Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine.

BACKGROUND: The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known. METHODS: In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru. RESULTS: A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose. CONCLUSIONS: AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).

Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis.

BACKGROUND: Long-term topical treatment is often required for atopic dermatitis (AD), a chronic inflammatory skin disease. OBJECTIVE: To assess the long-term safety results from a multicenter, open-label, 48-week safety study (AD-303) of patients (N = 517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, a topical phosphodiesterase-4 inhibitor, after completing a 28-day phase 3 pivotal study (AD-301, AD-302). METHODS: Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28-day treatment period with crisaborole applied twice daily was initiated. Adverse events (AEs), including treatment-emergent AEs (TEAEs), and serious AEs were analyzed. RESULTS: During the pivotal studies and AD-303, 65% of patients reported ≥1 TEAE, most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment-related AEs (overall, 10.2%) were dermatitis atopic (3.1%), application-site pain (2.3%), and application-site infection (1.2%). Nine patients (1.7%) discontinued the long-term study because of TEAEs. LIMITATIONS: Long-term efficacy was not analyzed. CONCLUSION: Crisaborole ointment had a low frequency of treatment-related AEs over 48 weeks of treatment of patients with AD.

Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults.

BACKGROUND: Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. OBJECTIVE: We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792). METHODS: Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. RESULTS: More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = .005; 48.5% vs 29.7%, P < .001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P ≤ .001). Treatment-related adverse events were infrequent and mild to moderate in severity. LIMITATIONS: Short study duration was a limitation. CONCLUSIONS: Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD.

Crisaborole Topical Ointment, 2% in Patients Ages 2 to 17 Years with Atopic Dermatitis: A Phase 1b, Open-Label, Maximal-Use Systemic Exposure Study.

BACKGROUND: Phosphodiesterase-4 (PDE4) is a promising target in atopic dermatitis (AD) treatment. The pharmacokinetics (PK), safety, and efficacy of crisaborole topical ointment, 2% (formerly AN2728) (Anacor Pharmaceuticals, Palo Alto, CA), a boron-based benzoxaborole PDE4 inhibitor, were evaluated in children with mild to moderate AD. METHODS: This phase 1b, open-label, maximal-use study of crisaborole topical ointment, 2% applied twice daily (dose 3 mg/cm(2) ) for 28 days enrolled patients ages 2 to 17 years with extensive AD involving 25% or more or 35% or more treatable body surface area, depending on age. Primary PK and safety assessments included systemic exposure to crisaborole and its metabolites after 7 days of treatment and the incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy assessments included change from baseline in Investigator Static Global Assessment (ISGA), treatment success (ISGA score ≤1 with a two-grade or greater improvement from baseline), and improvement in five AD signs and symptoms. RESULTS: Of 34 patients enrolled, 31 completed the study. Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8. Twenty-three of 34 patients reported one or more TEAEs; 95% were mild or moderate and one patient discontinued because of a TEAE. Mean ISGA scores declined from 2.65 at baseline to 1.15 at day 29, 47.1% of patients achieved treatment success, and 64.7% of patients achieved ISGA scores of clear (0) or almost clear . Mean severity scores for AD signs and symptoms declined throughout the study. CONCLUSIONS: This open-label study provides evidence that crisaborole topical ointment, 2% was well tolerated, with limited systemic exposure under maximal-use conditions in patients ages 2 years and older.

A Maximum-Use Trial of Ruxolitinib Cream in Adolescents and Adults with Atopic Dermatitis.

