Mancini Josette, Dubus Jean-Christophe, Jouve Elisabeth, Roux Jean-Christophe, Franco Patricia, Lagrue Emmanuelle, Castelnau Pierre, Cances Claude, Chaix Yves, Rougeot-Jung Christelle, Cornu Catherine, Desportes Vincent, Vallée Louis, Bahi-Buisson Nadia, Truillet Romain, Attolini Laurence, Villard Laurent, Blin Olivier, Micallef Joëlle
Neuropediatric Unit Aix Marseille University Children Hospital APHM, Timone, Neurosciences Institute Marseille France.
Pneumology Pediatric Unit Aix Marseille University Children Hospital CNRS URMITE 6236A PHM Marseille France.
Ann Clin Transl Neurol. 2017 Dec 27;5(2):118-127. doi: 10.1002/acn3.468. eCollection 2018 Feb.
Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2-deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT.
The trial was a 6-month, multicenter, randomized, double-blind, placebo-controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2-3 mg/kg Desipramine per day (high Desipramine), 1-2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention-to-treat analysis was applied.
The median change in AHI from baseline to 6 months was -31 (IQR: -37 to -11) for the high Desipramine, -17.5 (IQR: -31 to 13) for the low Desipramine, and -13 (IQR:-31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups ( = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (= -0.44; = 0.0002) was underlined.
This first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.
雷特综合征（RTT）是一种伴有呼吸障碍的严重神经发育疾病，在每10000例女性出生中约有1例受影响。去甲丙咪嗪，一种去甲肾上腺素再摄取抑制剂，可减少RTT模型Mecp2基因缺陷小鼠的呼吸暂停次数。我们计划进行一项2期试验，以测试其对36名RTT女孩呼吸模式的疗效和安全性。
该试验为一项为期6个月的多中心、随机、双盲、安慰剂对照研究，已在ClinicalTrials.gov注册，编号为NCT00990691。根据临床检查诊断并经基因分型确认的女孩按1:1:1的比例随机分配，分别接受每天2 - 3毫克/千克去甲丙咪嗪（高剂量去甲丙咪嗪）、每天1 - 2毫克/千克去甲丙咪嗪（低剂量去甲丙咪嗪）或安慰剂。主要结局是呼吸暂停低通气指数（AHI）的变化，AHI由每小时呼吸暂停和低通气事件的数量定义，在基线后6个月进行评估。采用意向性分析。
高剂量去甲丙咪嗪组从基线到6个月时AHI的中位数变化为 - 31（四分位间距：- 37至 - 11），低剂量去甲丙咪嗪组为 - 17.5（四分位间距：- 31至13），安慰剂组为 - 13（四分位间距：- 31至0）。我们未发现各组间这些变化存在任何显著差异（P = 0.781）。去甲丙咪嗪血浆浓度与AHI之间存在显著的负相关（P = - 0.44；P = 0.0002）。
去甲丙咪嗪的这项首次临床试验未显示出临床疗效。尽管需要进一步研究，但去甲丙咪嗪浓度与AHI改善之间的显著相关性为在RTT中测试去甲肾上腺素能途径提供了额外且相关的理由。
