Search

Study Objectives To assess long-term efficacy and safety of lemborexant (LEM), a novel dual orexin receptor antagonist, versus placebo in adults with insomnia disorder. Methods This was a 12-month, global, multicenter, randomized, double-blind, parallel-group phase 3 study comprising a 6-month placebo-controlled period (reported here) followed by a 6-month active-treatment-only period (reported separately). A total of 949 participants with insomnia (age ≥18 years) were randomized, received treatment with an oral dose of placebo or LEM (5 mg [LEM5] or 10 mg [LEM10]) and were analyzed. Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored throughout the study. Results Decreases from baseline in patient-reported (subjective) sleep onset latency and subjective wake after sleep onset, and increases from baseline in subjective sleep efficiency, were significantly greater with LEM5 and LEM10 versus placebo. Significant benefits over placebo were observed at the end of month 6, and at most time points assessed over the 6-month period, indicating long-term sustained efficacy of LEM. A significantly greater percentage of sleep onset responders and sleep maintenance responders were observed with LEM treatment versus placebo. Participants treated with LEM reported a significant improvement in quality of sleep after 6 months versus placebo. The majority of TEAEs were mild or moderate. There was a low rate of serious TEAEs and no deaths. Conclusions LEM5 and LEM10 provided significant benefit on sleep onset and sleep maintenance in individuals with insomnia disorder versus placebo, and was well tolerated. Clinical trial registration ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39

Myopathy is a typical clinical finding among patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), but the variability in such findings has not been properly established. We have previously determined the prevalence of patients with 3243A>G in a defined population in northern Finland and characterized a group of patients who represent a good approximation to a population-based cohort. We report here on examinations performed on patients belonging to this cohort in order to determine the frequency of myopathy and to evaluate the clinical, histological, ultrastructural and single fibre mtDNA variability in muscle involvement. Fifty patients with 3243A>G underwent a thorough structured interview and clinical examination. Muscle histology, ultrastructure and single fibre analysis were examined in a subset of patients. A clinical diagnosis of myopathy was made in 50% of cases [95% confidence interval (CI), 36-64] and abnormalities in muscle histology were found in 72% (95% CI, 55-86). Moderate limb weakness leading to functional impairment was the most common myopathic sign, but mild weakness, ptosis and external ophthalmoplegia could also be found. The presence of intramitochondrial crystals and cytochrome c oxidase (COX)-negative fibres and variation in mitochondrial size and shape were more common in the muscles of the myopathic patients. Longitudinal variations in mutation heteroplasmy were examined in single muscle fibres from two severely affected patients. Although the total variation in mutation heteroplasmy along four ragged red fibres (RRFs) was small, the mutation heteroplasmy in five 10 microm segments was clearly lower (median 68%, range 64-74%) than that in the neighbouring segments. There were also segments with deviant mutation load in histologically normal fibres in one patient. The highest incidence of myopathy was in the fifth decade of life, but, apart from age, no other clinical variables such as gender, muscle heteroplasmy, physical inactivity or diabetes were associated with an increased risk of myopathy. The clinical presentation of myopathy is highly variable in patients with 3243A>G.