Use of oral live-attenuated polio vaccines (OPV), and injected inactivated polio vaccines (IPV) has almost achieved global eradication of wild polio viruses. To address the goals of achieving and ...maintaining global eradication and minimising the risk of outbreaks of vaccine-derived polioviruses, we tested novel monovalent oral type-2 poliovirus (OPV2) vaccine candidates that are genetically more stable than existing OPVs, with a lower risk of reversion to neurovirulence. Our study represents the first in-human testing of these two novel OPV2 candidates. We aimed to evaluate the safety and immunogenicity of these vaccines, the presence and extent of faecal shedding, and the neurovirulence of shed virus.
In this double-blind, single-centre phase 1 trial, we isolated participants in a purpose-built containment facility at the University of Antwerp Hospital (Antwerp, Belgium), to minimise the risk of environmental release of the novel OPV2 candidates. Participants, who were recruited by local advertising, were adults (aged 18–50 years) in good health who had previously been vaccinated with IPV, and who would not have any contact with immunosuppressed or unvaccinated people for the duration of faecal shedding at the end of the study. The first participant randomly chose an envelope containing the name of a vaccine candidate, and this determined their allocation; the next 14 participants to be enrolled in the study were sequentially allocated to this group and received the same vaccine. The subsequent 15 participants enrolled after this group were allocated to receive the other vaccine. Participants and the study staff were masked to vaccine groups until the end of the study period. Participants each received a single dose of one vaccine candidate (candidate 1, S2/cre5/S15domV/rec1/hifi3; or candidate 2, S2/S15domV/CpG40), and they were monitored for adverse events, immune responses, and faecal shedding of the vaccine virus for 28 days. Shed virus isolates were tested for the genetic stability of attenuation. The primary outcomes were the incidence and type of serious and severe adverse events, the proportion of participants showing viral shedding in their stools, the time to cessation of viral shedding, the cell culture infective dose of shed virus in virus-positive stools, and a combined index of the prevalence, duration, and quantity of viral shedding in all participants. This study is registered with EudraCT, number 2017-000908-21 and ClinicalTrials.gov, number NCT03430349.
Between May 22 and Aug 22, 2017, 48 volunteers were screened, of whom 15 (31%) volunteers were excluded for reasons relating to the inclusion or exclusion criteria, three (6%) volunteers were not treated because of restrictions to the number of participants in each group, and 30 (63%) volunteers were sequentially allocated to groups (15 participants per group). Both novel OPV2 candidates were immunogenic and increased the median blood titre of serum neutralising antibodies; all participants were seroprotected after vaccination. Both candidates had acceptable tolerability, and no serious adverse events occurred during the study. However, severe events were reported in six (40%) participants receiving candidate 1 (eight events) and nine (60%) participants receiving candidate 2 (12 events); most of these events were increased blood creatinine phosphokinase but were not accompanied by clinical signs or symptoms. Vaccine virus was detected in the stools of 15 (100%) participants receiving vaccine candidate 1 and 13 (87%) participants receiving vaccine candidate 2. Vaccine poliovirus shedding stopped at a median of 23 days (IQR 15–36) after candidate 1 administration and 12 days (1–23) after candidate 2 administration. Total shedding, described by the estimated median shedding index (50% cell culture infective dose/g), was observed to be greater with candidate 1 than candidate 2 across all participants (2·8 95% CI 1·8–3·5 vs 1·0 0·7–1·6). Reversion to neurovirulence, assessed as paralysis of transgenic mice, was low in isolates from those vaccinated with both candidates, and sequencing of shed virus indicated that there was no loss of attenuation in domain V of the 5ʹ-untranslated region, the primary site of reversion in Sabin OPV.
We found that the novel OPV2 candidates were safe and immunogenic in IPV-immunised adults, and our data support the further development of these vaccines to potentially be used for maintaining global eradication of neurovirulent type-2 polioviruses.
