Safety and Efficacy of Lemborexant in Patients With Irregular Sleep-Wake Rhythm Disorder and Alzheimer's Disease Dementia: Results From a Phase 2 Randomized Clinical Trial.

BACKGROUND: Irregular sleep-wake rhythm disorder (ISWRD) is a common sleep disorder in individuals with Alzheimer's disease dementia (AD-D). OBJECTIVES: This exploratory phase 2 proof-of-concept and dose-finding clinical trial evaluated the effects of lemborexant compared with placebo on circadian rhythm parameters, nighttime sleep, daytime wakefulness and other clinical measures of ISWRD in individuals with ISWRD and mild to moderate AD-D. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Sites in the United States, Japan and the United Kingdom. PARTICIPANTS: Men and women 60 to 90 years of age with documentation of diagnosis with AD-D and Mini-Mental State Exam (MMSE) score 10 to 26. INTERVENTION: Subjects were randomized to placebo or one of four lemborexant treatment arms (2.5 mg, 5 mg, 10 mg or 15 mg) once nightly at bedtime for 4 weeks. MEASUREMENTS: An actigraph was used to collect subject rest-activity data, which were used to calculate sleep-related, wake-related and circadian rhythm-related parameters. These parameters included least active 5 hours (L5), relative amplitude of the rest-activity rhythm (RA) and mean duration of sleep bouts (MDSB) during the daytime. The MMSE and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) were used to assess for changes in cognitive function. RESULTS: Sixty-two subjects were randomized and provided data for circadian, daytime and nighttime parameters (placebo, n = 12; lemborexant 2.5 mg [LEM2.5], n = 12; lemborexant 5 mg [LEM5], n = 13, lemborexant 10 mg [LEM10], n = 13 and lemborexant 15 mg [LEM15], n = 12). Mean L5 showed a decrease from baseline to week 4 for LEM2.5, LEM5 and LEM15 that was significantly greater than with placebo (all p < 0.05), suggesting a reduction in restlessness. For RA, LS mean change from baseline to week 4 versus placebo indicated greater distinction between night and day with all dose levels of lemborexant, with significant improvements seen with LEM5 and LEM15 compared with placebo (both p < 0.05). The median percentage change from baseline to week 4 in MDSB during the daytime indicated a numerical decrease in duration for LEM5, LEM10 and LEM15, which was significantly different from placebo for LEM5 and LEM15 (p < 0.01 and p = 0.002, respectively). There were no serious treatment-emergent adverse events or worsening of cognitive function, as assessed by the MMSE and ADAS-Cog. Lemborexant was well tolerated. No subjects discontinued treatment. CONCLUSIONS: This study provides preliminary evidence of the potential utility of lemborexant as a treatment to address both nighttime and daytime symptoms in patients with ISWRD and AD-D.

Baseline autoantibody profiles predict normalization of complement and anti-dsDNA autoantibody levels following rituximab treatment in systemic lupus erythematosus.

B cells are thought to play a major role in the pathogenesis of systemic lupus erythematosus (SLE). Rituximab (RTX), a chimeric anti-CD20 mAb, effectively depletes CD20( +) peripheral B cells. Recent results from EXPLORER, a placebo-controlled trial of RTX in addition to aggressive prednisone and immunosuppressive therapy, showed similar levels of clinical benefit in patients with active extra-renal SLE despite effective B cell depletion. We performed further data analyses to determine whether significant changes in disease activity biomarkers occurred in the absence of clinical benefit. We found that RTX-treated patients with baseline autoantibodies (autoAbs) had decreased anti-dsDNA and anti-cardiolipin autoAbs and increased complement levels. Patients with anti-dsDNA autoAb who lacked baseline RNA binding protein (RBP) autoAbs showed increased complement and decreased anti-dsDNA autoAb in response to RTX. Other biomarkers, such as baseline BAFF levels or IFN signature status did not predict enhanced effects of RTX therapy on complement or anti-dsDNA autoAb levels. Finally, platelet levels normalized in RTX-treated patients who entered the study with low baseline counts. Together, these findings demonstrate clear biologic activity of RTX in subsets of SLE patients, despite an overall lack of incremental clinical benefit with RTX in the EXPLORER trial.

A genetic screen for behavioral mutations that perturb dopaminergic homeostasis in mice.

Disruption of dopaminergic (DA) systems is thought to play a central role in the addictive process and in the pathophysiology of schizophrenia. Although inheritance plays an important role in the predisposition to these disorders, the genetic basis of this is not well understood. To provide additional insight, we have performed a modifier screen in mice designed to identify mutations that perturb DA homeostasis. With a genetic background sensitized by a mutation in the dopamine transporter (DAT), we used random chemical mutagenesis and screened for mutant mice with locomotor abnormalities. Four mutant lines were identified with quantitatively elevated levels of locomotor activity. Mapping of mutations in these lines identified two loci that alter activity only when dopamine levels are elevated by a DAT mutation and thus would only have been uncovered by this type of approach. One of these quantitative trait loci behaves as an enhancer of DA neurotransmission, whereas the other may act as a suppressor. In addition, we also identified three loci which are not dependent on the sensitized background but which also contribute to the overall locomotor phenotype.

Power and sample size for ordered categorical data.

We propose a new method for computing power and sample size for linear rank tests of differences between two ordered multinomial populations. The method is flexible in that it is applicable to any general alternative hypothesis and for any choice of rank scores. We show that the method, though asymptotic, closely approximates existing exact methods. At the same time it overcomes the computational limitations of the exact methods. This advantage makes our asymptotic approach more practical for sample size computations at the planning stages of a large study. We illustrate the method with data arising from both proportional and non-proportional odds models in the two ordered multinomial setting.