Efficacy and Safety of Intranasal Betahistine in the Treatment of Surgery-Induced Acute Vestibular Syndrome: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Study : Otology & Neurotology

Secondary Logo

Journal Logo


Efficacy and Safety of Intranasal Betahistine in the Treatment of Surgery-Induced Acute Vestibular Syndrome: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Study

Van de Heyning, Paul; Betka, Jan; Chovanec, Martin; Devèze, Arnaud§; Giannuzzi, Anna Lisa; Krempaská, Silvia; Przewoźny, Tomasz∗∗; Scheich, Matthias††; Strupp, Michael‡‡; Van Rompaey, Vincent; Meyer, Thomas§§

Author Information
Otology & Neurotology 44(5):p 493-501, June 2023. | DOI: 10.1097/MAO.0000000000003856



Acute vestibular syndrome (AVS) is described as sudden onset of continuous vertigo lasting days to weeks and associated with nausea, head motion intolerance, and unstable balance (1,2). Underlying disorders include vestibular neuritis, multiple sclerosis, postconcussion syndrome, or stroke, among others, with traumatic, inflammatory, vascular, or genetic mechanisms altering vestibular inputs (1,3). Reduced postural control and gaze stability together with associated neurovegetative symptoms can have a significant effect on patients’ day-to-day functioning and quality of life (4). AVS frequently improves spontaneously through vestibular compensation based on restoration, habituation, and adaptation processes (4). Central compensation may be aided by pharmacologic treatment or vestibular rehabilitation therapy.

Histamine is known to play a key role in the regulation of vestibular function and recovery after lesions through central vestibular compensation (5). Betahistine is a histamine analog that acts at the histamine H1 and H3 receptors and modulates the release of other neurotransmitters, particularly GABA (5–7). It has been shown to increase the synthesis and release of histamine in the vestibular nuclei, restore the excitability of vestibular neurons, and help to rebalance bilateral neuronal activity of the peripheral vestibular system (5,8). Further, betahistine has been shown to increase inner ear blood flow (9–11).

Betahistine is widely used for the treatment of vestibular disorders (12). However, evidence for betahistine’s therapeutic utility is not unequivocal (13,14). Apart from the challenging nature of Ménière’s disease and difficulties in measuring outcomes, betahistine’s clinical efficacy has also been limited by its poor oral bioavailability, which is reported to be only around 1% (15). After absorption, the compound undergoes extensive presystemic metabolism by monoamine oxidase (MAO) enzymes, and its primary metabolite 2-pyridylacetic acid has no known pharmacologic activity in humans. Accordingly, plasma levels of betahistine after standard oral dosing (up to 48 mg/day) are very low and have been reported to be undetectable or below 0.5 ng/mL (16–18).

As shown in a cat model of unilateral vestibular neurectomy, higher exposure to betahistine results in more pronounced postural function recovery and significantly accelerated vestibular compensation; in addition, the histaminergic activity of the neurons in the tuberomammillary nuclei was significantly increased (19). Two clinical trials in vestibular neurectomy suggested beneficial effects of betahistine on vestibular compensation also in humans (20,21). Intranasal administration of betahistine allows to avoid the first-pass effects associated with oral intake and achieve higher systemic exposure because there is only little MAO presence in the nasal mucosa (22).

The phase 2 TRAVERS trial (multicenter randomized controlled phase 2 trial to evaluate AM-125 in the treatment of acute peripheral vertigo after surgery) was conducted to test the safety and efficacy of intranasal betahistine for proof of concept in the well-defined model of surgery-induced AVS.


Study Design and Participants

TRAVERS comprised a dose escalation (A) and a subsequent parallel dose part (B). For reference, an oral betahistine group was included (open label; Supplemental Digital Content 1, https://links.lww.com/MAO/B592). The trial involved 12 recruiting sites (tertiary referral centers) in Belgium, Czech Republic, France, Germany, Italy, Poland, and Slovakia, which enrolled eligible patients between July 2019 and February 2022. It was registered on the EU Clinical Trials Register (EudraCT 2018-002474-52) and was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonisation and Good Clinical Practice guidelines. The study was approved by appropriate independent ethics committees and regulatory agencies.

Eligible participants were 18–70 years old and scheduled for vestibular schwannoma (VS) resection (Koos grades I–III; Samii grades T1–T3b; ≤30 mm in diameter in cerebellopontine angle, not displacing the brainstem), labyrinthectomy, or vestibular neurectomy. Larger tumors were excluded because of their compression of central nervous structures, which affects vestibular function, vestibular compensation, and the performance of balance tests (21). Preoperative vestibular function was confirmed by caloric videonystagmography (sum of bithermal maximum slow phase velocity >6°/s on affected side and >10°/s contralaterally). Three days postsurgery, before randomization, the presence of AVS was confirmed by observation of 1) vertigo (illusion of movement rated ≥2 on European Evaluation of Vertigo (EEV) questionnaire), 2) spontaneous nystagmus beating toward the contralateral side, and 3) deviation of the subjective visual vertical (SVV) >2.5° from the true vertical.

