Abstract
Objective: Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipra-mine, 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. Methods: 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 Desi-pramine), 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. Results: The median change in AHI from baseline to 6 months was À31 (IQR: À37 to À11) for the high Desipramine, À17.5 (IQR: À31 to 13) for the low Desipramine, and À13 (IQR:À31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups (P = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (r = À0.44; P = 0.0002) was underlined. Interpretation: This first clinical trial of desipra-mine 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. 118