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Summary Background Airway neutrophilic inflammation is a pathological feature in some patients with severe asthma. Stimulation of the chemokine receptor CXCR2 mediates neutrophil migration into the airways. We investigated the safety and efficacy of AZD5069, a CXCR2 antagonist, as an add-on therapy in patients with uncontrolled severe asthma. Methods In this multicentre, randomised, double-blind, placebo-controlled, dose-finding trial, we enrolled patients aged 18 years or older with uncontrolled asthma despite combination therapy with long-acting β 2 agonists and medium-dose or high-dose inhaled corticosteroids. Patients were randomised in a 1:1:1:1 ratio via an interactive voice-response or web-response system to receive 5, 15, or 45 mg oral AZD5069 twice daily or matched placebo. The primary endpoint was the number of severe asthma exacerbations in 6 months. Safety was assessed in the 6-month treatment period and an optional 6-month safety extension. This trial is registered with ClinicalTrials.gov , number NCT01704495 . Findings 640 patients with a mean age of 52 (SD 11·8) years were randomised, 478 to receive AZD5069 (5 mg n=160, 15 mg n=156, and 45 mg n=162) and 162 placebo. No dose of AZD5069 reduced the rate of severe exacerbations compared with placebo (rate ratio for 5 mg 1·29, 90% CI 0·79–2·11; for 15 mg 1·53, 0·95–2·46; and for 45 mg 1·56, 0·98–2·49). Treatment with AZD5069 was generally well tolerated. The most commonly reported adverse event overall was nasopharyngitis, seen in 18 (11·5%) receiving 5 mg, 13 (8·5%) receiving 15 mg, and 18 (11·2%) receiving 45 mg AZD5069, and 31 (19·5%) of those receiving placebo. Interpretation Treatment with this selective CXCR2 antagonist did not reduce the frequency of severe exacerbations in patients with uncontrolled severe asthma. These findings bring into question the role of CXCR2-mediated neutrophil recruitment in the pathobiology of exacerbations in severe refractory asthma. Funding AstraZeneca. [ABSTRACT FROM AUTHOR]

Background: Community-acquired bacterial pneumonia (CABP) is a leading cause of morbidity and mortality, and treatment recommendations, each with specific limitations, vary globally. We aimed to compare the efficacy and safety of solithromycin, a novel macrolide, with moxifloxacin for treatment of CABP.Methods: We did this global, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial at 114 centres in North America, Latin America, Europe, and South Africa. Patients (aged ≥18 years) with clinically and radiographically confirmed pneumonia of Pneumonia Outcomes Research Team (PORT) risk class II, III, or IV were randomly assigned (1:1), via an internet-based central block randomisation procedure (block size of four), to receive either oral solithromycin (800 mg on day 1, 400 mg on days 2-5, placebo on days 6-7) or oral moxifloxacin (400 mg on days 1-7). Randomisation was stratified by geographical region, PORT risk class (II vs III or IV), and medical history of asthma or chronic obstructive pulmonary disease. The study sponsor, investigators, staff, and patients were masked to group allocation. The primary outcome was early clinical response, defined as an improvement in at least two of four symptoms (cough, chest pain, sputum production, dyspnoea) with no worsening in any symptom at 72 h after the first dose of study drug, with a 10% non-inferiority margin. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT-01756339.Findings: Between Jan 3, 2013, and Sept 24, 2014, we randomly assigned 860 patients to receive solithromycin (n=426) or moxifloxacin (n=434). Patients were followed up to days 28-35 after first dose. Solithromycin was non-inferior to moxifloxacin in achievement of early clinical response: 333 (78·2%) patients had an early clinical response in the solithromycin group versus 338 (77·9%) patients in the moxifloxacin group (difference 0·29, 95% CI -5·5 to 6·1). Both drugs had a similar safety profile. 43 (10%) of 155 treatment-emergent adverse events in the solithromycin group and 54 (13%) of 154 such events in the moxifloxacin group were deemed to be related to study drug. The most common adverse events, mostly of mild severity, were gastrointestinal disorders, including diarrhoea (18 [4%] patients in the solithromycin group vs 28 [6%] patients in the moxifloxacin group), nausea (15 [4%] vs 17 [4%] patients) and vomiting (ten [2%] patients in each group); and nervous system disorders, including headache (19 [4%] vs 11 [3%] patients) and dizziness (nine [2%] vs seven [2%] patients).Interpretation: Oral solithromycin was non-inferior to oral moxifloxacin for treatment of patients with CABP, showing the potential to restore macrolide monotherapy for this indication.Funding: Cempra. [ABSTRACT FROM AUTHOR]