Exclusion criteria included prior radiotherapy, preoperative vestibular rehabilitation or gentamicin therapy, other ongoing peripheral vestibular disorders, ongoing or planned antihistamine, antiemetic, or benzodiazepine treatment. Patients with contraindicating surgery-related complications; relevant orthopedic or visual limitations; psychiatric, respiratory, cardiovascular, or neurological disorders; relevant limitations for intranasal delivery; pheochromocytoma; or a history of alcoholism or drug abuse were also excluded. Women who were breastfeeding, pregnant, or who planned a pregnancy during the study, or women of childbearing potential who declared being unwilling or unable to practice an effective method of contraception were not included.

Written informed consent was obtained from each patient before the performance of any study-specific procedures.

Randomization and Masking

At baseline (day 3), patients in part A were randomized to receive AM-125 (1, 10, or 20 mg) or placebo nasal sprays (vehicle only) at a 4:1 ratio. Escalation to the next higher dose was based on the review of safety data from the ongoing dose cohort up to day 14 by an independent data and safety monitoring board and their approval. After the selection of two active dose levels in an interim analysis, a fresh set of patients were randomized in part B to active or placebo at a 1:1:1 ratio. The study drug was identical in appearance for active and placebo and revealed no differences during administration. It was provided to study sites in numbered but otherwise identical kits. Patients were randomized centrally to a kit number using an integrated electronic data capture/interactive web response system with stratification for age (<50 yr/≥ 50 yr), as balance test performance starts to deteriorate in the fifth decade (23,24). Patients, study personnel, and trial sponsor were blinded about the assigned treatments throughout the entire study.


The study consisted of a screening visit up to 4 weeks before surgery, randomization, and baseline assessments on day 3 postsurgery and follow-up visits on days 7, 14, 28, and 42. Baseline safety assessments included a general physical examination, nose and throat examination, vital signs, hematology, and blood chemistry and a urine pregnancy test for women of childbearing age. At each study visit, the standing on foam (SOF) test, using a board on top of the cushion, and the tandem Romberg test (TRT) were performed (eyes closed, max 30 s). Additionally, the tandem gait test (TGT) with walking on a straight line for a maximum of 20 steps was conducted. All balance tests were repeated thrice, and the best value was used for further evaluation. SVV was determined with the “bucket test” (25), using the mean of 10 trials, and spontaneous nystagmus with noncaloric videonystagmography or Frenzel goggles.

Before balance tests, investigators evaluated vertigo and its main symptoms with the EEV (26); patients completed the Vestibular Rehabilitation Benefit Questionnaire (VRBQ [27]; part B only). Nasal tolerability was self-assessed through the Total Nasal Symptom Score (TNSS) questionnaire predose and 10, 30, and 60 minutes postdose.

Treatment started on day 3 and was self-applied t.i.d. until day 28 at 7:00 AM, 1:00 PM, and 7:00 PM (±1 h) with one puff of spray into each nostril (0.1 mL of betahistine 5, 50, or 100 mg/mL or placebo formulation) and orally by tablet (16 mg betahistine). Plasma concentrations of betahistine were determined for exposure verification up to 60 minutes after administration at day 3 (first dose) and day 28 (last dose) in part A. Patients were instructed to perform twice a day a standardized vestibular rehabilitation program (28,29) during the treatment period. Compliance with treatment and rehabilitation therapy was recorded in a patient diary.


The improvement in TRT from baseline was selected as primary efficacy outcome. Secondary endpoints included the improvement in SOF, TGT, SVV, and frequency of horizontal spontaneous nystagmus. Improvement in the VRBQ was an exploratory endpoint. The primary safety endpoint was the frequency of moderate or severe nasal symptoms. Secondary endpoints included the frequency of adverse events (AEs) and any nasal symptoms.

Statistical Methods

Efficacy analyses were performed on the “intention-to-treat set”, which included all randomized patients, and on the “per protocol” set, who received at least on dose of study drug and had no major protocol deviations interfering with the primary endpoint analysis. The “safety population” analysis set included all patients who received study drug.

