Introduction

Treatment of vestibular vertigo is based on addressing the causative disease. Betahistine is most often used as a pharmaceutical therapy for Meniere's disease and other diseases accompanied by central and peripheral vestibular vertigo [1–6].

Betahistine is a partial agonist of histamine H1 receptors and an antagonist of histamine H3 receptors; it contributes to vestibular compensation and prevents the relapse of various diseases of the peripheral and central vestibular system that manifest as paroxysmal dizziness [7]. The efficacy of betahistine in the treatment of Meniere's disease and the prevention of vestibular vertigo attacks has been demonstrated in a large number of studies [8–11]. Betahistine is recommended as a treatment for the prevention of vestibular vertigo attacks and Meniere's disease exacerbations by both European [12] and the latest American clinical guidelines [13].

Treatment of most vestibular diseases requires long-term administration of betahistine, which raises the question of whether more convenient dosage forms, including prolonged-release forms, could increase patient adherence to treatment [14, 15].

Modified release (MR) betahistine 48 mg is a new formulation with a biphasic release of betahistine, which provides an initial rapid release phase to achieve a desired therapeutic concentration of betahistine, followed by an extended plateau that represents a prolonged release phase. It is assumed that betahistine MR 48 mg once daily could increase patients' treatment adherence, which is especially important with long-term therapy.

Here, the results of a clinical study aimed at evaluating the efficacy and safety of betahistine MR 48 mg once daily versus Betaserc® 24 mg twice daily in patients with Meniere's disease or vestibular vertigo are presented.

Materials and methods

A multicentre, randomized, double-blind, comparative clinical study was conducted at 18 clinical centres in the Russian Federation. The study was sponsored by the Development Company Chemical Diversity Research Institute Joint-Stock Company, RF, and commissioned by Abbott Products Operations AG, Switzerland. The study was reviewed and approved by the local ethics committee, and the patients provided their written consent to participate in this study.

The study included male and female patients aged between 18 and 75 years with a diagnosis of vestibular vertigo based on vestibular dysfunction, including definitive, probable or possible Meniere's syndrome/disease, according to the criteria of the American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNS), with at least 2 vertigo attacks within the 4 weeks prior to enrolment in the study and a total score on the Dizziness Handicap Inventory (DHI) scale of at least 31 points. The patients were randomized to one of two treatment groups and received double-blind treatment. The first group of patients received 1 tablet of betahistine MR 48 mg and 1 placebo tablet matched to Betaserc® 24 mg in the morning and one placebo tablet matched to Betaserc® 24 mg in the evening. In the second group, the patients received 1 placebo tablet matched to betahistine MR 48 mg and 1 tablet of Betaserc® 24 mg in the morning, and one tablet of Betaserc® 24 mg in the evening. From the beginning of screening and during the 12 weeks of treatment with the study drug, vestibular gymnastics and taking drugs to treat vertigo were not allowed, except for dimenhydrinate as a rescue medication.

The study consisted of a screening period of 4 weeks, a study drug treatment period of 12 weeks, and a follow-up period of 4 weeks. At visits (weeks 4, 8 and 12 after the onset of therapy), the efficacy and safety variables of the therapy were evaluated, and the drug was recorded and dispensed. The primary efficacy variable was the change from baseline in the DHI total score (0—100 points) after week 12 of treatment. Secondary efficacy variables were the changes in the scores for the physical, functional and emotional subdomains of the DHI scale; the changes in vertigo intensity, as measured using a visual analogue scale (VAS); the changes in the frequency, intensity and duration of vertigo attacks based on patient diaries; and the Clinical Global Impression – Improvement scale (CGI-I) score. The safety evaluation consisted of recording adverse events (AEs) and assessing the results of physical examinations, laboratory tests and ECG.

The study objective was to demonstrate that betahistine MR 48 mg once daily is non-inferior to Betaserc® 24 mg twice daily with respect to the primary endpoint: the change in the DHI total score after 12 weeks of study drug treatment. The predefined non-inferiority margin was selected on the basis of the minimum significant difference from placebo while maintaining at least 50% of the effect [10] and was set to 9 points on the DHI. With a one-sided significance level of 0.025 and a statistical power of 90%, the hypothesis of non-inferior efficacy was tested by calculating a one-sided 97.5% confidence interval (CI) for the difference in the mean change in the DHI total score between the two groups. Changes were compared between the two groups using a mixed model, with study site as the random factor and the baseline DHI total score as the covariate. Differences in secondary efficacy data between the two groups were analysed using the same model that was used in the primary analysis. Intragroup changes were tested for significance using the paired Student’s t-test or Wilcoxon’s test.

