Efficacy and safety of betahistine treatment in patients with Meniere’s disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial)
BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.h6816 (Published 21 January 2016) Cite this as: BMJ 2016;352:h6816
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We are unclear how the primary outcome was defined in this trial--specifically, whether it is a rate or a count, and how missing data were handled.
The publication in The BMJ defines the primary outcome as a rate "The primary efficacy outcome was the individual attack rate standardised on a 30 day interval (starting from timepoint 1—defined as the date of first intake, with the day of first study drug intake being day 1). The number of evaluated days was defined as the number of days with non-missing information about the patient’s vertigo status, as provided by the daily diary recordings. For example, a patient with 12 attacks during 75 documented days (that is, 75÷30=2.5 intervals) has the rate 12÷2.5=4.8. The 15 undocumented days out of the prespecified 90 day assessment period (starting day 181, ending day 270) were considered as missing at random." [1]
However the protocol [2], and two registry entries [3] [4] define the primary outcome as a count, e.g. the protocol states: "Primary efficacy endpoint is the number of vertigo attacks in the three treatment arms during the last three months of the nine months treatment period." [2]
Could the authors clarify this point, as the two methods would seem to treat missing data differently?
References
[1] http://www.bmj.com/content/352/bmj.h6816
[2] http://www.bmj.com/content/bmj/suppl/2016/01/21/bmj.h6816.DC1/adrc027003...
[3] http://www.isrctn.com/ISRCTN44359668?link_type=ISRCTN&access_num=ISRCTN4...
[4] https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-000752-32/DE
Competing interests: Peter Doshi is an associate editor at The BMJ.
Long term low dose betahistine in Meniere’s disease
MGWard MbChB MRCGP, October 2017
While attending a GP update course in Glasgow I was concerned when one of the presenters suggested that, in the light of a BMJ article (BMJ 2016,352:h6816) regarding a German study looking at the efficacy of betahistine treatment for Meniere’s disease, that as GPs we should review all our patients taking long term betahistine with a view to stopping what he described as “inappropriate” medication.
As a GP and Meniere’s sufferer I found this alarming being counter to my own experience. My Meniere’s first presented in my early 20s as transient left hearing associated with fullness sensation and sound distortion loss and recurred in my mid 30s. Each time spontaneous resolution occurred and it was not until in my 50s that symptoms recurred in association with episodes of vertigo. These became more frequent and more severe and a formal diagnosis was made and I was started on betahistine 8mg 3 times daily. The effect on the vertigo episodes seemed dramatic and I have only had one mild episode since taking it regularly. On the basis of personal experience I believe that betahistine can reduce the frequency and severity of Meniere’s related vertigo episodes whilst having little influence on audiological symptoms and audiometric decline.
Whilst it is possible my vertigo episodes settled by coincidence when I started to take betahistine I am very reluctant to stop it as the vertigo episodes had become quite debilitating. If the symptoms had progressed further, or started to occur with little warning, it could have threatened my driving and work as a GP. I liken the situation to someone who has been treated for epilepsy for many years and after being seizure free for a time a neurologist might advise a trial without medication but the patient declines for fear of losing his/her driving license. It would be unusual in such circumstance for a doctor to insist that a patient should stop the anticonvulsant.
I have concerns about the German study and I think further research is required. The study concluded that the frequency of vertigo episodes as recorded over 3 month follow up (months 7-9 of treatment) was no different between the treatment and placebo cohorts. I raise the following issues that might impact on the validity of the results and conclusions.
• The trial involved randomised selection of patients to receive either betahistine or placebo with follow up symptom recording in accordance with protocol. However both arms of the trial patients received “doctored” preparations. The betahistine tablets and placebo tablets were over coated with mannitol and aerosil. Mannitol is a licensed drug used widely in the USA and has diuretic properties and interacts with an extensive list of drugs. It has listed side effects including dizziness. Can the authors exclude the possibility of a confounding effect even if the dose of mannitol was small?