Efficacy endpoint analyses for intranasal treatments were performed in a mixed-effect model with repeated measures using pooled part A and part B data. Randomized treatment, time, and time-by-randomized treatment interaction were fitted as fixed effects with baseline value as a covariate. Patients were included as a random effect, and the analysis was stratified by age. Because this was a proof-of-concept study, no alpha adjustment for multiplicity was applied. The primary safety endpoint was analyzed using exact logistic regression.

The sample size was estimated based on published data from an independent trial in VS patients (30). For part A, a size of 10 patients per dose was estimated to establish a dose–response function. For part B, n = 24 per arm were estimated to provide 80% power to detect a treatment effect of 5.8 seconds at the one-sided alpha level of 0.05.


Patient Flow and Characteristics

The CONSORT (31) trial profile is shown in Figure 1. A total of 169 patients were screened of whom 108 were randomized and treated intranasally and 16 were treated orally; 92.6% of patients completed the study. Baseline demographics and VS characteristics are presented in Table 1. Mean patient age was 52 years; the majority of participants was female (60%). The mean VS size was 10.3 mm, with Koos grade II accounting for 62% of cases, followed by grade I (26%) and grade III (12%). Preoperatively, the average canal paresis was 28.7%. At baseline, all patients experienced spontaneous nystagmus (mean, 43.4 beats/30 s), a mean SVV of 7.0°, and EEV score of 11.6 points (Table 2). Postural control was poor with mean time to failure of 1.5 and 3.6 seconds for the TRT and SOF tests, respectively, and 1.8 steps to failure for the TGT. Overall, patient demographics were similar across treatment groups, whereas characteristics of the tumor, surgical approaches, and postsurgical AVS and balance test performance showed more variability.

FIG. 1:
Patient flow diagram. A total of 169 patients were screened for the TRAVERS trial, of which 108 were enrolled into the double-blind main part of the trial for randomization to intranasal betahistine (AM-125) or placebo and 16 into an open-label arm to receive oral betahistine for reference. In part A of the trial, escalating doses of AM-125 (1, 10, and 20 mg) and intranasal placebo were administered at a ratio of 8:2. Between part A and part B, while results from dose escalation where read out to select two active intranasal dose levels for part B, the open-label group was enrolled. In part B, patients were randomized to one of three parallel dose groups: AM-125 at 10 or 20 mg or placebo. For analyses, data from patients in parts A and B were pooled. In the main part of the trial, a total of 108 patients were included in the “intention-to-treat” (ITT) analysis set and 90 patients in the “per protocol” analysis set (open-label arm: 16 and 15 patients, respectively). Three patients terminated the trial prematurely because of adverse events and 2 patients for other reasons, 2 patients withdrew consent, and 1 patient was lost to follow-up (open-label group: 1 patient withdrew consent). The “safety population” analysis set was congruent with the ITT analysis set.
TABLE 1 - Patient demographics and vestibular schwannoma characteristics
Gender, n (%) Placebo (n = 32) AM-125 1 mg (n = 9) AM-125 10 mg (n = 34) AM-125 20 mg (n = 33)
Male 10 (31) 4 (44) 16 (47) 14 (42)
Female 22 (69) 5 (56) 18 (53) 19 (58)
Age (yr)
Mean ± SD 52.4 ± 10.5 48.7 ± 12.3 52.4 ± 10.4 52.2 ± 10.9
Range (yr) 24 to 68 25 to 67 30 to 69 29 to 69
Surgery indication, n (%)
Vestibular schwannoma 30 (94) 9 (100) 33 (97) 32 (97)
 Endolymphatic sac carcinoma 1 (3) 0 (0) 1 (3) 0 (0)
 Vestibular neurectomy 0 (0) 0 (0) 0 (0) 1 (3)
 Facial nerve schwannoma 1 (3) 0 (0) 0 (0) 0 (0)
Vestibular schwannoma size (mm)
 Mean ± SD 11.6 ± 8.7 8.7 ± 8.1 8.3 ± 7.7 10.5 ± 7.8
 Median 12.0 7.0 10.0 11.5
 Range 0–28 0–23 0–28 0–25
Canal paresis (calorics) (%)
 Mean ± SD 35.3 ± 24.9 33.2 ± 23.1 26.2 ± 21.1 24.9 ± 18.7
 Median 28.3 37.5 26.6 25.6
 Range 4–94 4–69 0–79 0–81
Koos grade, n (%)
 Grade I 5 (17) 3 (33) 12 (36) 7 (22)
 Grade II 21 (70) 5 (56) 19 (58) 20 (62)
 Grade III 4 (13) 1 (11) 2 (6) 5 (16)
Operated side, n (%)
 Right 18 (56) 6 (67) 19 (56) 17 (52)
 Left 14 (44) 3 (33) 15 (44) 16 (48)
Surgical approach, n (%)
 Middle fossa craniotomy 4 (12) 1 (11) 5 (15) 4 (12)
 Translabyrinthine craniotomy 13 (41) 4 (44) 13 (38) 13 (39)
 Retrosigmoid craniotomy 10 (31) 3 (33) 11 (32) 16 (49)
 Retrolabyrinthine craniotomy 5 (16) 1 (11) 5 (15) 0 (0)
Canal paresis: Jongkee’s formula (absolute values). Intention-to-treat analysis set.

