A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation.

OBJECTIVE: To evaluate the pharmacokinetic and safety profile of a novel continuous release and absorption melatonin (CRA-melatonin) compared with an immediate-release melatonin (IR-melatonin) product. METHODS: The REM Absorption Kinetics Trial (REMAKT), an open-label, single-center, randomized, single-dose, 2-way crossover trial, compared the pharmacokinetic and safety profile of CRA-melatonin (5 mg) with IR-melatonin (5 mg) in healthy adult volunteers. The study was conducted from March 18, 2016, to April 20, 2016. RESULTS: Ten subjects completed REMAKT. Plasma melatonin levels exceeded the targeted maintenance threshold level of 1,000 pg/mL for a median of 6.7 hours for CRA-melatonin compared with 3.7 hours for IR-melatonin. The median Cmax was 4,690 pg/mL for CRA-melatonin and 23,352 pg/mL for IR-melatonin. In REMAKT, there were no treatment-emergent adverse events reported in the CRA-melatonin arm. Five treatment-emergent adverse events occurred with IR-melatonin. CONCLUSIONS: The novel, well-tolerated CRA-melatonin was shown to achieve quick release and then continuous release and absorption of melatonin for up to 7 hours, making it a significant advancement in the pharmacokinetic release profile of exogenous melatonin delivery and, therefore, an important potential consideration as a baseline therapy for sleep.

A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity.

BACKGROUND: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder. AIMS: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires. RESULTS: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence. CONCLUSIONS: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.

Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): Results from a first-in-human randomised, placebo-controlled phase 1/2 study.

BACKGROUND: A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. METHODS: In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18-64years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). RESULTS: A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11-15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. CONCLUSIONS: Single-dose vaccination of SA4Ag in healthy adults aged 18-64years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. TRIAL REGISTRATION NUMBER: NCT01364571.

Safety, tolerability, and immunogenicity of a single dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy older adults: Results of a randomised trial.

BACKGROUND: The decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18-64years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM197) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted. METHODS: In this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65-85years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays. RESULTS: The results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels. CONCLUSIONS: Single-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65-85years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85years. TRIAL REGISTRATION NUMBER: NCT01643941.

A randomized, double-blind, single-dose, placebo-controlled, multicenter, polysomnographic study of gabapentin in transient insomnia induced by sleep phase advance.

STUDY OBJECTIVES: To evaluate the effects of single doses of gabapentin 250 and 500 mg on polysomnographic (PSG) and participant-reported sleep measures in a 5-h phase advance insomnia model. METHODS: Adults reporting occasional disturbed sleep received gabapentin 500 mg (n = 125), 250 mg (n = 125), or placebo (n = 127) 30 min prior to bedtime and were in bed from 17:00 to 01:00, ∼5 h before their habitual bedtime. Sleep was assessed by PSG, post-sleep questionnaire, and the Karolinska Sleep Diary (KSD). Next-day residual effects (Digit Symbol Substitution Test [DSST] and Stanford Sleepiness Scale [SSS]) and tolerability were assessed. RESULTS: Demographics were comparable among groups. Among PSG endpoints, wake after sleep onset (primary endpoint) (135.7 [placebo], 100.7 [250 mg], and 73.2 [500 mg] min) was significantly lower and total sleep time (TST) (311.4, 356.5, and 378.7 min) significantly greater in both gabapentin groups versus placebo. Latency to persistent sleep was not significantly different among groups. Percent slow wave sleep (12.6%, 15.4%, and 17.0%, respectively) was significantly greater and percent stage 1 (15.1%, 11.8%, and 10.8%, respectively) significantly lower relative to placebo. Gabapentin was associated with significantly higher values of KSD Sleep Quality Index and reported TST versus placebo; no other reported outcomes were significant. Neither gabapentin dose produced evidence of next-day residual effects as measured by DSST and SSS. Adverse events were infrequent (< 5%). CONCLUSION: Participants with occasional disturbed sleep treated with gabapentin showed significantly longer sleep duration and greater depth (versus placebo) in response to a phase advance manipulation known to disrupt sleep maintenance.

The effect of armodafinil on patient-reported functioning and quality of life in patients with excessive sleepiness associated with shift work disorder: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To examine whether treatment with armodafinil for 6 weeks affected patient-reported overall functioning and daily quality of life compared with placebo in patients with excessive sleepiness associated with shift work disorder. METHOD: This 6-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 45 sleep centers across the United States between February and October 2010. Patients included in the study were 18 to 65 years of age and diagnosed with excessive sleepiness associated with shift work disorder on the basis of the International Classification of Sleep Disorders: Diagnostic and Coding Manual, Second Edition and DSM-IV-TR criteria. These patients also experienced late-in-shift sleepiness between 4 AM and 8 AM (Karolinska Sleepiness Scale score ≥ 6) and were functionally impaired (Global Assessment of Functioning score < 70). Patients were administered 150 mg of armodafinil or placebo on nights worked, and efficacy measures included changes in patient-reported overall functioning (modified Sheehan Disability Scale [SDS-M]) and daily quality of life (10-question Functional Outcomes of Sleep Questionnaire [FOSQ-10]). RESULTS: Patients treated with armodafinil had significantly greater improvement in SDS-M composite scores at final visit (last observation carried forward) (-6.8 vs -4.5, respectively, P = .0027) than those receiving placebo. Although the armodafinil group, compared to the placebo group, showed a greater improvement in total FOSQ-10 score from baseline to final visit (+3.4 vs +2.7, respectively, P = .0775), a statistically significant improvement was observed only at week 6 (+3.6 vs +2.7, respectively, P = .0351). CONCLUSIONS: These findings are consistent with our previous report on clinician-rated measures of efficacy by demonstrating that armodafinil improves patient-rated functioning in patients with shift work disorder. Additionally, the current findings show for the first time that armodafinil may have benefits on quality of life after 6 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01080807.

