
patients who did not receive any intervention to follow
the natural course of the disease, the placebo e,ect
could not be accurately assessed and di,erentiated
from spontaneous remission and fluctuation of
symptoms.
WHAT THIS STUDY ADDS
Cu
ent evidence is limited as to whether betahistine
prevents vertigo attacks caused by Meniere’s disease,
compared with placebo. The trial provides information
on symptom relief on placebo intervention which is
elevant for the design of future studies on potential
disease modifying treatments in patients with
Meniere’s disease.
FUNDING, COMPETING INTERESTS, DATA SHARING
Support from the German Federal Ministry of
Education and Research (BMBF support code
01KG0708). Potential competing interests have been
eported in full at the end of the paper on thebmj.com.
Data are available from the co
esponding author
( XXXXXXXXXX) or
iostatistician ( XXXXXXXXXX).
STUDY REGISTRATION
EudraCT no XXXXXXXXXX; ISRCTN no ISRCTN XXXXXXXXXX.
Introduction
Meniere’s disease is characterised by recu
ent attacks
of vertigo, fluctuating sensorineural hearing loss, aural
fullness, and tinnitus.1 Its histopathological hallmark
is endolymphatic hydrops.2 3 Lifetime prevalence of the
disease in the United States is reported as 190 per
XXXXXXXXXXpeople, with a ratio of 1.89 women to every
WHAT IS ALREADY KNOWN ON THIS TOPIC
Acute vertigo attacks caused by Meniere’s disease greatly a,ect patients’ quality of
life and perceived wellbeing
The disease’s natural history is one of remission and recu
ence; because
participants must "rst have active vertigo to enrol in a study, spontaneous
improvement through regression to the mean is expected
Observational studies or low quality randomised controlled trials of low and
moderate betahistine doses have produced contradictory results on treatment
e!cacy, and have not investigated the e,ect of an experimental intervention from
the patient’s perspective with respect to vertigo attack prophylaxis
WHAT THIS STUDY ADDS
Long term prophylactic treatment with betahistine dihydrochloride (at daily doses
2×24 mg or 3×48 mg) does not change the time course of vertigo episodes related
to Meniere’s disease compared with placebo
Placebo intervention as well as betahistine treatment showed the same reduction
of attack rates over the study’s nine month treatment period
Reliable and valid instruments that measure subjective vertigo symptoms (in
particular, vertigo attacks caused by Meniere’s disease) are lacking; derivation of
de"nite or probable attacks caused by Meniere’s disease, on the basis of raw
patient recordings in vertigo diaries, is methodologically challenging and requires
prespeci"ed rules
on 18 June 2021 by guest. Protected by copyright.
http:
w
w
w
.bm
j.com
BM
J: first published as XXXXXXXXXX
m
j.h6816 on 21 January 2016. D
ow
nloaded from
-
-
doi: XXXXXXXXXX
mj.h6816 | BMJ 2016;352:h6816 | the bmj
RESEARCH
2
man. 4 5 Annual incidence of the disease in the USA was
15.3 per XXXXXXXXXXpeople (age adjusted rate).6 The peak
age of onset is during the fifth and sixth decade.7
For patients with Meniere’s disease, unpredictable
vertigo attacks are the most important and unpleasant
symptom. Although the disease is clinically problem-
atic and the target of several treatments, there are so far
no validated instruments related to vertigo that are
ased on patient reported outcomes (PRO) for compre-
hensively evaluating disease severity in a clinical trial.
Treatment should aim to stop or reduce the number and
severity of acute attacks of vertigo, reduce or eliminate
tinnitus, and prevent impaired vestibular function and
hearing loss. Given the chronic nature of the disease
and the fluctuating and episodic pattern of symptoms,
the long term effectiveness of any prophylactic drug
should be investigated.
Many therapeutic approaches to Meniere’s disease
have been studied. These include a low salt diet and
diuretics,8 intratympanic steroid application,9 10 or
minimal invasive interventions (such as insertion of a
ventilation tube into the tympanic mem
ane,11 12 endo-
lymphatic sac surgery,13 or pulsed low pressure delivery
(using Meniett devices XXXXXXXXXXFor patients who do not
espond to these treatments, more aggressive proce-
dures can be considered, such as intratympanic appli-
cation of gentamycin,18 19 plugging of the semicircular
canal, labyrinthectomy, or neurectomy XXXXXXXXXXHowever,
these interventions are i
eversible and could damage
the cochlear and vestibular organ; furthermore, a
ecent Cochrane review could not show any evidence of
enefit in a surgical approach.24 25
Betahistine is a licensed drug for Meniere’s dis-
ease-like symptom complexes, which contains the
active ingredient betahistine dihydrochloride (maxi-
mum daily dose 48 mg) or betahistine dimesylate (max-
imum daily dose 36 mg). Betahistine is a strong H3
antagonist and a weak H1 agonist26 with three sites of
action. Firstly, it increases dose-dependent cochlear
lood flow,27 mainly via the H3 receptor as an inverse
agonist.28 Because betahistine has a strong first pass
effect and is metabolised in the liver into three metabo-
lites, not only betahistine but also its major metabolite
aminoethylpyridine increases cochlear blood flow.29
Secondly, betahistine increases histamine turnover in
the central nervous and vestibular system, also mainly
via the H3 receptor. Thirdly, it decreases vestibular
input in the peripheral vestibular system, with possible
involvement with the H3 and H4 receptors.