TABLE 2 - Baseline vestibular characteristics (day 3)
Placebo (n = 32) AM-125 1 mg (n = 9) AM-125 10 mg (n = 34) AM-125 20 mg (n = 33)
Spontaneous nystagmus, beats/30 seconds
 Mean ± SD 39.3 ± 22.7 43.3 ± 15.5 45.4 ± 21.2 44.3 ± 20.4
 Median 33.5 43 44.5 37
 Range 3–120 13–60 8–111 16–101
Subjective visual vertical, degrees
 Mean ± SD 7.0 ± 3.6 5.8 ± 4.4 7.0 ± 4.4 6.6 ± 3.5
 Median 6.2 5.1 6.3 5.5
 Range 2.4–16.6 1.4–16.0 2.6–26.5 2.6–17.7
Vestibular Rehabilitation Benefit Questionnaire
 Mean ± SD 44.0 ± 25.5 49.1 ± 22.6 43.9 ± 21.2
 Median 43.2 53.0 45.1
 Range 8–87 3–80 0–75
European Evaluation of Vertigo scale
 Mean ± SD 10.8 ± 3.6 10.8 ± 3.8 11.7 ± 3.8 12.2 ± 3.6
 Median 10.5 12.0 12.0 12.0
 Range 5–19 4–15 5–19 7–19
Tandem Romberg test (s)
 Mean ± SD 1.5 ± 2.3 6.0 ± 10.2 0.7 ± 1.1 1.1 ± 3.2
 Median 0.5 2.0 0.0 0.0
 Range 0–11 0–30 0–3 0–17
Standing on Foam test (s)
 Mean ± SD 5.8 ± 10.0 8.0 ± 13.1 2.4 ± 7.1 2.0 ± 6.3
 Median 0.0 0.0 0.0 0.0
 Range 0–30 0–30 0–30 0–30
Tandem Gait test, steps
 Mean ± SD 2.3 ± 4.5 5.1 ± 6.4 2.0 ± 4.8 0.7 ± 1.4
 Median 0.0 3.0 0.0 0.0
 Range 0–20 0–20 0–20 0–5
The Vestibular Rehabilitation Benefit Questionnaire was collected only in part B of the trial (n = 25 for each treatment group). Intention-to-treat analysis set.

Interim Analysis

In part A, doses could be escalated without any treatment-related safety or tolerability issues to the maximum of 20 mg. The interim analysis comprised 33 patients and showed a dose-dependent improvement in balance; therefore, the two highest active doses, 10 and 20 mg, were selected for part B.

Efficacy Outcomes

In the main analysis, the AM-125 20-mg group showed the most pronounced improvement, followed by the AM-125 10-mg and placebo groups (see Supplemental Digital Content 2 for tabulated efficacy outcomes, https://links.lww.com/MAO/B593). By the end of the treatment period at day 28, mean TRT time to failure improved 3.5 seconds more in the AM-125 20-mg group compared with the placebo group (90% confidence interval; difference in least square means, 0.2 to 6.7 s; p = 0.08) and 0.8 seconds longer in the AM-125 10-mg group (90% CI = −2.4 to 4 s; p = 0.692) versus placebo. In the per protocol population, the corresponding differences reached 5.0 and 0.9 seconds (p = 0.024 and p = 0.649). The treatment effect started to appear at day 14 but was essentially no longer apparent by day 42, i.e., 2 weeks after last dose (Fig. 2A). The SOF test showed much more rapid improvement in balance than TRT; at day 14, mean time to failure was 3.7 seconds longer in the AM-125 20-mg group compared with the placebo group (90% CI = −0.6 to 8.0 s; p = 0.158), but later time points showed outcomes converging between treatment groups (Fig. 2B).

FIG. 2:
Improvement from baseline (day 3 post surgery) in time to failure in balance test for the intention-to-treat analysis set (n = 99). A, Tandem Romberg test; B, standing on foam test. Mixed-effects model with repeated measures using baseline time to failure and age as covariates; least square means with standard error means.

