Efficacy and Safety of a Fixed-Dose Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg in the Treatment of Patients with Vestibular Vertigo: An Individual Patient Data Meta-Analysis of Randomised, Double-Blind, Controlled Clinical Trials,Clinical Drug Investigation

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Efficacy and Safety of a Fixed-Dose Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg in the Treatment of Patients with Vestibular Vertigo: An Individual Patient Data Meta-Analysis of Randomised, Double-Blind, Controlled Clinical Trials
Clinical Drug Investigation ( IF 2.9 ) Pub Date : 2022-07-21 , DOI: 10.1007/s40261-022-01184-0
Arne W Scholtz ₁ , Frank Waldfahrer ₂ , Regina Hampel ₃ , Gerhard Weisshaar ₄

Affiliation

Background and Objective

The source data of four individual randomised, double-blind, reference- and/or placebo-controlled clinical trials with virtually identical study design were pooled for the present meta-analysis. The main objective was to further evaluate the efficacy and safety of the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg in comparison to various other antivertigo treatments in patients suffering from central and/or peripheral vestibular vertigo.

Methods

Adult male and female outpatients were subjected to a 4-week treatment with the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg, cinnarizine (20 mg, 50 mg), dimenhydrinate (40 mg, 100 mg), betahistine dimesylate (12 mg), betahistine dihydrochloride (16 mg) and placebo, respectively. The primary efficacy endpoint was the reduction of a validated mean vertigo score (MVS), a composite score of 12 individual vertigo symptoms, the intensities of which were each evaluated by the patients on a 5-point visual analogue scale. For analysis of primary and further secondary efficacy endpoints, baseline-adjusted analysis of covariance (ANCOVA) was used to calculate adjusted least squares means (LSM) with associated two-sided 95% confidence intervals (CIs) for the difference in MVS reductions between treatment groups. Moreover, various sensitivity analyses, responder and subgroup analyses as well as descriptive analyses with respect to safety/tolerability of the treatments were conducted.

Results

Of 795 randomised patients, 779 belonged to the intent-to treat (ITT) and 723 to the per-protocol (PP) population. The main efficacy analysis was based on the ITT population (mean age 52.1 years, 61% female). The mean decrease of the MVS from baseline to Week 4 in the cinnarizine/dimenhydrinate group (−1.10) proved to be significantly larger than in any of the comparator groups. LSM differences for comparators versus the fixed combination ranged between 0.16 (95% confidence interval (CI) 0.03; 0.30, p = 0.017) for cinnarizine 20 mg and 0.60 (95% CI 0.42; 0.78; p < 0.001) for betahistine dimesylate 12 mg in favour of the fixed combination. Furthermore, after 4 weeks of treatment, 74 patients (24.7%) in the cinnarizine/dimenhydrinate group were completely symptom free (MVS = 0), a significantly greater proportion than in any of the comparator groups. Sensitivity analyses showed that baseline characteristics such as age, sex, duration of vertigo and antivertigo pretreatment had only a very minor and clinically non-relevant impact on the efficacy results regarding the primary efficacy outcome. Subgroup analyses with respect to age groups (< 65 years/≥ 65 years) and sex showed no significant differences in efficacy within any of the treatment groups. All treatments were well tolerated. A total of 55 patients (6.9%) reported 75 non-serious adverse events (AEs), and 19 patients (2.4%) discontinued the study prematurely because of AEs. Nearly 95% of the patients (cinnarizine/dimenhydrinate group: 97.9%) rated the tolerability of the study medications as either “good” or “very good”.

Conclusion

The findings of the present meta-analysis indicate that the fixed combination of cinnarizine and dimenhydrinate is a safe and potentially superior treatment option for patients suffering from central and/or peripheral vestibular vertigo, as compared to current standard treatments such as cinnarizine, dimenhydrinate or betahistine given alone in monotherapy.

中文翻译：

桂利嗪 20 mg 和苯海拉明 40 mg 固定剂量组合治疗前庭性眩晕患者的疗效和安全性：随机、双盲、对照临床试验的个体患者数据荟萃分析

背景与目的

本荟萃分析汇集了四项具有几乎相同研究设计的个体随机、双盲、参考和/或安慰剂对照临床试验的源数据。主要目的是进一步评估桂利嗪 20 mg 和苯海拉明 40 mg 的固定组合与其他各种抗眩晕治疗在患有中枢性和/或外周前庭性眩晕的患者中的疗效和安全性。

方法

成年男性和女性门诊患者接受 4 周桂利嗪 20 毫克和苯海拉明 40 毫克、桂利嗪（20 毫克、50 毫克）、苯海拉明（40 毫克、100 毫克）、倍他司汀二甲磺酸盐（12 毫克）的固定组合治疗。 , 倍他司汀二盐酸盐 (16 mg) 和安慰剂, 分别。主要疗效终点是经过验证的平均眩晕评分 (MVS) 的降低，这是 12 种单独眩晕症状的综合评分，其强度由患者在 5 点视觉模拟量表上进行评估。对于主要和进一步次要疗效终点的分析，基线调整协方差分析 (ANCOVA) 用于计算调整后的最小二乘均值 (LSM) 以及相关的双边 95% 置信区间 (CI)，以了解治疗之间 MVS 降低的差异团体。而且，

结果

在 795 名随机患者中，779 名属于意向治疗 (ITT) 人群，723 名属于符合方案 (PP) 人群。主要疗效分析基于 ITT 人群（平均年龄 52.1 岁，61% 女性）。桂利嗪/苯海拉明组的 MVS 从基线到第 4 周的平均下降 (-1.10) 被证明明显大于任何比较组。比较器与固定组合的 LSM 差异在 0.16（95% 置信区间 (CI) 0.03；0.30，p = 0.017）之间，桂利嗪 20 mg 和 0.60（95% CI 0.42；0.78；p< 0.001) 对于倍他司汀二甲磺酸盐 12 mg，有利于固定组合。此外，在治疗 4 周后，桂利嗪/苯海拉明组的 74 名患者（24.7%）完全无症状（MVS = 0），这一比例显着高于任何对照组。敏感性分析表明，年龄、性别、眩晕持续时间和抗眩晕预处理等基线特征对主要疗效结果的疗效结果仅具有非常轻微且临床上不相关的影响。关于年龄组（< 65 岁/≥ 65 岁）和性别的亚组分析显示，任何治疗组的疗效均无显着差异。所有治疗均耐受良好。共有 55 名患者 (6.9%) 报告了 75 起非严重不良事件 (AE)，19 名患者 (2. 4%) 因不良事件提前终止研究。近 95% 的患者（桂利嗪/苯海拉明组：97.9%）将研究药物的耐受性评为“好”或“非常好”。