Department of Neurology, The Ohio State University, Columbus, Ohio, United States of America.
PLoS One. 2011;6(7):e21296. doi: 10.1371/journal.pone.0021296. Epub 2011 Jul 6.
Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.
This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.
Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.
This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.
多项证据表明丙戊酸（VPA）可能对脊髓性肌萎缩症（SMA）患者有益。SMA CARNIVAL 试验是一项评估口服 VPA 和左旋肉碱治疗 SMA 儿童的两部分前瞻性试验。第 1 部分针对 2-8 岁非运动型儿童，采用 12 个月的交叉设计。我们在此报告第 2 部分，即 12 个月前瞻性、开放标签 VPA 和左旋肉碱治疗运动型 SMA 儿童的试验。
本研究涉及 33 名经基因证实的 3 型 SMA 受试者，年龄 3-17 岁。受试者在 4-6 周内进行两次基线评估，然后接受 VPA 和左旋肉碱治疗 12 个月。评估在基线、3、6 和 12 个月进行。主要结局包括安全性、不良事件以及 6 和 12 个月时使用改良哈默史密斯运动功能量表扩展版（MHFMS-Extend）、计时运动测试和精细运动模块评估的运动功能变化。次要结局包括尺神经复合肌肉动作电位幅度（CMAP）、手持测力计、肺功能和儿科生活质量量表评分的变化。
28 名受试者完成了研究。VPA 和肉碱通常耐受良好。尽管 85%的受试者发生了不良事件，但通常是轻微和短暂的。17%的受试者体重增加了 20%以上。6 个月或 12 个月时，任何主要结局均无显著变化。一些肺功能测量指标在一年后如预期的正常生长而有所改善。CMAP 显著改善，提示存在适度的生物学效应，但无临床意义。
这项研究与 CARNIVAL 第 1 部分研究一起表明，VPA 不能改善 SMA 儿童的肌力或功能。本研究中使用的结局是可行和可靠的，可用于未来的 SMA 试验。
Clinicaltrials.gov NCT00227266。