Both TGT and SVV showed rapid improvement as well, but no meaningful differences between treatment groups. By day 28, median SVV had already improved to <2.5° and TGT to the maximum of 20 steps across all treatment groups. The frequency of spontaneous nystagmus decreased most in the active treated groups; the treatment effect was largest at day 14 where the AM-125 10-mg group showed a decrease of 7.4 beats/30 s versus placebo (90% CI = −14.6 to −0.1 beats/30 s; p = 0.096) (Fig. 3A). From day 28, a separation in the share of patients with complete resolution of spontaneous nystagmus became apparent, with 45% of patients in the AM-125 20-mg group no longer showing this clinical sign at day 42, 31% in the AM-125 10-mg group, and 26% in the placebo group, respectively (Fig. 3B). The VRBQ showed a trend for superior improvement for the AM-125 20-mg group over the placebo group at all study visits (1.2–3.8 percentage points), primarily driven by ameliorations in the dizziness and quality of life subscales.

FIG. 3:
A, Reduction in frequency of horizontal spontaneous nystagmus/30 seconds from baseline (3 days postsurgery). Mixed-effects model with repeated measures using baseline frequency of spontaneous nystagmus and age as covariates; least square means with standard error means. B, Percentage of patients with resolution of horizontal spontaneous nystagmus. Intention-to-treat analysis set (n = 99).

Further analysis revealed that certain patients who were barely able at baseline to perform the TRT achieved maximum SOF scores. As post hoc sensitivity analysis, we excluded patients if their baseline SOF time to failure was ≥10 seconds, a level that separated outliers from the bulk of low-performing patients (7 in the placebo and 2 in each of the active treated groups). Their exclusion had no effect on the overall pattern of TRT recovery but resulted in a larger differential in improvement between the AM-125 20-mg group and the placebo group at days 14 and 28 of 3.7 and 4.6 seconds, respectively (90% CI = 0.4 to 7.1 s, p = 0.069 and 0.6 to 8.5 s, p = 0.059) (Fig. 4).

FIG. 4:
Improvement from baseline (day 3 post surgery) in time to failure in tandem Romberg test for the subpopulation defined post hoc with time to failure of <10 seconds at baseline standing on foam test (n = 88). Mixed-effects model with repeated measures using baseline time to failure and age as covariates; least square means with standard error means.

Safety and Tolerability Outcomes

Peak plasma exposure of betahistine in the AM-125 20-mg group was almost 4 ng/mL (Tmax 10 min).

TNSS at baseline across treatment groups was 0.8 (out of 21) points; the maximum during the treatment period was reported 10 minutes after the first administration at 0.9, 1.4, 1.6, and 1.8 points in the placebo, AM-125 1-mg, 10-mg, and 20-mg groups, respectively. Ten minutes after the last dose on day 28, the score was 0.4, 0.6, 1.8, and 1.1 points, respectively. The incidence of moderate or severe nasal symptoms was 18.8%, 11.1%, 29.4%, and 27.3%. Severe nasal symptoms were rare and transitory, affecting 1, 0, 3, and 2 patients (sneezing, nasal congestion; in two cases before dosing).

Treatment-emergent AEs (TEAEs) were observed for similar proportions of patients, affecting 60%, 67%, 56%, and 70% in the placebo, AM-125 1-mg, 10-mg, and 20-mg groups. Most TEAEs were related to surgery rather than treatment; the latter were observed in 9%, 22%, 3%, and 15% of patients and mostly mild. Treatment-related TEAEs were transitory and most frequently concerned the nose (4 patients with discomfort, pruritus, or epistaxis—placebo, 1; AM-125 1 mg, 1; AM-125 20 mg, 2) and headache (3 patients—AM-125 1 mg, 2; AM-125 20 mg, 1). Nonfatal serious AEs were recorded for 0, 1, 2, and 5 patients, none of which was considered treatment related. One patient in the AM-125 10-mg group and 2 patients in the AM-125 20-mg group discontinued the study because of AEs (headaches and insomnia, related; meningitis, pulmonary embolism, unrelated). Treatment compliance was high, ranging from 92.6% in the AM-125 1-mg group to 99.1% in the placebo group.


TRAVERS is the first proof-of-concept trial with intranasal betahistine in AVS patients. It provided further evidence that intranasal delivery is a feasible, safe, and well-tolerated alternate administration route for betahistine. Thanks to the avoidance of hepatic first-pass metabolism, significantly higher plasma concentrations are possible than with oral administration—the peak concentration after 20 mg i.n. was at least eight times higher than reported for 24 mg p.o. (16). Elimination of intranasal betahistine in a previous pharmacokinetic study in healthy volunteers by the sponsor of the present trial showed a relatively short half-life of 15 minutes (oral, 10 min; unpublished data), hence the need for t.i.d. dosing.

