INTRODUCTION
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 1,3 4 vestibular compensation based on restoration, habituation, and adaptation processes (4
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 5,8 betahistine has been shown to increase inner ear blood flow (9–11
Betahistine is widely used for the treatment of vestibular disorders (12 betahistine ’s therapeutic utility is not unequivocal (13,14 betahistine ’s clinical efficacy has also been limited by its poor oral bioavailability, which is reported to be only around 1% (15 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 betahistine on vestibular compensation also in humans (20,21 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.
MATERIALS AND METHODS
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
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
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
Procedures
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
Before balance tests, investigators evaluated vertigo and its main symptoms with the EEV (26 27
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
Endpoints
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
RESULTS
Patient Flow and Characteristics
The CONSORT (31 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 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. 2 A). 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. 2 B).
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. 3 A). 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. 3 B). 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 (T max 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.
DISCUSSION
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 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 33
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
TRAVERS sought to avoid enrolling patients with pronounced preoperative vestibular compensation given that this might affect postsurgery recovery (34,35 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 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 vestibular compensation occurs (43 44
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.
Acknowledgments
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.
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