Background At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. Methods We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. Results The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. Conclusions The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427 .)

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ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

IntroductionWe report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.MethodsThis was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.ResultsIn total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34–3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.ConclusionIn this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.Trial RegistrationClinicalTrials.gov identifier NCT02799784.FundingGlaxoSmithKline.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-017-0626-4) contains supplementary material, which is available to authorized users.

BackgroundIndacaterol is a novel, once-daily (o.d.) inhaled, long-acting β2-agonist in development for chronic obstructive pulmonary disease (COPD). This 12-week, double-blind study compared the efficacy, safety, and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD.MethodsEfficacy variables included 24-h trough FEV1 (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (primary endpoint) and after Day 1, and the percentage of COPD days with poor control (i.e., worsening symptoms). Safety was assessed by adverse events (AEs), mean serum potassium and blood glucose, QTc (Fridericia), and vital signs.ResultsPatients were randomised (n = 416, mean age 63 years) to receive either indacaterol 150 μg o.d. (n = 211) or placebo (n = 205) via a single-dose dry-powder inhaler; 87.5% completed the study. Trough FEV1 (LSM ± SEM) at Week 12 was 1.48 ± 0.018 L for indacaterol and 1.35 ± 0.019 L for placebo, a clinically relevant difference of 130 ± 24 mL (p < 0.001). Trough FEV1 after one dose was significantly higher with indacaterol than placebo (p < 0.001). Indacaterol demonstrated significantly higher peak FEV1 than placebo, both on Day 1 and at Week 12, with indacaterol-placebo differences (LSM ± SEM) of 190 ± 28 (p < 0.001) and 160 ± 28 mL (p < 0.001), respectively. Standardised AUC measurements for FEV1 (between 5 min and 4 h, 5 min and 1 h, and 1 and 4 h post-dose) at Week 12 were all significantly greater with indacaterol than placebo (p < 0.001), with LSM (± SEM) differences of 170 ± 24, 180 ± 24, and 170 ± 24 mL, respectively. Indacaterol significantly reduced the percentage of days of poor control versus placebo by 22.5% (p < 0.001) and was also associated with significantly reduced use of rescue medication (p < 0.001). The overall rates of AEs were comparable between the groups (indacaterol 49.3%, placebo 46.8%), with the most common AEs being COPD worsening (indacaterol 8.5%, placebo 12.2%) and cough (indacaterol 6.2%, placebo 7.3%). One patient died in the placebo group. Serum potassium and blood glucose levels did not differ significantly between the two groups, and no patient had QTc >500 ms.ConclusionsIndacaterol 150 μg o.d. provided clinically significant and sustained bronchodilation, reduced rescue medication use, and had a safety and tolerability profile similar to placebo.Trial registrationNCT00624286