Importantly, TRAVERS could confirm earlier data that the compound is well tolerated within the nasal cavity. Older work had suggested that betahistine’s agonistic activity at the H1 receptor dilates nasal capacitance vessels and increases nasal secretion which might cause tolerability issues (32). However, more recent work highlighted the compound’s vasoconstrictive effects through direct agonistic activity at adrenergic α2 receptors and/or inhibition of H3 receptors, which results in reduced noradrenaline release and thus could counteract H1-mediated effects (33). Tolerability was further supported using a buffered formulation appropriate for the nasal cavity.

TRAVERS showed a dose-dependent improvement of balance as measured by the TRT under AM-125 treatment. The increase in TRT time to failure was corroborated by a higher share of patients with full resolution of spontaneous nystagmus than in controls, which suggests enhanced vestibular compensation. The treatment effect became apparent at day 14, which is consistent with previous findings, whereas betahistine’s effects are not only dose but also time dependent (7); it widened further to the end of the treatment period. It was accompanied by a trend for improvement in patient-reported vestibular deficit (VRBQ), in particular quality of life and dizziness symptoms.

TRAVERS sought to avoid enrolling patients with pronounced preoperative vestibular compensation given that this might affect postsurgery recovery (34,35). Patients with well-developed vestibular compensation on the tumor side can expect faster spontaneous postoperative recovery and may therefore respond less to pharmacologic treatment. The finding that >10% of randomized patients performed very well on the SOF test (notably with eyes closed) just 3 days after surgery, indicating strong preoperative vestibular compensation, suggests that inclusion criteria were not fully adequate. Indeed, post hoc exclusion of these cases showed more pronounced treatment effects.

Apart from preoperative compensation levels, vestibular recovery may be influenced by various other, partly interrelated factors, including tumor size, degree of canal paresis, functional integrity of central vestibular and cerebellar centers, age, surgical approach, presence of postsurgical complications, rehabilitation therapy, visual and proprioceptive function, or physical activity levels (4,34–40). In TRAVERS, older patients tended to show less improvement, with the covariate approaching or reaching statistical significance with the balance tests, but not for the VRBQ or frequency of spontaneous nystagmus. Although the effect of age was at least partially controlled through stratification, there were imbalances between treatment groups with respect to other factors, which may have affected outcomes. For example, the placebo group accounted for more than half of the patients with strong baseline SOF performance, and its mean preoperative canal paresis was about 10 percentage points higher than in the AM-125 20-mg group. More pronounced preoperative canal paresis tends to be associated with more rapid SVV improvement (41).

One of the objectives for the present trial was to assess the suitability of various efficacy outcome measures. As expected, the TRT was the most challenging balance test. The effect size for AM-125 20 mg at day 28 as measured by Cohen’s rule of thumb was 0.44 for the full population and 0.52 in the post hoc analysis without strong SOF performers, i.e., of small to moderate size. By day 42, there still remained room for improvement to reach preoperative levels. SOF and TGT outcomes improved more rapidly and essentially reached preoperative levels, close to the maximum, at day 42. In case of SOF, performance was facilitated by use of a board on top of the foam pad, and in case of TGT by visual input. Given the potential for ceiling effects and the lesser focus on vestibular input, both measures appeared to be less relevant than the TRT.

Nystagmography was the sole fully objective outcome measure in TRAVERS and provides information about the tonic firing rate of the vestibular afferents. It is especially useful to determine uncompensated asymmetry in vestibular function (42). The nystagmus is usually proportional to the patient’s symptoms and will become smaller as vestibular compensation occurs (43). Its frequency declined indeed largely in parallel with the improvement in AVS symptoms and subjective vestibular deficit. Most patients still experienced spontaneous nystagmus at day 42, whereas the other measures had already reached or returned toward preoperative levels. Faster improvement in subjective rather than objective measures was also observed in a chemical labyrinthectomy study (44). This may be explained by increased patient confidence to cope with vestibular imbalance in daily life.

Given the many influential factors potentially involved, TRAVERS could have benefited from a larger size. Another limitation of the study was the publication of interim results after part A, which may have influenced patient and investigator expectations in part B of potential treatment benefits. In addition, no adjustment for multiplicity was made and alpha was 0.1. However, this was considered adequate for a therapeutic exploratory study and justified given the dearth of reliable reference values.

In conclusion, the TRAVERS trial suggests that intranasal betahistine may help accelerate vestibular compensation and alleviate signs and symptoms of vestibular dysfunction in surgery-induced AVS. Further evaluation in a confirmatory manner with a larger sample size, refined inclusion criteria, and focus on TRT, nystagmography, and patient-reported vestibular deficit for efficacy outcomes appears warranted.