• Aerosil (fumed silica) also has potential toxicity effects/interactions.
• Considerable measures were taken to make the placebo preparations identical to the treatment preparations so could human error have resulted in batch mix up with significant numbers of the randomised treatment group receiving placebo instead of betahistine and or vice versa? This would confound the results.
• The study results might be more meaningful if symptom recording was started from the outset and continued for a full 12 months. Why were months 7-9 chosen? My apparent benefit was evident within the first month of treatment and has continued.
• The dose regimens used in Germany seem high
with low dose regime stated as 24-48mg and high dose regime 3 x 48mg/day. This could make any detectable benefit of a truly low dose regime using the NHS prescribable 8mg tabs x 3 per day (as used by me and no doubt many others in the UK) obscured by the relative majority receiving the higher dose German regimes. Can the authors exclude the possibility that higher doses negate a positive low dose benefit? To my knowledge in the UK 24mg tablets and 48mg are not available and the strengths commonly used are 8mg and 16mg tablets. Thus the German treatment regimens and results may not be directly comparable to the UK .
• Is it possible that true and severe acute vertigo frequency decline may have been obscured by a predominance of none vestibular related dizziness symptom recording?
• Was there in depth analysis of the drop out patients in both groups to exclude the possibility of a statistically significant drop out in the placebo group because of symptom relapse?
• Meniere’s is a rare disease (estimated at 1-2/1000). With the absence of a definitive test and with symptoms of dizziness being relatively common is it possible that the trial included significant numbers of patients who in fact do not have the disease confounding results? The ENT Professor who I first consulted expressed the view that Meniere’s disease was over diagnosed.
I think that calls for GPs to withdraw betahistine medication for those patients who feel it has reduced their symptoms is premature, particularly in asserting that the medication is “inappropriate”. Like many epilepsy sufferers, continued medication might prove to be unnecessary but patients who have faith in their medication and where symptom recurrence could have potentially draconian effects for their work or risk their driving license, should not in my view be made to feel obligated to cease their medication.
I believe there is a need to undertake further studies before advocating widespread cessation of betahistine therapy. I call for more research into the disease, its pathogenesis and the role of betahistine. I am intrigued by existing research* that has demonstrated that betahistine increases cochlea blood flow in guinea pigs which could be an indicator of therapeutic effect mechanism. This could provide at least one direction for further research and a better understanding of the condition.
*Betahistine metabolites increase cochlea blood flow in guinea pigs in vivo: authors Bertlich, Mattis, Ihler Fritz International Journal of Audiology, Vol 53(10), Oct 2014 pp.753-759
Competing interests: No competing interests
Dear Editor,
The results showing a lack of efficacy for betahistine in the randomized clinical trial performed by Adrion et al. (1) will not come as a surprise for most of ENT doctors dealing with Meniere´s disease (MD), since it is a phenotypically heterogeneous disorder. Although the clinical diagnosis is well established by the previous criteria of the American Academy of Otolaryngology-Head and Neck Surgery (1995), and later by the more precise criteria of the Bárány Society (2015), the clinical scenario is more complex. We know that the migraine is a comorbidity in over 30% of MD patients (2)(3). Furthermore, it has been reported that during vertigo episodes, 45% of patients experienced at least one migraine symptom (4), 41% of patients suffered from headaches and 8.4% of patients reported experiencing migraine-type headaches (5). Despite the fact that low-to-mid frequency sensorineural hearing loss is the most common audiometric finding at early stages, other hearing profiles have been described (6). Moreover, a vestibular hypofunction in caloric testing is observed in up to 75% of patients with MD (7), whereas a normal bithermal caloric response has been reported in up to 50% of patients in some series. The clinical course of the episodes of vertigo and hearing loss is also variable (8). Bilateral involvement has been reported in 25-40% of patients, and a family history is found in 8-9% of sporadic cases (9)(10). Finally, subsets of patients with other otologic co-morbidities such as otosclerosis or benign paroxysmal positional vertigo have been described. All these findings show that the clinical picture is variable and it is not only limited to the classical triad.