Results

Population description

Three hundred three (303) patients were assessed for eligibility, and thirty-nine (39) of them were excluded because they did not meet the inclusion criteria or met at least one exclusion criterion (Figure 1). Two hundred sixty-four (264) patients (132 in each group) were randomized and received the study drug treatment; of these, 255 completed the study according to the protocol, including 126 (95.5%) patients treated with betahistine MR and 129 (97.7%) patients who received Betaserc®. The two treatment groups were comparable in terms of demographic and other baseline characteristics (Table 1). The majority of the patients were women (76.0%), and the median age was 56 years. Meniere's disease was diagnosed in 35.6% and 34.1% of the patients in the betahistine MR group and the Betaserc® group, respectively, and another vestibular disorder was diagnosed in 64.4% and 65.9%, respectively.

Fig. 1. Changes in the Dizziness Handicap Inventory total score throughout the study.

Note: the data are presented for the efficacy evaluation population (N = 264) as mean values ± standard deviation; p <0.001 for comparing the mean values at week 4, 8 and 12 to the baseline value within each group; p = 0.095 for comparing groups at week 4, p = 0.072 — at week 8 and p = 0.428 at week 12.

Table 1. Demographic and other baseline characteristics

Note. * — mean ± standard deviation.

Efficacy evaluation

At baseline, the mean DHI total score was 57.8 ± 15.6 points in the betahistine MR group and 57.5 ± 16.2 points in the Betaserc® group. After 4 weeks of treatment, there was a statistically significant decrease in the DHI total score in both groups (p <0.001), and this decrease continued until the end of treatment (Figure 2). In 72.7% of the patients in the betahistine MR group and 72.0% of the patients in the Betaserc® group, the decrease in the DHI total score after week 12 of therapy was 18 points or more. The mean DHI score decrease was 32.0 ± 20.7 points in the betahistine MR group, which was similar to the decrease observed in the reference group, the Betaserc® group: 31.8 ± 19.8 points.

Fig. 2. Changes in vertigo intensity using the Visual Analogue Scale (VAS).

Note: the data are presented for the efficacy evaluation population (N = 264) as mean values ± standard deviation; p <0.001 for comparing the mean values at week 4, 8 and 12 to the baseline value within each group; p = 0.940 for comparing groups at week 4, p = 0.3 — at week 8 and p = 0.152 at week 12.

The baseline adjusted difference in the mean DHI change score between the betahistine MR group and Betaserc® group with one-sided 97.5% CI was 0.9 (–5.3) points. Because the upper confidence limit (+5.3) did not exceed the predefined non-inferiority margin of 9 points, non-inferiority of betahistine MR 48 mg once daily to Betaserc® 24 mg twice daily was established. An exploratory analysis in the subgroups of patients with Meniere's disease and vestibular vertigo demonstrated non-inferiority in these separate subgroups. In patients with Meniere’s disease, the adjusted difference between the mean DHI changes was — 2.2 with 97.5% CI (—6.4), and in patients with other vestibular vertigo, the adjusted difference was — 2.4 with 97.5% CI (–7, 2]).

The mean decreases in the DHI functional subscale score after 12 weeks of therapy were 12.1 ± 8.3 and 12.1 ± 8.8 points in patients taking betahistine MR or Betaserc®, respectively; for the emotional subscale, the mean decreases were 8.9 ± 8.4 and 9.2 ± 8.0 points; and for the physical subscale, the mean decreases were 10.1 ± 7.3 and 10.7 ± 7.1 points (p <0.001 within each group). Between the groups, no statistically significant difference in the change in each of the DHI subscales was demonstrated (p> 0.05).

At baseline, the mean frequency of vertigo attacks during the 4 weeks preceding the screening period was 7.8 ± 5.8 attacks in the betahistine MR group and 7.0 ± 4.9 attacks in the Betaserc® group. After 12 weeks of treatment, the mean number of attacks during the preceding 4 weeks was reduced to 2.7 ± 4.6 in the betahistine MR group and 2.4 ± 4.2 in the Betaserc® group (p <0.001 within each group). There was also a statistically significant decrease in the frequency of attacks with moderate and severe intensity compared with the baseline values; the frequency of attacks was reduced by 4.3 ± 5.6 in the betahistine MR group and by 3.3 ± 3.4 in the Betaserc® group (p <0.001 within each group) (Table 2). The mean frequency of attacks recorded during the 4 weeks after the completion of the study treatment period was 2.3 ± 2.9 attacks in the betahistine MR group and 2.4 ± 4.0 in the Betaserc® group, suggesting a prolonged posttreatment effect of both drugs.

Table 2. Evaluation of the number of vertigo attacks in the previous 4 weeks based on patient diaries

Note. * — mean ± standard deviation (median); ⁺ — p <0.001 for within-group comparisons with baseline data.

