Designing, Conducting, Monitoring, and Analyzing Data from Pragmatic Randomized Clinical Trials: Proceedings from a Multi-stakeholder Think Tank Meeting.

In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable. Yet the benefits of relying on real-world data sources must be weighed against difficulties with ensuring data integrity and completeness. Additionally, appropriately monitoring patient safety in randomized trials of new drugs using healthcare system data that might not be available in real time can be quite difficult. Recognizing that these and other concerns are critical to the development and acceptability of PCTs, a group of stakeholders from academia, industry, professional organizations, regulatory bodies, government agencies, and patient advocates discussed a path forward for PCT growth and sustainability at a think tank meeting entitled "Monitoring and Analyzing Data from Pragmatic Streamlined Randomized Clinical Trials," which took place in January 2019 (Washington, DC). The goals of this meeting were to: (1) evaluate study design and methodological options specific to PCTs that have the potential to yield high-quality evidence; (2) discuss best practices to ensure data quality in PCTs; and (3) identify appropriate methods for study monitoring. Proceedings from the think tank meeting are summarized in this manuscript.

The effect of budesonide/formoterol maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever use: an exploratory analysis of two randomised, controlled studies with comparisons to standard therapy.

BACKGROUND: Divergent strategies have emerged for the management of severe asthma. One strategy utilises high and fixed doses of maintenance treatment, usually inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA), supplemented by a short-acting ß2-agonist (SABA) as needed. Alternatively, budesonide/formoterol is used as both maintenance and reliever therapy. The latter is superior to fixed-dose treatment in reducing severe exacerbations while achieving similar or better asthma control in other regards. Exacerbations may be reduced by the use of budesonide/formoterol as reliever medication during periods of unstable asthma. We examined the risk of a severe exacerbation in the period after a single day with high reliever use. METHODS: Episodes of high reliever use were quantified and exacerbations occurring post-index day with these episodes were examined post hoc in two double-blind studies comparing the efficacy and safety of budesonide/formoterol maintenance and reliever therapy (Symbicort SMART™, Turbuhaler®) 160/4.5 µg twice daily plus as needed with similar or higher maintenance doses of ICS/LABA plus SABA or formoterol. RESULTS: Budesonide/formoterol maintenance and reliever therapy significantly reduced the risk of episodes of high reliever use (>6 inhalations/day) vs. all alternative ICS/LABA regimens. With conventional fixed-dose treatment the need for exacerbation treatment within 21 days ranged from 6.0-10.1% of days post-index for all regimens compared with 2.5-3.4% of days with budesonide/formoterol maintenance and reliever therapy. CONCLUSIONS: Budesonide/formoterol maintenance and reliever therapy reduces the incidence of high reliever episodes and the exacerbation burden immediately following these episodes vs. alternative ICS/LABA plus SABA regimens at up to double the maintenance dose of ICS. TRIAL REGISTRATION: These studies do not have registration numbers as they were conducted before clinical trial registration was required.

Safety of formoterol in patients with asthma: combined analysis of data from double-blind, randomized controlled trials.

BACKGROUND: Concerns exist that regular long-acting beta(2)-adrenergic agonist (LABA) therapy may increase the risk of serious asthma-related events. OBJECTIVE: To assess risks of formoterol-containing versus non-LABA treatment by using a large asthma database. METHODS: This analysis included all blind, parallel-arm, randomized, active-controlled and/or placebo-controlled AstraZeneca-sponsored asthma studies with formoterol-containing and non-LABA comparator arms. Serious adverse events were assessed for inclusion in all-cause death, asthma-related death, asthma-related intubation, and asthma-related hospitalization categories by using blind adjudication. Data were combined across trials; relative risk (RR) was assessed by using Mantel-Haenszel methods. RESULTS: Data were from 13,542 formoterol-randomized and 9968 non-LABA patients 4 years or older (42 trials), of whom 93% and 89%, respectively, received inhaled corticosteroid as part of randomized treatment or allowed medication. Incidence of all-cause death was low (n=3 and n=4, respectively), with numerically lower all-cause deaths/1000 patient-treatment years in the formoterol-treated group (0.53) versus the non-LABA group (0.82) (RR, 0.64; 95% confidence interval [CI], 0.14-2.92). No asthma-related deaths and 1 asthma-related intubation (formoterol-treated group) occurred. Asthma-related hospitalizations/1000 patient-treatment years were lower numerically in the formoterol-treated group (12.1) versus the non-LABA group (16.4) (RR, 0.73; 95% CI, 0.54-1.01), with fewer study discontinuations in the formoterol-treated group (12.7% vs 15.4%, respectively; RR, 0.79; 95% CI, 0.74-0.85). Relative to non-LABA, increasing daily formoterol dose (>/=4.5, 9, 18, 36 mug) did not increase the rate or incidence of asthma-related hospitalization. CONCLUSION: No evidence of increased risk of asthma-related hospitalization, no asthma-related deaths, and a low incidence of all-cause death and asthma-related intubation were seen with formoterol-containing versus non-LABA treatment.

Vascular effects of anandamide and N-acylvanillylamines in the human forearm and skin microcirculation.

The endocannabinoid anandamide is an emerging potential signalling molecule in the cardiovascular system. Anandamide causes vasodilatation, bradycardia and hypotension in animals and has been implicated in the pathophysiology of endotoxic, haemorrhagic and cardiogenic shock, but its vascular effects have not been studied in man. Human forearm blood flow and skin microcirculatory flow were recorded using venous occlusion plethysmography and laser-Doppler perfusion imaging (LDPI), respectively. Each test drug was infused into the brachial artery or applied topically on the skin followed by a standardized pin-prick to disrupt the epidermal barrier. Anandamide failed to affect forearm blood flow when administered intra-arterially at infusion rates of 0.3-300 nmol min(-1). The highest infusion rate led to an anandamide concentration of approximately 1 microM in venous blood as measured by mass spectrometry. Dermal application of anandamide significantly increased skin microcirculatory flow and coapplication of the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine inhibited this effect. The TRPV1 agonists capsaicin, olvanil and arvanil all induced concentration-dependent increases in skin blood flow and burning pain when administered dermally. Coapplication of capsazepine inhibited blood flow and pain responses to all three TRPV1 agonists. This study shows that locally applied anandamide is a vasodilator in the human skin microcirculation. The results are consistent with this lipid being an activator of TRPV1 on primary sensory nerves, but do not support a role for anandamide as a circulating vasoactive hormone in the human forearm vascular bed.