Endolymphatic hydrops is considered more as an epiphenomenon associated with several inner ear disorders, including MD (11). Current epidemiological data evidence strong associations between allergy, autoimmune diseases, and MD (12)(13). This suggests that food or respiratory allergens, infectious agents, vascular events or genetic factors could trigger an imbalance in inner ear homeostasis. Several regulatory factors such as the innate immune response, the endocrine system or the autonomic nervous system may also influence the development of the partial or complete phenotype observed in familial MD (14). The cumulative effect of one or several triggers and the individual response may explain the clinical heterogeneity observed in MD phenotype (15).
Betahistine is a structural analogue of histamine that acts as weak partial postsynaptic histamine H1 receptor agonist and presynaptic H3 receptor antagonist. Betahistine acts not only to improve labyrinthine microcirculation, but also acts on the histaminergic system at a central level (16). The clinical efficacy of betahistine has been evaluated in several trials and there is conflicting evidence. Undoubtedly, the study by Adrion et al. is rigorous and methodologically sound, but other studies, including some from the same group of authors, have reported a significant benefit, especially at high-doses and long term prophylactic treatment (17)(18). A meta-analysis including twelve double-blind, randomized, placebo-controlled clinical studies with betahistine in patients suffering from vestibular vertigo or Ménière's disease performed in 2013 concluded the therapeutic benefit of betahistine on vertiginous symptoms in both Ménière's disease and vestibular vertigo (19).
These reported discrepancies among several studies could be explained not only by methodological bias (20), but also may be related to the clinical heterogeneity of MD.
The clinical variability observed probably reflects different underlying mechanisms contributing to MD. Therefore, we can hypothesize the existence of a subset of patients with an allergical background which could explain the benefits of betahistine reported in some studies. This hypothesis needs to be contrasted in future clinical studies.
An improved phenotyping of these patients, including a precise characterization of the headache during vertigo episodes to differentiate vestibular migraine and MD (5), and also towards other aspects such as allergy, autoimmunity and genetic factors, could induce a greater understanding of the pathophysiology of the disorder and the development of effective treatment strategies.
REFERENCES
1. Adrion C, Fischer CS, Wagner J, Gürkov R, Mansmann U, Strupp M. Efficacy and safety of betahistine treatment in patients with Meniere's disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial). BMJ 2016;352:h6816.
2. Parker W. Menière's disease. Etiologic considerations. Arch Otolaryngol Head Neck Surg 1995;121:377-82.
3. Shin JE, Kim CH, Park HJ. Vestibular abnormality in patients with Meniere's disease and migrainous vertigo. Acta Otolaryngol 2013;133:154-8.
4. Radtke A, Lempert T, Gresty MA, Brookes GB, Bronstein AM, Neuhauser H. Migraine and Ménière's disease: is there a link? Neurology 2002;59:1700-4.
5. Lopez-Escamez JA, Dlugaiczyk J, Jacobs J et al. Accompanying symptoms overlap during attacks in Menière's disease and vestibular migraine. Front Neurol 2014;5:265.
6. Mancini F, Catalani M, Carru M, Monti B. History of Meniere's disease and its clinical presentation. Otolaryngol Clin North Am 2002;35:565-80.
7. Wang HM, Tsai SM, Chien CY, Ho KY. Analysis of auditory and vestibular function in patients with unilateral Meniere's disease. Acta Otolaryngol 2012;132:1246-51
8. Perez-Garrigues H, Lopez-Escamez JA, Perez P et al. Time course of episodes of definitive vertigo in Meniere's disease. Arch Otolaryngol Head Neck Surg 2008;134:1149-54.