Efficacy and tolerability of armodafinil: effect on clinical condition late in the shift and overall functioning of patients with excessive sleepiness associated with shift work disorder.

OBJECTIVE: This study examined the effect of armodafinil on late-in-shift clinical condition, wakefulness, and overall functioning of patients with shift work disorder. METHODS: Patients with clinically diagnosed shift work disorder received armodafinil or placebo on nights worked for 6 weeks. Patients included in the study experienced late-in-shift sleepiness between 4 AM and 8 AM (Karolinska Sleepiness Scale ≥6) and were functionally impaired (Global Assessment of Functioning <70). Efficacy was determined by improvements in clinical condition (Clinical Global Impression-Change), late-in-the-shift Karolinska Sleepiness Scale score, and overall Global Assessment of Functioning score. Tolerability was assessed. RESULTS: Patients receiving armodafinil showed significant improvements in late-in-shift clinical condition, wakefulness, and global functioning, compared to placebo at final visit. Armodafinil was generally well tolerated. CONCLUSIONS: Armodafinil improved clinical condition and wakefulness late in the night shift of patients with shift work disorder. Overall patient functioning was also improved.

APD125, a selective serotonin 5-HT(2A) receptor inverse agonist, significantly improves sleep maintenance in primary insomnia.

INTRODUCTION: Insomnia is a condition affecting 10% to 15% of the adult population and is characterized by difficulty falling asleep, difficulty staying asleep, or nonrestorative sleep, accompanied by daytime impairment or distress. This study evaluates APD125, a selective inverse agonist of the 5-HT(2A) receptor, for treatment of chronic insomnia, with particular emphasis on sleep maintenance. In phase 1 studies, APD125 improved sleep maintenance and was well tolerated. METHODOLOGY: Adult subjects (n=173) with DSM-IV defined primary insomnia were randomized into a multicenter, double-blind, placebo-controlled, 3-way crossover study to compare 2 doses of APD125 (10 mg and 40 mg) with placebo. Each treatment period was 7 days with a 7- to 9-day washout period between treatments. Polysomnographic recordings were performed at the initial 2 screening nights and at nights (N) 1/2 and N 6/7 of each treatment period. RESULTS: APD125 was associated with significant improvements in key sleep maintenance parameters measured by PSG. Wake time after sleep onset decreased (SEM) by 52.5 (3.2) min (10 mg) and 53.5 (3.5) min (40 mg) from baseline to N 1/2 vs. 37.8 (3.4) min for placebo, (P < 0.0001 for both doses vs. placebo), and by 51.7 (3.4) min (P = 0.01) and 48.0 (3.6) min (P = 0.2) at N 6/7 vs. 44.0 (3.8) min for placebo. Significant APD125 effects on wake time during sleep were also seen (P < 0.0001 N 1/2, P < 0.001 N 6/7). The number of arousals and number of awakenings decreased significantly with APD125 treatment compared to placebo. Slow wave sleep showed a statistically significant dose-dependent increase. There was no significant decrease in latency to persistent sleep. No serious adverse events were reported, and no meaningful differences in adverse event profiles were observed between either dose of APD125 and placebo. APD125 was not associated with next-day psychomotor impairment as measured by Digit Span, Digit Symbol Copy, and Digit Symbol Coding Tests. CONCLUSIONS: APD125 produced statistically significant improvements in objective parameters of sleep maintenance and sleep consolidation and was well tolerated in adults with primary chronic insomnia.

Efficacy and tolerability of modified-release indiplon in elderly patients with chronic insomnia: results of a 2-week double-blind, placebo-controlled trial.

STUDY OBJECTIVE: Indiplon is a nonbenzodiazepine GABA potentiator, which exhibits pharmacologic selectivity for GABA(A) receptors containing the alpha1 subunit. The aim of the present study was to evaluate the efficacy and safety of a 15-mg nightly dose of modified-release indiplon tablets in elderly patients with primary insomnia characterized by sleep-maintenance difficulties. METHODS: Two hundred twenty-nine elderly patients, aged 65 to 85 years, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for primary insomnia were randomly assigned to 2 weeks of nightly treatment with either indiplon, 15 mg, or placebo in a double-blind, parallel-group design. Daily sleep diaries were completed to collect patient reports of subjective total sleep time, wake time after sleep onset, number of awakenings after sleep-onset, latency to sleep onset, and sleep quality. Patient global impression ratings of various parameters of sleep were assessed on a weekly basis. RESULTS: The least square mean total sleep time was significantly improved with indiplon versus placebo at week 1 (377 +/- 4 min vs. 328 +/- 4 min; p < .0001) and week 2 (373 +/- 5 min vs. 337 +/- 5 min; p < .0001). Indiplon also significantly improved subjective wake after sleep onset, subjective number of awakenings after sleep onset, subjective sleep-onset latency, sleep quality, and patient global impression ratings of sleep at both weeks 1 and 2. The number and severity of adverse events and rates of discontinuation due to adverse effects were comparable in the indiplon and placebo groups. CONCLUSIONS: In elderly patients with primary insomnia characterized by sleep-maintenance difficulty, indiplon, 15 mg, was well tolerated and significantly improved all patient-reported measures of sleep during 2 weeks of treatment.