the assignment is journal appraisal, the questions need to be answered by reading the document and guide
the bmj | BMJ 2016;352:h6816 | doi: 10.1136/bmj.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 Correspondence 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/bmj.h6816) Cite this as: BMJ 2016;352:h6816 http://dx.doi.org/10.1136/bmj.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, randomised, placebo controlled, three arm, parallel group, phase III, dose de"ning superiority trial conducted in 14 German tertiary referral centres (for neurology or ear, nose, and throat). Adults aged 21-80 years (mean age 56 years) with de"nite unilateral or bilateral 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=0.759). Compared with placebo, attack rate ratios were 1.036 (95% con"dence interval 0.942 to 1.140) and 1.012 (0.919 to 1.114) for low dose and high dose betahistine, respectively. The overall monthly attack rate fell signi"cantly by the factor 0.758 (0.705 to 0.816; P<0.001). the="" population="" based,="" mean="" monthly="" incidence="" averaged="" over="" the="" assessment="" period="" was="" 2.722="" (1.304="" to="" 6.309),="" 3.204="" (1.345="" to="" 7.929),="" and="" 3.258="" (1.685="" to="" 7.266)="" for="" the="" placebo,="" low="" dose="" betahistine,="" and="" high="" dose="" betahistine="" groups,="" respectively.="" 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="" current="" 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="" relevant="" 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="" reported="" in="" full="" at="" the="" end="" of="" the="" paper="" on="" thebmj.com.="" data="" are="" available="" from="" the="" corresponding="" author="" (michael.strupp@med.uni-muenchen.de)="" or="" biostatistician="" (mansmann@ibe.med.uni-muenchen.de).="" study="" registration="" eudract="" no="" 2005-000752-32;="" isrctn="" no="" isrctn44359668.="" introduction="" meniere’s="" disease="" is="" characterised="" by="" recurrent="" 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="" 100="" 000="" people,="" 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="" recurrence;="" 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="" 10.1136/bm="" j.h6816="" on="" 21="" january="" 2016.="" d="" ow="" nloaded="" from="" -=""> - doi: 10.1136/bmj.h6816 | BMJ 2016;352:h6816 | the bmj RESEARCH 2 man. 4 5 Annual incidence of the disease in the USA was 15.3 per 100 000 people (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 based 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 membrane,11 12 endo- lymphatic sac surgery,13 or pulsed low pressure delivery (using Meniett devices)).14-17 For patients who do not respond 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.20-23 However, these interventions are irreversible and could damage the cochlear and vestibular organ; furthermore, a recent Cochrane review could not show any evidence of benefit 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 blood 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 resorption 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.33 34 According 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, randomised controlled trials that meet high quality standards are lacking, either due to inadequate diag- nostic criteria or methods,35 or because the effect of betahistine treatment on vertigo was assessed inade- quately. To summarise, the limitations of the evidence base 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- rior to the lower dose, and that the treatment effect of betahistine on the incidence of attacks of vertigo became 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 betahistine (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 10.1136/bm j.h6816 on 21 January 2016. D ow nloaded from -> -- -- -- the bmj | BMJ 2016;352:h6816 | doi: 10.1136/bmj.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 reduction 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