The decrease in vertigo intensity, as measured by the VAS, in patients taking betahistine MR at week 12 of therapy reached 32.5 ± 26.7 mm; in patients taking Betaserc®, it was 35.9 ± 25.1 mm (p <0.001 within each group, p = 0.152 for the between-group comparison).

The proportion of patients reporting severe or very severe symptoms during vertigo attacks decreased from 67.5% at baseline to 17.5% at Visit 5 (week 12) among patients in the betahistine MR group and from 69.7% to 17.4% of patients in the Betaserc® group (Table 3). The total number of severe and very severe attacks during the last 4 weeks decreased from 270 at baseline to 56 at Visit 5 and from 226 to 61 attacks after taking betahistine MR and Betaserc®, respectively. During treatment, a decrease in the duration of vertigo attacks was observed (Table 4). At baseline, attacks lasting 11 to 60 min were observed in 59.8% of patients in the betahistine MR group and 62.1% of patients in the Betaserc® group; attacks lasting from 1 hour to 6 hours were observed in 43.9% and 34.8% of patients, respectively. At Visit 5 (week 12), attacks lasting from 11 to 60 min were recorded in 20.5% of patients taking betahistine MR and 15.2% of patients taking Betaserc®; attacks lasting from 1 hour to 6 hours were recorded in 15.2% and 11.4% of patients, respectively.

Table 3. Assessment of the intensity of vertigo attacks based on data from patient diaries

Note: Evaluations were based on information in the patient's diary for the 4 weeks preceding the visit; the data for the efficacy evaluation population are presented as X (%)/Y, where X = the number of patients who experienced at least one event in this group, % = the percentage of patients who experienced at least one event in this group, and Y = the total number of events.

Table 4. Assessment of the duration of vertigo attacks based on data from patient diaries

Note: Evaluations were based on information in the patient's diary for the 4 weeks preceding the visit; the data are presented for the efficacy evaluation population as X (%)/Y, where X = the number of patients who experienced at least one event in this group, % = the percentage of patients who experienced at least one event in this group, and Y = the total number of events.

After 12 weeks of treatment, a marked or significant improvement was observed in 67.4% of the patients in the betahistine MR group and in 72.0% of the patients in the Betaserc® group. A slight improvement was observed in 22.0% and 14.4% of the patients, while no change was observed in 5.3% and 8.3% of the patients. Slight worsening was observed in 3.0% and 3.8% of the patients, respectively. In the betahistine MR group, significant deterioration was reported in 1 patient.

Safety evaluation and adverse reactions

During the study, 140 AEs in 44 (33.3%) patients taking betahistine MR and 160 AEs in 43 (32.6%) patients taking Betaserc® were reported. Most AEs were mild or moderate in severity and were not related to study drug intake, according to the investigators. Drug-related AEs developed in 7 (5.3%) and 13 (9.8%) patients in the betahistine MR and Betaserc® groups, respectively. In 3 cases, AEs resulted in the withdrawal of patients from the study. In the betahistine MR group, 2 AEs, nausea and dyspepsia, developed in 2 (1.5%) patients and resulted in their withdrawal from the study. Both AEs were of moderate severity and resolved completely. In the Betaserc® group, 1 AE – pain in the upper abdomen – resulted the withdrawal of 1 (0.8%) patient; the AE was of moderate severity and resolved completely. There were no relevant changes in the laboratory assessments between the groups. Overall, the safety profiles of the betahistine MR and the Betaserc® groups were similar.

Discussion

Treatment for many vestibular diseases requires the long-term administration of betahistine. In the case of Meniere's disease, betahistine is sometimes used for months or even years (the recommended course of therapy is 3—6 months) [16]. This raises the question of whether more convenient formulations, including prolonged ones, will help support patient treatment adherence (fulfilment, persistence and compliance) and possibly improve treatment efficacy. Furthermore, combining different formulations with new behavioural science approaches to treatment, together with patient support programmes, may further support a potential improvement in clinical outcome.

The main objective of the study was to evaluate the efficacy of betahistine MR 48 mg compared to registered Betaserc® 24 mg in patients with Meniere's disease or vestibular vertigo. The primary parameter for evaluating efficacy was the change in the DHI total score from baseline. The DHI scale has been validated to quantify the physical, functional and emotional aspects of dizziness and is widely used in clinical studies [16]. After 12 weeks of therapy, there was a statistically significant decrease in the DHI total score compared to baseline values in both patients taking Betahistine MR and patients taking Betaserc®; additionally, there was a statistically significant decrease in the total score for each of the three DHI sub-scales. Non-inferiority in change of DHI total score at week 12 compared to baseline was established between the treatment arms in the total study population and separately in subgroups of patients with Meniere’s disease and vestibular vertigo.

