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Ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution seems to be efficacious and safe in treating acute otitis externa (AOE) compared with ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solution alone.To evaluate the superiority of ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution compared with ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solution alone in treating AOE.A phase 3 randomized, double-blind, active-controlled clinical trial was conducted between August 1, 2017, and September 14, 2018, at 36 centers in the US. The study population comprised 493 patients aged 6 months or older with AOE of less than 21 days' duration with otorrhea, moderate or severe otalgia, and edema, as well as a Brighton grading of II or III (tympanic membrane obscure but without systemic illness). Statistical analysis was performed from November 14, 2018, to February 14, 2019.Participants were randomly assigned to receive ciprofloxacin plus fluocinolone, ciprofloxacin, or fluocinolone twice daily for 7 days and were evaluated on day 1 (visit 1; baseline), days 3 to 4 (visit 2; conducted via telephone), days 8 to 10 (visit 3; end of treatment), and days 15 to 17 (visit 4; test of cure).The primary outcome was therapeutic cure (clinical and microbiological) at the end of the treatment period. The principal secondary end point was the time to end of ear pain. Efficacy analyses were conducted in the microbiological intent-to-treat population, clinical intent-to-treat population, and microbiological intent-to-treat population with Pseudomonas aeruginosa and Staphylococcus aureus.A total of 493 patients (254 female patients [51.5%]; mean [SD] age, 38.2 [23.1] years) were randomized (197 to receive ciprofloxacin plus fluocinolone, 196 to receive ciprofloxacin, and 100 to receive fluocinolone). Therapeutic cure in the modified intent-to-treat population with ciprofloxacin plus fluocinolone (63 of 103 [61.2%]) was statistically comparable to that of ciprofloxacin (49 of 91 [53.8%]; difference in response rate, 7.3%; 95% CI, -6.6% to 21.2%; P = .30) and fluocinolone (20 of 45 [44.4%]; difference in response rate, 16.7%; 95% CI, -0.6% to 34.0%; P = .06) at visit 3 and significantly superior to ciprofloxacin at visit 4 (90 of 103 [87.4%] vs 69 of 91 [75.8%]; difference in response rate, 11.6%; 95% CI, 0.7%-22.4%; P = .04). A statistically faster resolution of otalgia was achieved among patients treated with ciprofloxacin plus fluocinolone (median, 5.0 days [range, 4.2-6.3 days]) vs ciprofloxacin (median, 5.9 days [range, 4.3-7.3 days]; 95% CI, 4.3-7.3 days; P = .002) or fluocinolone (median, 7.7 days [range, 6.7-9.0 days]; 95% CI, 6.7-9.0 days; P .001). Ciprofloxacin plus fluocinolone demonstrated statistical superiority in sustained microbiological response vs ciprofloxacin (94 of 103 [91.3%] vs 74 of 91 [81.3%]; difference in response rate, 9.9%; 95% CI, 0.3%-19.6%; P = .04) and fluocinolone (34 of 45 [75.6%]; difference in response rate, 15.7%; 95% CI, 2.0%-29.4%; P = .01) and in the microbiological outcome vs fluocinolone by visit 3 (99 of 103 [96.1%] vs 37 of 45 [82.2%]; difference in response rate, 13.9%; 95% CI, 2.1%-25.7%; P = .01) and ciprofloxacin by visit 4 (97 of 103 [94.2%] vs 77 of 91 [84.6%]; difference in response rate, 9.6%; 95% CI, 0.9%-18.2%; P = .02). Fifteen adverse events related to study medications were registered, all of which were mild or moderate.Ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution was efficacious and safe in treating AOE but did not demonstrate superiority vs ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solutions alone in the main study end point of therapeutic cure.ClinicalTrials.gov Identifier: NCT03196973.

Backgroud: coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine.Methods: in this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases.Results: a total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%).Conclusions: the CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.).

BackgroundREGEN-COV antibody cocktail (casirivimab with imdevimab) rapidly reduced viral load and decreased medically-attended visits in the phase 1/2 portion of this trial; REGEN-COV, retains activity in vitro against emerging SARS-CoV-2 variants of concern.MethodsThe phase 3 portion of this adaptive, randomized, master protocol, included 4,057 Covid-19 outpatients with one or more risk factors for severe disease. Patients were randomized to a single treatment of intravenous placebo, or various doses of REGEN-COV, and followed for 28 days. The prespecified hierarchical analysis first compared REGEN-COV 2400mg dose vs concurrent placebo, then compared the 1200mg dose vs concurrent placebo, for endpoints assessing risk of hospitalization or death, and time to symptom resolution. Safety was evaluated in all treated patients.ResultsBoth REGEN-COV 2400mg and 1200mg significantly reduced Covid-19-related hospitalization or all-cause death compared to placebo (71.3% reduction [1.3% vs 4.6%; pConclusionsTreatment with REGEN-COV was well-tolerated and significantly reduced Covid-19-related hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load.(Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)

Background In the phase 1–2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. Methods In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. Results Covid-19–related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P