How betahistine might have an effect in the prophy-
lactic treatment of Meniere’s disease is so far unknown.
It could lead to an improvement of labyrinthine micro-
circulation, thereby rebalancing the production and
esorption of endolymph. The drug was first registered
in Europe in the 1970s and has been administered to
more than 100 million patients so far. In Germany, beta-
histine is the first line treatment for Meniere’s disease in
clinical practice, before consideration of endolymphatic
sac surgery or ablative gentamicin treatment.30 The
drug is inexpensive and well tolerated, and is one of the
most frequently prescribed drugs for Meniere’s disease
in Europe.31 32 In the USA, betahistine is not approved by
the Food and Drug Administration but can be easily
obtained through US compounding pharmacies with a
prescription.
Several clinical studies assessing the effect of beta-
histine on the vestibular system and, to a lesser degree,
audiological symptoms suggested that the drug
improved these symptoms XXXXXXXXXXAccording to a Cochrane
systematic review of betahistine for Meniere’s disease
or syndrome, there is, however, insufficient evidence to
indicate whether betahistine has any effect.33 So far,
andomised controlled trials that meet high quality
standards are lacking, either due to inadequate diag-
nostic criteria or methods,35 or because the effect of
etahistine treatment on vertigo was assessed inade-
quately. To summarise, the limitations of the evidence
ase for preventive treatment strategies for Meniere’s
disease include:
• Predominance of trials investigating short term
effects (treatment periods of six months or less)
• Inclusion criteria of enrolled patients (for instance,
no differentiation between patients with the disease
and patients with other causes of vertigo)
• High dropout rates35 with potential for considerable
attrition bias
• Small trials or few placebo controlled trials36
• Varying quality of outcome measures for assessing
efficacy (including quality of life scores, functional
impairment, disability, and the number and severity
of acute attacks of vertigo).33
The dose of betahistine in these studies varied between
16 and 72 mg per day, which might explain the differ-
ences in symptom relief observed. Even higher doses of
up to 480 mg per day have shown benefit for severe
cases in a small case series, suggesting a possible effect
of high dose regimens in the treatment of Meniere’s dis-
ease.37 The drug seems to retain a good tolerability pro-
file. On the basis of many years’ clinical experience, the
dose was successively increased to 48 mg three times a
day, pointing towards the role of long term treatment
(up to 12 months). This dose increase was supported by
an open, uncontrolled, non-masked study without a
placebo arm that compared a high dose regimen of 48
mg three times daily with the recommended standard
dose of 16 or 24 mg three times daily.36 This non-inter-
ventional study showed that the higher dose was supe-
ior to the lower dose, and that the treatment effect of
etahistine on the incidence of attacks of vertigo
ecame more prominent over time.
Owing to variable methodological rigour and short-
comings in previous trials including the potential risk
of bias, the medical treatment of Meniere’s disease with
etahistine (BEMED) trial was designed. This investiga-
tor initiated, prospective, longitudinal, multicentre,
double blind, randomised, placebo controlled, three
arm, parallel group, phase III superiority trial aimed to
assess the long term prophylactic effects of betahistine
dihydrochloride in two different doses and placebo. The
doses and placebo were administered continuously for
nine months, and investigators observed their effect on
on 18 June 2021 by guest. Protected by copyright.
http:
w
w
w
.bm
j.com
BM
J: first published as XXXXXXXXXX
m
j.h6816 on 21 January 2016. D
ow
nloaded from
-
--
--
--
the bmj | BMJ 2016;352:h6816 | doi: XXXXXXXXXX
mj.h6816
RESEARCH
3
the frequency, duration, and severity of acute attacks
caused by Meniere’s disease, vertigo related impair-
ment of quality of life, and vestibular and audiological
function.
The trial also aimed to ascertain the speed of effect—
that is, whether the two active doses can be distin-
guished from each other or from placebo by how quickly
eduction in attack frequency is achieved.38 Addition-
ally, the tolerance and adverse events were examined.
We report the prespecified efficacy and safety analyses
at nine months for the BEMED trial.
Methods
Study population and protocol
Study participants were recruited by the outpatient diz-
ziness services in the neurology department or the ear,
nose, and throat department of 14 German university
hospitals. Patients were enrolled in the study from 31
March 2008 (first patient, first visit) to 5 November 2013
(last patient, last visit), including a three month
follow-up. Patients aged 18-80 years were eligible for
enrolment if they presented with two or more definitive
spontaneous episodes of vertigo of at least