BACKGROUND: Ruxolitinib cream is a topical formulation of ruxolitinib, an inhibitor of Janus kinase 1 and Janus kinase 2. OBJECTIVE: We aimed to determine the safety, tolerability, and bioavailability of 1.5% ruxolitinib cream under maximum-use conditions in patients with atopic dermatitis. Efficacy was evaluated as an exploratory objective. METHODS: Eligible patients aged ≥ 12-65 years with atopic dermatitis, an Investigator's Global Assessment score ≥ 2, and ≥ 25% affected body surface area were enrolled in an open-label, maximum-use phase I study conducted in the USA and Canada. Patients applied 1.5% ruxolitinib cream twice daily to lesions identified at baseline for the first 28 days and continued use only on active lesions for an additional 28 days (extension period). Safety was assessed by frequency, duration, and severity of treatment-emergent adverse events. Plasma concentrations of ruxolitinib and pharmacokinetic parameters were assessed as secondary endpoints. RESULTS: Overall, 41 patients (median age, 17 years; 51% male) were enrolled and 37 (90.2%) entered the extension period, all of whom completed the study. Treatment-emergent adverse events were reported in 13 patients (31.7%). Treatment-related adverse events were reported in four patients (9.8%). The mean (standard deviation) steady-state plasma concentration was 104 (309) nM during the first 28 days, well below the half-maximal inhibitory concentration of Janus kinase-mediated myelosuppression in the bone marrow (281 nM), and decreased further during the extension period. Higher plasma concentrations were detected in a few patients who were treated for a very high affected body surface area. At day 56, 94.6% of patients achieved ≥ 75% improvement in the Eczema Area and Severity Index. CONCLUSIONS: Under maximum-use conditions, ruxolitinib cream was generally well tolerated, with approximately one-third of patients experiencing treatment-emergent adverse events and few treatment-related adverse events. The mean steady-state plasma concentration of ruxolitinib was well below the level expected to affect bone marrow production of blood cells, with a small number of patients exhibiting higher plasma concentrations. In addition, ruxolitinib cream showed a high level of efficacy in patients with atopic dermatitis involving ≥ 25% affected body surface area. GOV IDENTIFIER: NCT03920852.

Citrate does not change viscoelastic haemostatic assays after cardiopulmonary bypass.

Context: Viscoelastic hemostatic assays (VHA) are commonly used to identify specific cellular and humoral causes for bleeding in cardiac surgery patients. Cardiopulmonary bypass (CPB) alterations to coagulation are observable on VHA. Citrated VHA can approximate fresh whole blood VHA when kaolin is used as the activator in healthy volunteers. Some have suggested that noncitrated blood is more optimal than citrated blood for point-of-care analysis in some populations. Aims: To determine if storage of blood samples in citrate after CPB alters kaolin activated VHA results. Settings and Design: This was a prospective observational cohort study at a single tertiary care teaching hospital. Methods and Material: Blood samples were subjected to VHA immediately after collection and compared to samples drawn at the same time and stored in citrate for 30, 90, and 150 min prior to kaolin activated VHA both before and after CPB. Statistical Analysis Used: VHA results were compared using paired T-tests and Bland-Altman analysis. Results: Maximum clot strength and time to clot initiation were not considerably different before or after CPB using paired T-tests or Bland-Altman Analysis. Conclusions: Citrated samples appear to be a clinically reliable substitute for fresh samples for maximum clot strength and time to VHA clot initiation after CPB. Concerns about the role of citrate in altering the validity of the VHA samples in the cardiac surgery population seem unfounded.

Growth and Post-Deposition Treatments of SrTiO3 Films for Dye-Sensitized Photoelectrosynthesis Cell Applications.

Sensitized SrTiO3 films were evaluated as potential photoanodes for dye-sensitized photoelectrosynthesis cells (DSPECs). The SrTiO3 films were grown via pulsed laser deposition (PLD) on a transparent conducting oxide (fluorine-doped tin oxide, FTO) substrate, annealed, and then loaded with zinc(II) 5,10,15-tris(mesityl)-20-[(dihydroxyphosphoryl)phenyl] porphyrin (MPZnP). When paired with a platinum wire counter electrode and an Ag/AgCl reference electrode these sensitized films exhibited photocurrent densities on the order of 350 nA/cm(2) under 0 V applied bias conditions versus a normal hydrogen electrode (NHE) and 75 mW/cm(2) illumination at a wavelength of 445 nm. The conditions of the post-deposition annealing step-namely, a high-temperature reducing atmosphere-proved to be the most important growth parameters for increasing photocurrent in these electrodes.

Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis.

BACKGROUND: Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure. OBJECTIVE: To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR. METHODS: Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients. RESULTS: Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P < .001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P < .01) and -0.15 (95% CI, -0.24 to -0.06; P < .001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment. CONCLUSION: Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.