A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects

Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation: The data support further clinical studies investigating ASP8062 in patients with AUD.

Intrinsic and extrinsic contributions in non-linearity dielectric response of (Bi0.5Na0.3K0.2)TiO3-(Ba0.8Ca0.2)TiO3 based SrTiO3 ceramics driven by Rayleigh model

Pb-free ceramics of [(0.95-x)(Bi0.5Na0.3K0.2)TiO3-0.05(Ba0.8Ca0.2)TiO3 doped x(SrTiO3) (0.0 ≤ x ≤ 0.2) were prepared by solid solution technique. The effect of ST content on the crystal structure and morphology of the sintered ceramics were systemically investigated. Crossover phase transition from ferroelectric to relaxor accompanied by changes in the shape of grain morphology were observed by increasing ST-content. The phase crossover is caused by oxygen vacancies and 1attice distortion effect. The electrical properties for virgin and poled samples were investigated. All virgin samples belong (x ≤ 0.15) showed present ferroelectric to relaxor diffused phase transition however ST = 0.2, only relaxor to paraelectric phase transition was detected in whole range of temperature. The poled sample of ST = 0.2 showed present two phase transition similar to (ST ≤ 0.15) denote domain grow caused by domain wall displacement at high amplitude of electric field. The polarization response was studied under sub-switching cyclic of electric fie1ds at different temperatures. The non-linearity behavior showed both of ferroe1ectric and relaxor phase dominated by Rayleigh-type dynamic. The results suggest that in ferroelectric phase, the extrinsic contribution caused by domain wall motion is responsible for majority of dielectric contributions while in relaxor phase, the majority of dielectric contribution are comes from intrinsic contribution caused by lattice distortion effect. Corresponding author: [email protected]

Crossover from two-frequency pulse compounds to escaping solitons

The nonlinear interaction of copropagating optical solitons enables a large variety of intriguing bound-states of light. We here investigate the interaction dynamics of two initially superimposed fundamental solitons at distinctly different frequencies. Both pulses are located in distinct domains of anomalous dispersion, separated by an interjacent domain of normal dispersion, so that group velocity matching can be achieved despite a vast frequency gap. We demonstrate the existence of two regions with different dynamical behavior. For small velocity mismatch we observe a domain in which a single heteronuclear pulse compound is formed, which is distinct from the usual concept of soliton molecules. The binding mechanism is realized by the mutual cross phase modulation of the interacting pulses. For large velocity mismatch both pulses escape their mutual binding and move away from each other. The crossover phase between these two cases exhibits two localized states with different velocity, consisting of a strong trapping pulse and weak trapped pulse. We detail a simplified theoretical approach which accurately estimates the parameter range in which compound states are formed. This trapping-to-escape transition allows to study the limits of pulse-bonding as a fundamental phenomenon in nonlinear optics, opening up new perspectives for the all-optical manipulation of light by light.

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres.In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week. In period B, patients received eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A–B (n=20) or B–A (n=20). The primary efficacy endpoint was change in cough frequency assessed over 24 h (VitaloJAK). Primary safety endpoint was frequency and severity of adverse events (AEs).Thirty-seven patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg, 25%: 90% confidence interval, 11.5–36.5%; p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41–49% receiving eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5–21% with eliapixant: all were mild.Selective P2X3 antagonism with eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC.

Is Topical Application of Hyaluronic Acid in Oral Lichen Planus Effective? A Randomized Controlled Crossover Study

Hyaluronic acid (HA) has anti-inflammatory and anti-edematous effects and, thus, could be promising in the treatment of oral lichen planus (OLP). The aim of the study was to evaluate the effects of topical hyaluronic acid, compared to placebo, on salivary levels of calprotectin, interleukin-6 (IL-6), and bacteria, as well as clinical and subjective parameters. Fourteen patients with confirmed OLP were included. After random selection, patients started with either 0.2% hyaluronic acid or a placebo gel for 6 weeks. Following a wash-out period, the groups changed the application. Whole saliva, clinical parameters, and questionnaires were evaluated before and after the intervention, as well as after the crossover phase. Salivary calprotectin, IL-6, and inflammation-related bacteria were determined by ELISA and PCR, respectively. There were no significant differences in clinical or subjective outcome parameters, salivary levels of IL-6, calprotectin, or bacteria after the application of hyaluronic acid, compared to placebo. However, only nine patients completed the study, as five out of seven patients starting with placebo were lost to follow-up. Significant effects of HA on inflammatory mediators and clinical parameters in OLP patients could not be proven, although a trend in clinical severity improvement could be observed.

Results of crossover phase II component of randomized placebo-controlled trial evaluating oral THC/cannabis extract for refractory chemotherapy-induced nausea and vomiting (CINV).