The authors thank the two anonymous reviewers for their comments; Dr. Liliane Borel, Marseille, for her conceptional contributions; Luc Vereeck, Antwerp, for his input on the spontaneous recovery of balance after VS resection; and Dr Kevin Carroll for his biostatistical contributions. Sincere gratitude is also expressed to all participating patients who made this study possible and to all investigators and their staff: Belgium—Vincent Van Rompaey, Antwerp; Czech Republic—Jaromír Astl, Prague; Jan Betka, Prague; Martin Chovanec, Prague; Jan Klener, Prague; France—Arnaud Devèze, Marseille; Isabelle Mosnier, Paris; Germany—Matthias Scheich, Würzburg; Michael Strupp, Munich; Italy—Mario Sanna and Anna Lisa Giannuzzi, Piacenza; Poland—Magdalena Józefowicz-Korczyńska, Lodz; Tomasz Przewoźny, Gdansk; Slovakia—Juraj Koval and Silvia Krempaská, Košice.


1. Newman-Toker DE, Edlow JA. TiTrATE: a novel, evidence-based approach to diagnosing acute dizziness and vertigo. Neurol Clin 2015;33:577–99.
2. Steenerson KK. Acute vestibular syndrome. Continuum (Minneap Minn) 2021;27:402–19.
3. Bisdorff AR, Staab JP, Newman-Toker DE. Overview of the international classification of vestibular disorders. Neurol Clin 2015;33:541–50.
4. Lacour M, Helmchen C, Vidal PP. Vestibular compensation: the neuro-otologist's best friend. J Neurol 2016;263(Suppl 1):S54–64.
5. Lacour M. Betahistine treatment in managing vertigo and improving vestibular compensation: clarification. J Vestib Res 2013;23:139–51.
6. Bergquist F, Dutia MB. Central histaminergic modulation of vestibular function—a review. Sheng Li Xue Bao 2006;58:293–304.
7. Tighilet B, Trottier S, Lacour M. Dose- and duration-dependent effects of betahistine dihydrochloride treatment on histamine turnover in the cat. Eur J Pharmacol 2005;523(1–3):54–63.
8. Chen ZP, Zhang XY, Peng SY, et al. Histamine H1 receptor contributes to vestibular compensation. J Neurosci 2019;39:420–33.
9. Bertlich M, Ihler F, Weiss BG, et al. Role of capillary pericytes and precapillary arterioles in the vascular mechanism of betahistine in a guinea pig inner ear model. Life Sci 2017;187:17–21.
10. Ihler F, Bertlich M, Sharaf K, et al. Betahistine exerts a dose-dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo. PloS One 2012;7:e39086.
11. Dziadziola JK, Laurikainen EL, Rachel JD, Quirk WS. Betahistine increases vestibular blood flow. Otolaryngol Head Neck Surg 1999;120:400–5.
12. Agus S, Benecke H, Thum C, Strupp M. Clinical and demographic features of vertigo: findings from the REVERT registry. Front Neurol 2013;4:48.
13. Van Esch B, van der Zaag-Loonen H, Bruintjes T, van Benthem PP. Betahistine in Ménière's disease or syndrome: a systematic review. Audiol Neurootol 2022;27:1–33.
14. Murdin L, Hussain K, Schilder AG. Betahistine for symptoms of vertigo. Cochrane Database Syst Rev 2016;2016:CD010696.
15. Abbott. Betahistine dihydrochloride, orodispersible tablet (24 mg). Summary of Product Characteristics 2016:FI/H/827/01/DC.
16. Chen XY, Zhong DF, Duan JL, Yan BX. LC-MS-MS analysis of 2-pyridylacetic acid, a major metabolite of betahistine: application to a pharmacokinetic study in healthy volunteers. Xenobiotica 2003;33:1261–71.
17. Moorthy G, Sallee F, Gabbita P, et al. Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD. Biopharm Drug Dispos 2015;36:429–39.
18. Schmidt JT, Huizing EH. The clinical drug trial in Meniere's disease with emphasis on the effect of betahistine SR. Acta Otolaryngol Suppl 1992;497:1–189.
19. Tighilet B, Leonard J, Watabe I, et al. Betahistine treatment in a cat model of vestibular pathology: pharmacokinetic and pharmacodynamic approaches. Front Neurol 2018;9:431.
20. Colletti V. Medical treatment in Ménière's disease: avoiding vestibular neurectomy and facilitating postoperative compensation. Acta Otolaryngol Suppl 2000;544:27–33.
