Adhesion Evaluation of AG200-15: An Investigational Transdermal Contraceptive Delivery System.

INTRODUCTION: AG200-15, an investigational transdermal contraceptive delivery system or patch, is designed to be a low-dose, non-daily, combined hormonal contraceptive option for women. In this phase 1 study, the in vivo adhesion of the AG200-15 patch was compared to Xulane®, the only contraceptive patch available in the USA. METHODS: This phase 1, randomized, open-label, single-dose, two-treatment, two-period crossover adhesion study compared the 7-day adhesion of the AG200-15 and Xulane contraceptive patches. Eighty-three women, ages 18 to 35 years old, with body mass index (BMI) ≥ 19 kg/m2 and < 35 kg/m2, and weight ≥ 48 kg and < 90 kg were enrolled. Trained study site personnel used a five-point scale to assess patch adhesion daily. A score of 0 reflected at least 90% adhesion; while a score of 4 represented complete detachment of the patch. The primary objective was to compare the adhesion properties of the two patches; AG200-15 would be considered statistically non-inferior to Xulane if the upper 95% confidence limit (CL) of the mean difference in adhesion scores was below + 0.15. RESULTS: The overall mean (standard deviation) scores for AG200-15 (N = 78) and Xulane (N = 77) were 0.14 (0.28) and 0.39 (0.40), respectively (lower scores on the adhesion scale indicate better adhesion). The study demonstrated a difference in mean adhesion scores of - 0.24, meeting the prespecified non-inferiority criterion by demonstrating a one-sided upper CL of - 0.16. Thus, the in vivo adhesion of AG200-15 was shown to be non-inferior to that of Xulane. Most subjects experienced no skin irritation at the application site for either patch and no serious adverse event was reported in the study. CONCLUSION: The in vivo adhesion of AG200-15 is non-inferior to that of Xulane on the basis of the prespecified criterion of the upper bound of the one-sided 95% CL for the mean adhesion score difference being below + 0.15. Both patches were generally well tolerated. FUNDING: Agile Therapeutics, Inc.

Protection against Plasmodium falciparum malaria by PfSPZ Vaccine.

BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against homologous Pf (same strain as in the vaccine) controlled human malaria infection (CHMI) 3 weeks after 5 doses administered intravenously. The next step was to assess protective efficacy against heterologous Pf (different from Pf in the vaccine), after fewer doses, and at 24 weeks. METHODS: The trial assessed tolerability, safety, immunogenicity, and protective efficacy of direct venous inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects. RESULTS: Three weeks after final immunization, 5 doses of 2.7 × 105 PfSPZ protected 12 of 13 recipients (92.3% [95% CI: 48.0, 99.8]) against homologous CHMI and 4 of 5 (80.0% [10.4, 99.5]) against heterologous CHMI; 3 doses of 4.5 × 105 PfSPZ protected 13 of 15 (86.7% [35.9, 98.3]) against homologous CHMI. Twenty-four weeks after final immunization, the 5-dose regimen protected 7 of 10 (70.0% [17.3, 93.3]) against homologous and 1 of 10 (10.0% [-35.8, 45.6]) against heterologous CHMI; the 3-dose regimen protected 8 of 14 (57.1% [21.5, 76.6]) against homologous CHMI. All 22 controls developed Pf parasitemia. PfSPZ Vaccine was well tolerated, safe, and easy to administer. No antibody or T cell responses correlated with protection. CONCLUSIONS: We have demonstrated for the first time to our knowledge that PfSPZ Vaccine can protect against a 3-week heterologous CHMI in a limited group of malaria-naive adult subjects. A 3-dose regimen protected against both 3-week and 24-week homologous CHMI (87% and 57%, respectively) in this population. These results provide a foundation for developing an optimized immunization regimen for preventing malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT02215707. FUNDING: Support was provided through the US Army Medical Research and Development Command, Military Infectious Diseases Research Program, and the Naval Medical Research Center's Advanced Medical Development Program.

Peripheral artery disease and outcomes after myocardial infarction: an individual-patient meta-analysis of 28,771 patients in CAPRICORN, EPEHESUS, OPTIMAAL and VALIANT.

OBJECTIVES: To examine the prevalence of peripheral artery disease (PAD) and the relationship between PAD and cardiovascular (CV) outcomes in subjects with left ventricular systolic dysfunction, heart failure or both after acute myocardial infarction (MI). BACKGROUND: PAD is associated with poorer prognosis in patients with stable and unstable coronary heart disease but whether PAD is associated with worse outcomes following substantial acute MI is unknown. METHODS: Univariate and multivariate Cox proportional hazards modelling was used to compare clinical outcomes in an individual-patient meta-analysis of 4 trials (CAPRICORN, EPHESUS, OPTIMAAL and VALIANT). RESULTS: Of the 28,771 patients randomized, 2357 (8.2%) had PAD. These patients were older and had more co-morbidity and were less likely to be prescribed aspirin or a beta-blocker compared to patients without PAD. Over a mean follow-up of 2.7 years, 5121 (17.8%) patients died and 15,055 (52.3%) experienced CV death or hospitalization. PAD was an independent predictor of all individual and composite CV outcomes examined (including heart failure), with the exception of stroke. In patients with PAD (compared to those without PAD), the adjusted hazard ratio (HR) for all-cause mortality was 1.25 (95% CI 1.15-1.37; p<0.001) and the HR for CV death, non-fatal MI, non-fatal stroke or heart failure hospitalization was 1.24 (1.16-1.33; p<0.001). CONCLUSIONS: PAD is common and is an independent predictor of worse outcomes in patients already at high risk after MI because of left ventricular systolic dysfunction, heart failure or both. These patients represent an important group for intensive application of secondary preventive therapies.

Changes in benthic nutrient sources within a wetland after hydrologic reconnection.

Removing dams and levees to restore hydrologic connectivity and enhance ecosystem services such as nutrient removal has been an increasingly common management practice. In the present study, the authors assessed geochemical and biological changes following engineered levee breaches that reconnected eutrophic Upper Klamath Lake and Agency Lake, Oregon, USA, to an adjacent, historic wetland that had been under agricultural use for the last seven decades. Over the three-year study, the reconnected wetland served as a benthic source for both macronutrients (dissolved organic carbon [DOC], soluble reactive phosphorus [SRP], and ammonia) and micronutrients (dissolved iron and manganese). The magnitude of those benthic sources was similar to or greater than that of allochthonous sources. The highest DOC benthic flux to the water column occurred immediately after rewetting occurred. It then decreased during the present study to levels more similar to the adjacent lake. Dissolved ammonia fluxes, initially negative after the levee breaches, became consistently positive through the remainder of the study. Nitrate fluxes, also initially negative, became negligible two years after the levee breaches. In contrast to previous laboratory studies, SRP fluxes remained positive, as did fluxes of dissolved iron and manganese. Our results indicate that the timescales of chemical changes following hydrologic reconnection of wetlands are solute-specific and in some cases extend for multiple years beyond the reconnection event. During the present study, colonization of the reconnected wetlands by aquatic benthic invertebrates gradually generated assemblages similar to those in a nearby wetland refuge and provided further evidence of the multiyear transition of this area to permanent aquatic habitat. Such timescales should be considered when developing water-quality management strategies to achieve wetland-restoration goals.