The clinical efficacy of betahistine in patients with vestibular vertigo and Meniere's disease was demonstrated in comparative controlled studies with placebo and active control [9, 10, 17 ,18], in meta-analyses [8, 19], and in observational studies [11, 19, 20]. According to the results of a randomized, placebo-controlled clinical trial by Mira et al. (2003), the intensity of symptoms, as measured in patients with vestibular vertigo (N = 144) using the DHI, at week 12 of betahistine treatment decreased by 65%, while in the placebo group, it decreased by 35% (10). In the international observational study OSVaLD (2005—2006), in patients with vestibular vertigo (N = 1898), the total DHI score after 12 weeks of betahistine treatment decreased by 37.2 ± 22.7 compared with baseline (p <0.001) [20], while in the Russian population (N = 204), it decreased by 39.2 ± 17.6 (p <0.001) [21].

In both treatment groups, there was a statistically significant decrease in the number of attacks and in the intensity of attacks, as measured with a VAS. According to data from patient diaries, the proportion of patients with severe and very severe symptoms during attacks, as well as the proportion with prolonged vertigo attacks, significantly decreased. According to the CGI-I scale, most patients reported marked or significant improvement at the end of the treatment period. Moreover, the dynamics of the variables were comparable between both treatment groups. The efficacy of betahistine for reducing the frequency, intensity and duration of attacks has been confirmed by previous studies, including those that considered cases of prolonged use [9–11, 19, 22]. In an open-label study by Strupp et al. (2008), in patients with Meniere's disease (N = 112), the mean number of vertigo attacks decreased from 7.6 to 4.4 after taking betahistine for 12 months at a dose of 16 or 24 mg twice a day; there was a much more significant decrease, from 8.8 to 1.0 attacks, over a 12-month course of treatment with betahistine at a dose of 48 mg twice a day [9].

In both treatment groups, the effects of betahistine on reducing the frequency, intensity and duration of vertigo attacks persisted after discontinuation of therapy during the 4-week follow-up period. A similar observation was made previously in patients with vestibular vertigo in the VIRTUOSO follow-up programme (N = 309), which found that the frequency of attacks not only did not increase during the two-month follow-up period but continued to decrease, with a statistically significant difference from the treatment completion visit (p <0.001), suggesting the prolonged effect of therapy after its discontinuation [11].

No significant effects of betahistine on clinical laboratory values, vital signs or ECG parameters were found. This study also showed no relevant differences in the safety profile of Betahistine MR 48 mg once daily compared to Betaserc® 24 mg twice daily.

Conclusion

Betahistine MR 48 mg once daily is non-inferior to Betaserc® 24 mg twice daily for improving symptoms in patients with Meniere's disease or vestibular vertigo, according to DHI scores after 12 weeks of therapy. Overall, the safety profile of betahistine MR 48 mg once daily is comparable to the safety profile of Betaserc® 24 mg twice daily. Betahistine MR 48 mg is recommended for once-daily use, which is more convenient for patients and could increase adherence to the prescribed therapy.

Acknowledgements

The authors acknowledge the following centres as well as their administration for their participation in the study: First Moscow State Medical University n.a. I.M. Sechenov (Vladimir Parfenov); Neuro-clinic LLC (Alexey Boyko); Moscow City Clinical Hospital N67 (Mark Loskutnokov); the 24^th City Clinical Hospital of Moscow Health (Grigory Rodoman); Scientific Clinical Centre of Russian Railways PLC (Eugeny Seredkin); Pavlov First SPb State Medical University, Clinic of Otorhinolaryngology (Sergey Karpishchenko); Integrative Medical Technologies LLC (Natalya Safonova); Saint-Petersburg Research Institute of Ear, Throat, Nose and Speech (Sergey Ryazantsev); Smolensk State Medical University (Natalya Maslova); Republican Clinical Neurological Centre (Farid Khabirov); Saratov State Medical University named after V.I. Razumovsky (Nikolay Makarov); Yaroslavl Region Clinical Hospital N8 (Aleksandr Malygin); Rostov State Medical University (Victor Balyazin); Leningrad Regional Clinical Hospital (Leonid Zaslavsky); Scientific Clinical Centre of Otorhinolaryngology (Olga Zaytseva); Scientific and Research Clinical Institute of Otorhinolaryngology n.a. L.I. Sverzhevskiy (Natalia Kunelskaya); Volga District Medical Centre (VDMC) under Federal Medical and Biological Agency (FMBA) (Maria Klimycheva); Saint-Petersburg City Clinical Hospital N40 (Alina Agafyina).

The research was carried out with the support of ABBOTT LLC LABORATORIZ.