9. Hietikko E, Kotimäki J, Sorri M, Männikkö M. High incidence of Meniere-like symptoms in relatives of Meniere patients in the areas of Oulu University Hospital and Kainuu Central Hospital in Finland. Eur J Med Genet 2013;56:279-85
10. Requena T, Cabrera S, Martín-Sierra C, Price SD, Lysakowski A, Lopez-Escamez JA. Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease. Hum Mol Genet 2015;24:1119-26
11. Merchant SN, Adams JC, Nadol JB Jr. Pathophysiology of Meniere's syndrome: are symptoms caused by endolymphatic hydrops? Otol Neurotol 2005;26:74-81.
12. Gazquez I, Soto-Varela A, Aran I et al. High prevalence of systemic autoimmune diseases in patients with Menière's disease. PLoS One 2011;6:e26759.
13. Tyrrell JS, Whinney DJ, Ukoumunne OC, Fleming LE, Osborne NJ. Prevalence, associated factors, and comorbid conditions for Ménière's disease. Ear Hear 2014;35:e162-9.
14. Requena T, Espinosa-Sanchez JM, Cabrera S et al. Familial clustering and genetic heterogeneity in Meniere's disease. Clin Genet 2014;85:245-52.
15. Espinosa-Sanchez JM, Lopez-Escamez JA. Meniére´s disease. Handb Clin Neurol 2016 (in press).
16.Lacour M. Betahistine treatment in managing vertigo and improving vestibular compensation: clarification. J Vestib Res 2013;23:139-51.
17. Strupp M, Hupert D, Frenzel C, Wagner J, Hahn A, Jahn K, Zingler VC, Mansmann U, Brandt T. Long-term prophylactic treatment of attacks of vertigo in Menière's disease--comparison of a high with a low dosage of betahistine in an open trial. Acta Otolaryngol 2008;128:520-4.
18. Ganança MM, Caovilla HH, Ganança FF. Comparable efficacy and tolerability between twice daily and three times daily betahistine for Ménière's disease. Acta Otolaryngol 2009;129:487-92.
19. Nauta JJ. Meta-analysis of clinical studies with betahistine in Ménière's disease and vestibular vertigo. Eur Arch Otorhinolaryngol 2014;271:887-97
20. Harcourt J, Cosentino S. Betahistine for Meniere's disease. BMJ 2016;352:i46.
Juan M. Espinosa-Sanchez 1,2, Angel Batuecas-Caletrio 3, Jose A. Lopez-Escamez 1,4
1 Otology & Neurotology Group CTS495, Human DNA Variability Department, GENYO Centre for Genomics and Oncological Research Pfizer -University of Granada -Andalusian Regional Government, PTS Granada, SPAIN.
2 Department of Otolaryngology, Hospital San Agustin, Linares, Jaen, SPAIN
3 Department of Otolaryngology, Hospital Clínico Universitario, Salamanca, SPAIN
4 Department of Otolaryngology, Complejo Hospitalario Universitario de Granada, Granada, SPAIN
Correspondence: antonio.lopezescamez@genyo.es
Competing interests: No competing interests
Question about primary outcome definition in the BEMED trial: Author response
Dear Editor,
We thank Dr Doshi for his letter to our BMJ article [1] and would make the following points to clarify matters:
As stated in the trial registries, the protocol, the abstract or other parts of the main text, the pre-specified primary efficacy outcome measured for each study participant at each time interval was the absolute number (incidence) of Menière’s attacks per 30 days, hence a count outcome derived from the daily diary recordings. This means that the raw daily diary data (i.e., the documented vertigo symptoms evaluated according to prospectively defined rules) were summarized using absolute frequencies over the 30-day time intervals. Each patient’s diary was assessed for the whole study duration before unblinding.
As part of the principal outcome, the number of documented diary days per 30 days cannot be ignored in order to properly account for missing data concerning the patient’s vertigo status (see, e.g., the missingness map displayed in Figure S1 of the Web appendix 2). This implies the use of incidence rates (number of counts per day) for the time periods of interest. In this regard, we have to admit that the terminology we used could have been better.
The primary analysis approach was in line with the primary estimand including handling of missing data due to incomplete diary documentation or study treatment discontinuation.
