A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD.

BACKGROUND: Many patients with chronic obstructive pulmonary disease (COPD) still experience daily symptoms, exacerbations, and accelerated lung function decline, even when receiving maximal combined treatment with inhaled long-acting bronchodilators and corticosteroids. Novel treatment options are needed for these patients. Phosphodiesterases (PDEs) are enzymes that impact a range of cellular functions by modulating levels of cyclic nucleotides, and there is evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive (or perhaps synergistic) effects. This study investigated the efficacy and safety of ensifentrine, a first-in-class dual inhibitor of PDE 3 and 4, in patients with COPD. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 40-80% predicted and FEV1/forced vital capacity ratio ≤ 0.7. Patients were randomised equally to inhale nebulised ensifentrine 0.75, 1.5, 3 or 6 mg or placebo, all twice daily. PRIMARY OUTCOME: placebo-adjusted difference in peak FEV1 (assessed over 3 h) at Week 4. RESULTS: The study took place between July 2017 and February 2018. Of 405 patients randomly assigned to medication, 375 (92.6%) completed the study. For peak FEV1 at Week 4, all four ensifentrine doses were superior to placebo (p ≤ 0.0001) with least squares mean differences of 146 (95% CI 75-216), 153 (83-222), 200 (131-270) and 139 (69-210) mL for ensifentrine 0.75, 1.5, 3 and 6 mg, respectively. Respiratory symptoms (assessed using the Evaluating Respiratory Symptoms questionnaire) were also significantly improved with all ensifentrine doses at Week 4. Adverse events were reported by 33.3, 44.4, 35.4 and 36.3% patients with ensifentrine 0.75, 1.5, 3 and 6 mg, respectively, and 39.2% with placebo. CONCLUSIONS: In this four-week Phase IIb study, all four ensifentrine doses significantly improved bronchodilation and symptoms, with a dose-ranging effect from 0.75 to 3 mg twice daily, and all doses well tolerated. The study supports the continuing development of ensifentrine in COPD. TRIAL REGISTRATION: EudraCT 2016-005205-40, registered 30 May 2017.

The effect of digital media on children in their formative years.

Over the past 2 decades, personal digital devices have evolved to become portable, attractive, readily accessible, interactive, and ubiquitous. Although digital and social media have evidence-based benefits, including early learning, exposure to new ideas and knowledge, and increased opportunities for social contact and support, unsupervised and unchecked use of personal digital devices can have negative consequences for the physical and mental health of children in their formative years.The widespread use of portable digital devices has been accompanied by a concomitant rise in the prevalence of physical and mental health issues in children. Research suggests an association between these trends, which also may be considered from a public health perspective. Proposed interventions include the development and implementation of individual family media use plans for children of all ages.