Claassen Daniel O, Carroll Benjamin, De Boer Lisa M, Wu Eric, Ayyagari Rajeev, Gandhi Sanjay, Stamler David
Vanderbilt University, 1161 21st Avenue South A-0118, Nashville, TN 37232 USA.
Teva Pharmaceuticals, Frazer, PA USA.
J Clin Mov Disord. 2017 Mar 1;4:3. doi: 10.1186/s40734-017-0051-5. eCollection 2017.
Vesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. Deutetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations. In the First-HD trial, deutetrabenazine was efficacious in treating chorea and was generally well tolerated. In the absence of a head-to-head trial, we performed an indirect treatment comparison (ITC) of the tolerability of deutetrabenazine and tetrabenazine for the treatment of HD-associated chorea, as observed in the First-HD and TETRA-HD trials, using well-established comparison methods.
Data from the Phase III, 12-week, parallel-group, clinical trials First-HD ( = 90) and TETRA-HD ( = 84) were used to conduct an ITC of the tolerability of deutetrabenazine versus tetrabenazine using two anchor-based methods: Bucher comparison for unadjusted ITCs, and matching indirect comparison for adjusted ITCs. Overall adverse events (AEs; mild, moderate, and severe), serious AEs, specific AEs occurring in ≥10% of patients, and discontinuations (all-cause and AE-related) were included in the analysis. The risk differences of these outcomes for deutetrabenazine and tetrabenazine were estimated by subtracting the applicable placebo-adjusted risk in First-HD from that of TETRA-HD. Sensitivity analyses were performed to address differences between trials, and -values were obtained from z-tests.
Compared with tetrabenazine, deutetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses ( < 0.05 for each). Deutetrabenazine had a significantly lower rate of dose reduction or dose reduction/suspension in the unadjusted and adjusted analyses ( < 0.001 for each). Deutetrabenazine resulted in numerically more mild AEs, such as diarrhea and coughing; however, these results were not statistically significant.
This indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine.
ClinicalTrials.gov NCT01795859 and NCT00219804.
囊泡单胺转运体2（VMAT2）抑制剂可改善运动亢进，是治疗亨廷顿病（HD）舞蹈症的有效选择。在TETRA-HD试验中评估了丁苯那嗪治疗舞蹈症的效果，虽然有效，但因其药代动力学特性可能存在耐受性问题。氘代丁苯那嗪是一种新型VMAT2抑制剂，含有氘，可延长活性代谢物半衰期并使药物浓度波动最小化。在First-HD试验中，氘代丁苯那嗪治疗舞蹈症有效且总体耐受性良好。在缺乏头对头试验的情况下，我们使用成熟的比较方法，对First-HD和TETRA-HD试验中观察到的氘代丁苯那嗪和丁苯那嗪治疗HD相关舞蹈症的耐受性进行了间接治疗比较（ITC）。
来自III期、12周、平行组临床试验First-HD（n = 90）和TETRA-HD（n = 84）的数据用于使用两种基于锚定的方法对氘代丁苯那嗪与丁苯那嗪的耐受性进行ITC：未调整ITC的Bucher比较和调整ITC的匹配间接比较。分析包括总体不良事件（AE；轻度、中度和重度）、严重AE、≥10%患者发生的特定AE以及停药（全因和与AE相关）。通过从TETRA-HD中减去First-HD中适用的安慰剂调整风险来估计氘代丁苯那嗪和丁苯那嗪这些结局的风险差异。进行敏感性分析以解决试验之间的差异，并通过z检验获得P值。
与丁苯那嗪相比，在调整和未调整分析中，氘代丁苯那嗪发生中度至重度AE以及包括激越、静坐不能、抑郁、抑郁/激越性抑郁、嗜睡/昏睡、失眠和帕金森症在内的神经精神AE的风险均显著较低（每项P < 0.05）。在未调整和调整分析中，氘代丁苯那嗪的剂量减少或剂量减少/暂停率均显著较低（每项P < 0.001）。氘代丁苯那嗪导致的轻度AE在数值上更多，如腹泻和咳嗽；然而，这些结果无统计学意义。
这项间接治疗比较表明，对于HD舞蹈症的治疗，氘代丁苯那嗪与丁苯那嗪相比具有良好的耐受性。
ClinicalTrials.gov NCT01795859和NCT00219804。