21. Redon C, Lopez C, Bernard-Demanze L, et al. Betahistine treatment improves the recovery of static symptoms in patients with unilateral vestibular loss. J Clin Pharmacol 2011;51:538–48.
22. Chemuturi NV, Donovan MD. Metabolism of dopamine by the nasal mucosa. J Pharm Sci 2006;95:2507–15.
23. Agrawal Y, Carey JP, Hoffman HJ, Sklare DA, Schubert MC. The modified Romberg balance test: normative data in U.S. adults. Otol Neurotol 2011;32:1309–11.
24. Vereeck L, Wuyts F, Truijen S, Van de Heyning P. Clinical assessment of balance: normative data, and gender and age effects. Int J Audiol 2008;47:67–75.
25. Zwergal A, Rettinger N, Frenzel C, et al. A bucket of static vestibular function. Neurology 2009;72:1689–92.
26. Mègnigbêto CA, Sauvage JP, Launois R. The European Evaluation of Vertigo (EEV) scale: a clinical validation study [in French]. Rev Laryngol Otol Rhinol (Bord) 2001;122:95–102.
27. Morris AE, Lutman ME, Yardley L. Measuring outcome from vestibular rehabilitation, part II: refinement and validation of a new self-report measure. Int J Audiol 2009;48:24–37.
28. Cawthorne T. Vestibular Injuries. Proc R Soc Med 1946;39:270–3.
29. Cooksey FS. Rehabilitation in vestibular injuries. Proc R Soc Med 1946;39:273–8.
30. De Valck CFJ, Vereeck L, Wuyts FL, Van de Heyning PH. Failure of gamma-aminobutyrate acid-beta agonist baclofen to improve balance, gait, and postural control after vestibular schwannoma resection. Otol Neurotol 2009;30:350–5.
31. Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001;285:1987–91.
32. Shelton D, Eiser N. Histamine receptors in the human nose. Clin Otolaryngol Allied Sci 1994;19:45–9.
33. Bertlich M, Ihler F, Freytag S, et al. Histaminergic H3-heteroreceptors as a potential mediator of betahistine-induced increase in cochlear blood flow. Audiol Neurootol 2015;20:283–93.
34. Van Laer L, Hallemans A, Van Rompaey V, et al. Subjective perception of activity level: a prognostic factor for developing chronic dizziness after vestibular schwannoma resection? Front Neurol 2022;13:925801.
35. Čada Z, Balatková Z, Čakrt O, et al. Predictors of central vestibular compensation after surgery for vestibular schwannomas. Acta Otorhinolaryngol Ital 2019;39:46–52.
36. Ribeyre L, Frère J, Gauchard G, et al. Preoperative balance control compensation in patients with a vestibular schwannoma: does tumor size matter? Clin Neurophysiol 2015;126:787–93.
37. Devèze A, Montava M, Lopez C, et al. Vestibular compensation following vestibular neurotomy. Eur Ann Otorhinolaryngol Head Neck Dis 2015;132:197–203.
38. Saman Y, Bamiou DE, Gleeson M. A contemporary review of balance dysfunction following vestibular schwannoma surgery. Laryngoscope 2009;119:2085–93.
39. Parietti-Winkler C, Lion A, Frère J, et al. Prediction of balance compensation after vestibular Schwannoma surgery. Neurorehabil Neural Repair 2016;30:395–401.
40. Lacour M, Tardivet L, Thiry A. Posture deficits and recovery after unilateral vestibular loss: early rehabilitation and degree of hypofunction matter. Front Hum Neurosci 2022;15:776970.
41. Batuecas-Caletrio A, Santacruz-Ruiz S, Muñoz-Herrera A, et al. Vestibular compensation after vestibular schwannoma surgery: normalization of the subjective visual vertical and disability. Acta Otolaryngol 2013;133:475–80.
42. Mantokoudis G, Schubert MC, Saber Tehrani AS, Wong AL, Agrawal Y. Early adaptation and compensation of clinical vestibular responses after unilateral vestibular deafferentation surgery. Otol Neurotol 2014;35:148–54.
43. Hathiram BT, Khattar VS. Videonystagmography. Int J Otorhinolaryngol Clin 2012;4:17–24.
44. Pyykkö I, Eklund S, Ishizaki H, Aalto H. Postural compensation after intratympanic gentamicin treatment of Menière's disease. J Vestib Res 1999;9:19–26.

Betahistine; Vestibular compensation; Acute vestibular syndrome; Vestibular schwannoma; Surgery; Clinical trial; AM-125; Intranasal delivery

Supplemental Digital Content

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.