Bailey Donald B, Berry-Kravis Elizabeth, Wheeler Anne, Raspa Melissa, Merrien Florence, Ricart Javier, Koumaras Barbara, Rosenkranz Gerd, Tomlinson Mark, von Raison Florian, Apostol George
RTI International, Research Triangle Park, Durham, NC USA.
Department of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Centre, Chicago, IL 60612 USA.
J Neurodev Disord. 2016;8:1. doi: 10.1186/s11689-015-9134-5. Epub 2015 Dec 15.
A phase II randomized, placebo-controlled, double-blind study and subsequent open-label extension study evaluated the efficacy, safety, and tolerability of mavoglurant (AFQ056), a selective metabotropic glutamate receptor subtype-5 antagonist, in treating behavioral symptoms in adolescent patients with fragile X syndrome (FXS). A novel method was applied to analyze changes in symptom domains in patients with FXS using the narratives associated with the clinician-rated Clinical Global Impression-Improvement (CGI-I) scale.
In the core study, patients were randomized to receive mavoglurant (25, 50, or 100 mg BID) or placebo over 12 weeks. In the extension, patients received 100 mg BID mavoglurant (or the highest tolerated dose) for up to 32 months. Global improvement, as a measure of treatment response, was assessed using the CGI-I scale. Investigators assigning CGI-I scores of 1 (very much improved), 2 (much improved), 6 (much worse), or 7 (very much worse) were provided a standard narrative template to collect further information about the changes observed in patients. Investigator feedback was coded and clustered into categories of improvement or worsening to identify potential areas of improvement with mavoglurant. Treatment effect in each category was characterized using the Cochran-Mantel-Haenszel test.
A total of 134 and 103 patients had reached 2 weeks or more of core and extension study treatment, respectively, by the pre-assigned cutoff date for investigator feedback. In the core study, 34 CGI-I scores of 1 or 2 were reported in 28 patients; one patient scored 6. Analysis of the CGI-I narratives did not indicate greater treatment response in patients receiving mavoglurant compared with placebo in any specific improvement domain. There were 54 CGI-I scores of 1 or 2 in 47 patients in the extension study. The most frequently reported categories of improvement were behavior and mood (79.3 and 76.6 % in core and extension studies, respectively), engagement (75.9 and 78.7 %), and communication (69.0 and 61.7 %).
A method was established to capture and categorize FXS symptoms using CGI-I narratives. Although this method did not show benefit of drug over placebo, narratives from investigators were mostly based on parental report and thus do not represent a completely objective alternative assessment.
The studies described are registered at ClinicalTrials.gov with clinical trial identifier numbers NCT01357239 and NCT01433354.
一项II期随机、安慰剂对照、双盲研究以及随后的开放标签扩展研究评估了选择性代谢型谷氨酸受体5亚型拮抗剂mavoglurant（AFQ056）治疗脆性X综合征（FXS）青少年患者行为症状的疗效、安全性和耐受性。采用一种新方法，利用与临床医生评定的临床总体印象改善（CGI-I）量表相关的描述来分析FXS患者症状领域的变化。
在核心研究中，患者被随机分配接受mavoglurant（25、50或100mg，每日两次）或安慰剂治疗12周。在扩展研究中，患者接受100mg每日两次的mavoglurant（或最高耐受剂量）治疗长达32个月。使用CGI-I量表评估作为治疗反应指标的总体改善情况。给CGI-I评分为1（显著改善）、2（明显改善）、6（明显恶化）或7（显著恶化）的研究者提供一个标准描述模板，以收集有关观察到的患者变化的更多信息。对研究者反馈进行编码并归类为改善或恶化类别，以确定mavoglurant潜在的改善领域。使用 Cochr an-Mantel-Haenszel检验对每个类别中的治疗效果进行描述。
到预先指定的研究者反馈截止日期时，分别有134例和103例患者完成了核心研究和扩展研究至少2周的治疗。在核心研究中，28例患者报告了34个CGI-I评分为1或2；1例患者评分为6分。对CGI-I描述的分析未表明在任何特定改善领域接受mavoglurant治疗的患者与接受安慰剂治疗的患者相比有更大的治疗反应。在扩展研究中，47例患者中有54个CGI-I评分为1或2。最常报告的改善类别是行为和情绪（核心研究和扩展研究中分别为79.3%和76.6%）、参与度（75.9%和78.7%）以及沟通（69.0%和61.7%）。
建立了一种利用CGI-I描述来捕捉和分类FXS症状的方法。尽管该方法未显示药物优于安慰剂，但研究者的描述大多基于家长报告，因此并不代表一种完全客观的替代评估。
所描述的研究已在ClinicalTrials.gov注册，临床试验标识符为NCT01357239和NCT01433354。
