Prospective Randomized Group Controlled Study of Clinical Efficacy and Safety of the CE marked Vertidisan® App - RCT VH-90-D

The confirmatory group comparison revealed a highly significant (adjusted LSMean -7.9 score points, 95% confidence interval -9.5 to -6.2 score points, p<0.0001; Cohen’s d: 1.55) treatment effect of the app. With an average intragroup vertigo improvement of -66.2% (p<0.0001) VSS-sf-VER of the ITT population with imputation by JTR revealed that the Vertidisan group produced a significant and pronounced intragroup reduction of the VSS-sf-VER score with a clinically important effect size. In comparison, the TAU ITT group showed a significantly smaller intragroup reduction of no more than -16.8 % (p<0.0001). Sensitivity analyses were in line with the JTR results (Wilcoxon-Mann-Whitney: p<0.0001). Responder analyses revealed that after 12 weeks 87.73% of the app users were responders, while in the physiotherapy group only 25.47% were responders; rate difference 62.3%; 95% CI, 51.9% to 72.6%; P<0.0001. Within the app responder group the VSS-sf-VER score fell statistically significantly by -76.15% (p<0.0001). Thus, Vertidisan is effective in treating vertigo. Furthermore, Vertidisan`s efficacy is statistically significantly superior to physiotherapy. Moreover, the absolute values of the VSS-sf-VER scores achieved in both groups after 12 weeks differ significantly. The scores in the app group (JTR) were reduced to a mean value of 6.47 (SD 6.18) and a median value 4.48. This is in a significant contrast to the pretherapeutic severe vestibular symptomatology (classified as 12 score points and more). The mean and median values of the TAU group, however, remained in the range of a severe vestibular symptomatology (mean 13.30; SD 5.67; median 13.50) after 12 weeks. Subgroup analyses of the underlying diseases showed that the app is clinically and statistically significantly effective for the treatment of peripheral vertigo of various origins: diagnoses include BPPN (benign paroxysmal positioning nystagmus), bilateral and unilateral vestibulopathy, neuronitis/neuronopathy vestibularis, vestibular migraine, or even PPPD (persistent postural-perceptual dizziness) as comorbidity. This may be explained by the above mentioned Vertidisan treatment mechanism which is expected to induce an CVC activation in the brain. Efficacy is clinically and statistically significantly superior to TAU. The same is true with patients with a pretherapeutic history of vertigo induced falls: VSS-sf-VER score change revealed a pronounced therapy effect of the app of -56.78% (p<0.0001; JTR, ITT; physiotherapy -17.82%). The confirmatory intergroup change difference is statistically significant (LS Mean change difference -6.0; CI -9.2, -2.8; p=0.0004) and of an important effect size. Thus, Vertidisan is also effective in treating vertigo characterized by falls. Furthermore, this efficacy is statistically significantly superior to physiotherapy. In addition, fall avoidances were addressed but in a descriptive manner: there appears a striking difference between the Vertidisan and the control group: in each study month (30 days) the number of fall avoidances in the experimental group was significantly smaller than in the control group. Furthermore, in the app group the number of fall avoidances was decreasing over time whereas in the physiotherapy group no such decrease could be observed. Moreover, increasing numbers of finished Vertidisan sessions appeared to contribute to an increase of the efficacy of the app. To investigate vertigo related Quality of Life (QoL) and Dizziness induced disability the Dizziness Handicap Inventory (DHI) was applied. At week 12, the DHI score had improved by a mean of -30.1 in the App group and by -11.8 in the TAU group (adj. LS mean difference between groups, -14.2; 95% CI, -19.3 to -2; Cohen’s d = 1.48; p < 0.0001). The intergroup change comparison (group comparison) of the DHI showed a confirmatory statistically significant treatment difference in favor of the app group. Furthermore, the CGI-Improvement (CGI-I) score was determined at week 12. At week 12 the group comparison of the CGI-I showed a confirmatory statistically significant treatment difference in favor of the app group (p=0.0406). Moreover, the CGI-Severity (CGI-S) score was applied. At week 12, the CGI-S score had improved by a mean of -2.56 in the App group and -0.61 in the TAU group (adj. LS mean difference between groups, -1.5; 95% CI, -1.8 to -1.1; Cohen’s d = 2.46; P < 0.0001). The intergroup change comparison showed a confirmatory statistically significant treatment difference in favor of the app group. To determine distress changes, the Distress Thermometer (DT) was used. At week 12, the DT score had improved by a mean of -1.19 in the App group and -0.43 in the TAU group (adj. LS mean difference between groups, -0.6; 95% CI, -1.2 to -0.0; Cohen’s d = 0.42; P = 0.0427). The intergroup change comparison of the DT showed a confirmatory statistically significant treatment difference in favor of the app group. The VSS-sf-AA score served to investigate autonomic responses. At week 12, the VSS-sf-AA score had improved by a mean of -2.74 in the App group and -2.49 in the TAU group (adj. LS mean difference between groups, -0.6; 95% CI, -1.5 to +0.3; Cohen’s d = 0.08; P = 0.1763). Thus, this endpoint showed a positive but not significant trend in favour of the APP group. As an additional QoL indicator the SF36 instrument was applied. At week 12 the SF36 physical score (PCS) had improved by a mean of 9.47 in the App group and 4.26 in the TAU group (adj. LS mean difference between groups, 5.3; 95% CI, 1.4 to 9.2; Cohen’s d = 0.33; p= 0.0082). The group comparison of the SF-36 PCS showed a statistically significant treatment difference in favor of the app group. When the mental score (MCS) of the SF36 instrument was applied the MCS score had improved by a mean of 6.12 in the App group and by a mean of 4.06 in the TAU group (adj. LS mean difference between groups, 2.9; 95% CI, -0.6 to 6.4; Cohen’s d = 0.14; p= 0.1090). Thus, the results of the SF36 are very positive, but because of the non-significant endpoint VSS-sf-AA these can be interpreted only exploratorily. Safety data resulting from active surveillance indicate that the inherent rate and severity of Vertidisan complications is acceptable. Vertidisan produced burden are fully acceptable in relation to the benefits. Furthermore, burden produced by Vertidisan equals the burden produced by physiotherapy. Moreover, AR rate and quality equal those of conventional physiotherapy. Finally, complication rate and AR quality are significantly lower than those of surgery. Specifically, in contrast to physiotherapy and surgery no sARs have been observed. Thus, based on the findings it can be inferred that the probability of a patient experiencing a substantial benefit when using the Vertidisan App significantly outweighs the probability of suffering harm due to a risk of the device. Conclusion RCT results show a substantial benefit of Vertidisan for patients suffering from peripheral vertigo irrespective of the specific peripheral origin of the disease. Application of Vertidisan may result in a • reduction or even remission of vertigo, and in a • QoL improvement by reducing vertigo induced disability Specifically the RCT demonstrates • A statistically significant and clinically important reduction of vertigo over time through the use of the App. • A statistically significant and clinically important superiority in vertigo reduction of the app use in comparison to physiotherapy. • The effect size of the superiority represents an important clinical effect strength • Statistically significant disability reductions and thus QoL improvements were also observed revealing superiority of Vertidisan over the control. • From the safety findings it can be inferred that the probability of a patient experiencing a substantial benefit when using the Vertidisan App significantly outweighs the probability of suffering harm due to a risk of the device.