12008 Background: The aim of this multi-centre, randomised, double-blinded, placebo-controlled, phase 2/3 trial is to determine efficacy of addition of oral cannabis in adults with any malignancy of any stage, experiencing CINV during moderate-highly emetogenic intravenous chemotherapy, despite guideline-consistent anti-emetic prophylaxis, requiring ≥ 2 chemotherapy cycles. Here we report the crossover phase 2 component results. Methods: Treatment consisted of 1 cycle of oral THC 2.5mg/CBD 2.5mg (TN-TC11M) capsules tds days -1 to 5 and 1 cycle matching placebo in a crossover design, then blinded patient preference for a 3rd cycle. Primary end-point is difference in proportion of patients with ‘complete response’ (no emesis & no use of rescue medications) during 0-120 hours from chemotherapy between cycles. 80 patients provides 80% power with 2p of 0.1 to detect a 20% difference. Results: 81 patients recruited (2016-9). 72 completing 2 cycles are included in efficacy analyses. 78 not withdrawing consent are included in safety analyses. Median age was 55 years (range 29-80), 78% were female, 42% report historic cannabis use, 55% were treated with curative intent. Most common regimens were AC (26%), FOLFOX (17%). All received steroids & 5-HT3 antagonist, 79% received NK-1 antagonist, 4% received olanzapine. Efficacy is shown in table. 83% preferred cannabis to placebo. Most common bothersome cannabinoid-related adverse events (cannabis, placebo) were sedation (19%,4%), dizziness (10%,1%), disorientation (3%,0%). No SAEs were attributed to THC/CBD. Conclusions: Addition of oral THC/CBD to standard anti-emetics was associated with less nausea & vomiting but additional side effects. Most preferred THC/CBD to placebo. Based on these positive results, the definitive parallel phase 3 trial component continues (additional n=170). Acknowledgements: Trial participants, investigators, research staff. Funding from NSW Government Dept of Health. Clinical trial information: ACTRN12616001036404 . [Table: see text]

O83 Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors

BackgroundMK-5890 is a humanized agonist monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell–mediated responses. This first-in-human phase 1 study of MK-5890 evaluated the safety and efficacy of escalating doses of MK-5890 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.MethodsKey eligibility criteria included histologically or cytologically confirmed advanced solid tumor, measurable disease by RECIST v1.1, and ECOG PS ≤1. MK-5890 was tested alone (dose range, 2-700 mg) or with pembrolizumab (fixed dose, 200 mg). Patients with disease progression following MK-5890 monotherapy were eligible to cross over to combination treatment. The primary objective was safety and tolerability. Objective response rate by investigator per RECIST v1.1 was also evaluated. The database cutoff for this analysis was May 30, 2019.ResultsOf 44 patients enrolled, 25 received MK-5890 and 19 received MK-5890 plus pembrolizumab; their median age was 59.0 years, 61.4% were female, 47.7% had ECOG PS 1, and 13.6% previously received immune checkpoint inhibitor therapy. In the initial phase, dose-limiting toxicities (DLTs) were reported in 3 patients receiving MK-5890 and 1 patient receiving MK-5890 plus pembrolizumab; all DLTs were associated with infusion-related adverse events. Maximum tolerated dose was defined. Treatment-related adverse events (TRAEs) were reported in 40 patients (90.9%): 22 patients (88.0%) receiving MK-5890 and 18 patients (94.7%) receiving MK-5890 plus pembrolizumab. The most common TRAEs were fatigue (28.0%) and infusion-related reactions (28.0%) with MK-5890 and fatigue (36.8%) and pruritus (31.6%) with MK-5809 plus pembrolizumab. Grade 3-4 TRAEs were reported in 10 patients (22.7%): 6 patients (24.0%) receiving MK-5890 and 4 patients (21.1%) receiving MK-5890 plus pembrolizumab; no grade 5 events were observed. One patient (4.0%) achieved a partial response (PR) with MK-5890 and 1 patient (5.3%) achieved a PR with MK-5890 plus pembrolizumab. Fourteen patients entered the crossover phase to receive MK-5890 plus pembrolizumab. In the crossover phase, no DLTs were reported. TRAEs were reported in 12 patients (85.7%); the most common were pruritus (21.4%), rash (21.4%), and headache (14.3%). One patient (7.1%) reported grade 3-4 TRAEs of increased amylase and increased lipase; no grade 5 events were observed. Two patients (14.3%) achieved a complete response and 2 patients (14.3%) achieved a PR.ConclusionsTreatment with MK-5890, alone and in combination with pembrolizumab, demonstrated an acceptable safety profile. Early antitumor activity was observed in patients with advanced solid tumors in both monotherapy and combination therapy arms.