Following the principle of intention to treat (i.e. all participants that satisfied the exclusion criteria were analysed as belonging to the treatment arms to which they were randomized, regardless of whether they received or adhered to the allocated intervention for the full duration of the trial), this MAR-based analysis was performed according to an "all observed data strategy" [2]. This likelihood based approach of all observed outcome data conducted such that it is valid under MAR is optimally statistically efficient, and therefore was considered to be a reasonable primary analysis for this trial [3, 4].
Principal model:
The primary efficacy analysis for the outcome variable "number of Menière’s attacks per 30 days" was performed using a negative binomial generalized linear mixed model (NB GLMM) with a log link function, random intercept and random slope associated with time (see methods section of the article). One of the underlying key parametric assumptions was a linear time trend. To account for incomplete diary documentation (incomplete vertigo profile) an offset variable for the log-transformed absolute number of evaluated days ("time at risk", "exposure time") per 30 days was defined. Therefore, the observation window was allowed to vary for each 30 day time unit of a patient. The merits of using a negative binomial model accounting for an explicit dispersion parameter as an alternative way of inflating the variance to allow for this variation from patient to patient are reported elsewhere [e.g. 5-7].
Since it is important to pre-specify the precise definition of the primary endpoint together with the method of statistical analyses that will be applied a statistical analysis plan (SAP) was prepared (unpublished document). The SAP was updated as a result of the blind review of the data and finalized before the blind was broken. There was complete transparency in relation to protocol changes in our SAP where we devoted a whole chapter to the subject and the chosen principal model, as the primary analysis strategy outlined in the protocol which was purely based on hypothesis testing instead of specifying a target parameter of interest was no longer appropriate.
Besides, corresponding sensitivity analyses to assess the robustness of the longitudinal, subject-specific modelling approach used to address the scientific question were prospectively planned in the SAP as well.
The parameters of primary interest as a basis for a comparison between treatment conditions were 1.) the rate ratios (RR) - LD vs PL and HD vs PL - together with 2.) the overall decay rate of attacks over time on placebo, estimated from the mixed effects regression model. The underlying model assumed a group-specific decline in the number of attacks per 30 days over the nine time intervals, as well as individual variations of the baseline level and the speed of change ("speed of efficacy") for the number of attack per 30 days for the LD and HD group, respectively.
Measure of the intervention effect and pre-specified target estimate:
The applied modelling approach can be used to derive the treatment effect within the assessment period month 7 to 9 (time period of primary interest) pre-specified in the trial protocol. The estimated population-averaged (marginal) mean number of attacks per 30 days at month 7 to 9 can be interpreted as the population-level summary measure (treatment effect measure) addressing the scientific question of primary interest targeting the last 3 months of the 9-month treatment period.
REFERENCES
[1] Adrion C, Fischer CS, Wagner J, Gurkov R, Mansmann U, Strupp M On behalf of the BEMED study group. Efficacy and safety of betahistine treatment in patients with Meniere's disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial). BMJ 2016; 352: h6816.
[2] White IR, Carpenter J, Horton NJ. Including all individuals is not enough: lessons for intention-to-treat analysis. Clin Trials 2012; 9(4):396-407.
[3] National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials. Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and Social Sciences and Education. The National Academies Press, Washington, DC, 2010. URL www.nap.edu/catalog/12955.html.
[4] CHMP. Guideline on Missing Data in Confirmatory Clinical Trials. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), London, UK, 2010. URL http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin.... EMA/CPMP/EWP/1776/99 Rev. 1. Date for coming into effect: 1 January 2011.
[5] Keene ON, Calverley PM, Jones PW, Vestbo J, Anderson JA. Statistical analysis of exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Eur Respir J 2008;32(1):17-24.
[6] Suissa S. Statistical treatment of exacerbations in therapeutic trials of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173(8):842-6.
[7] Keene ON, Jones MR, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the TRISTAN study. Pharm Stat 2007;6(2):89-97.
Competing interests: No competing interests