背景:一项药物重新定位研究支持使用抗HIV药物依曲韦林作为Friedreich共济失调(FRDA)的疾病改善药物。Etavirine增加共济失调蛋白并纠正FRDA患者细胞中的生化缺陷。因为这些发现,由于依曲韦林显示出良好的安全性,我们开展了一项开放标签2期临床试验,评估依曲韦林在FRDA患者中的安全性和潜在疗效.
方法:将35例患者分为三个严重程度组,并随机分配给依曲韦林200mg/天或400mg/天。他们治疗了4个月。安全性终点是不良事件的数量和类型以及退出的数量。通过增量运动测试测量的峰值摄氧量和工作量的变化来表示疗效终点。SARA得分,心脏措施,QoL和残疾的衡量标准。数据收集在治疗开始前4个月(T-4),在开始(T0),在治疗结束(T4)和终止后4个月(T4)。
结果:依曲韦林的耐受性合理,不良事件一般为轻度.4个月的依曲韦林治疗没有显著增加峰值摄氧量,但与SARA评分进展的变化有关(p值<0.001),与治疗前和治疗后的4个月相比。它还显着增加了峰值工作量(p值=0.021)。未观察到心脏测量值的变化。健康和QoL指标显示药物暂停时恶化。
结论:在这项开放试验中,依曲韦林治疗是安全的,相当好的耐受性和明显改善神经功能和运动表现。即使不能排除安慰剂效应,这些结果提示,在一项随机安慰剂对照临床试验中,依曲韦林可能是FRDA中的一种潜在治疗药物.
BACKGROUND: A drug repositioning effort supported the possible use of the anti-HIV drug etravirine as a disease-modifying drug for Friedreich ataxia (FRDA). Etravirine increases frataxin protein and corrects the biochemical defects in cells derived from FRDA patients. Because of these findings, and since etravirine displays a favorable safety profile, we conducted a pilot open-label phase 2 clinical trial assessing the safety and potential efficacy of etravirine in FRDA patients.
METHODS: Thirty-five patients were stratified into three severity groups and randomized to etravirine 200 mg/day or 400 mg/day. They were treated for 4 months. Safety endpoints were the number and type of adverse events and number of dropouts. Efficacy endpoints were represented by changes in peak oxygen uptake and workload as measured by incremental exercise test, SARA score, cardiac measures, measures of QoL and disability. Data were collected 4 months before the start of the treatment (T - 4), at the start (T0), at the end (T4) and 4 months after the termination of the treatment (T + 4).
RESULTS: Etravirine was reasonably tolerated, and adverse events were generally mild. Four months of etravirine treatment did not significantly increase the peak oxygen uptake but was associated with a change in the progression of the SARA score (p value < 0.001), compared to the 4 months pre- and post-treatment. It also significantly increased peak workload (p value = 0.021). No changes in the cardiac measures were observed. Health and QoL measures showed a worsening at the suspension of the drug.
CONCLUSIONS: In this open trial etravirine treatment was safe, reasonably well tolerated and appreciably improved neurological function and exercise performance. Even though a placebo effect cannot be ruled out, these results suggest that etravirine may represent a potential therapeutic agent in FRDA deserving testing in a randomized placebo-controlled clinical trial.