Bill & Melinda Gates Foundation.
Abstract
Introduction
Effects of the dual orexin receptor antagonist lemborexant (LEM) on sleep architecture in adults ≥55y with insomnia disorder were assessed in Study E2006-G000-304 (Study 304; ...SUNRISE-1; NCT02783729). These post hoc analyses of Study 304 examined the acute effect of LEM on REM pressure (REM latency REM-L and REM by quarter of the night QoN).
Methods
This study was a 1mo, randomized, double-blind, placebo- and active-controlled (zolpidem tartrate extended-release 6.25mg ZOL) study of LEM (5mg, LEM5; 10mg, LEM10). Subjects received placebo (n=208), ZOL (n=263), LEM5 (n=266), or LEM10 (n=269). Two nights of PSGs were recorded at baseline, first 2 (N1/2), and last 2 (N29/30) treatment nights.
Results
Baseline REM-L (minutes) was similar across treatments (98.4–101.4). Significant decreases from baseline in REM-L were observed for LEM5 (−42.6 53.9) and LEM10 (−49.652.9) vs placebo (−6.954.5) and ZOL (0.254.2) on N1/2 (all P<0.0001). No difference was observed for ZOL vs placebo. Baseline REM (minutes) for each QoN was similar across treatments. In Q1, mean(SD) REM (minutes) on N1/2 was 16.5(9.7), 19.7(10.5), 10.3(8.2), and 8.5(7.6) for LEM5, LEM10, placebo, and ZOL, respectively. The difference was significant for LEM5 and LEM10 vs placebo and ZOL (all P<0.0001), and ZOL vs placebo (P<0.05). In Q2, mean(SD) REM on N1/2 was 19.2(9.4), 21.6(10.0), 17.9(8.9), and 17.2(9.3) for LEM5, LEM10, placebo, and ZOL, respectively. The difference was significant for LEM10 vs placebo (P<0.0001) and for LEM5 and LEM10 vs ZOL (P<0.01, P<0.0001, respectively). No difference was observed for ZOL vs placebo. In Q3, mean(SD) REM on N1/2 was 23.3(10.3), 25.9(9.7), 20.8(9.4), and 22.8(9.9) for LEM5, LEM10, placebo, and ZOL, respectively. The difference was significant for LEM5, LEM10, and ZOL vs placebo (P<0.01, P<0.0001, P<0.05, respectively) and LEM10 vs ZOL (P<0.001). In Q4, mean (SD) REM on N1/2 was 23.8(9.4), 26.1(11.0), 21.6(10.9), and 22.5(10.1) for LEM5, LEM10, placebo, and ZOL, respectively. The differences were significant for LEM5 and LEM10 vs placebo (P<0.05, P<0.0001, respectively), and for LEM10 vs ZOL (P<0.0001). Generally, similar findings were noted at N29/30; these data will be reported.
Conclusion
LEM, but not ZOL, acutely increases REM pressure as evidenced by REM latency and REM duration per quarter.
Support (if any)
Eisai Inc.
Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown.
To investigate the efficacy and safety ...of rituximab compared with placebo as an add-on to standard of care for MG.
This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids.
Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo.
Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment.
Of 87 potentially eligible patients, 25 were randomized to rituximab (mean SD age, 67.4 13.4 years; 7 28% female) and 22 to placebo (mean SD age, 58 18.6 years; 7 32% female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 95% CI, 1.20-5.11). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 4%; placebo, 8 36%). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event.
A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment.
ClinicalTrials.gov Identifier: NCT02950155.
A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We ...evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.
This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674.
Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 0·6% of 4440 in the ChAdOx1 nCoV-19 group vs71 1·6% of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three 0·2% of 1367 vs 30 2·2% of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 0·5% of 5807 vs 101 1·7% of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.
ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.
UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
There is substantial evidence that systemic biases influence the scholarly peer review process. Many scholars have advocated for double‐blind peer review (also known as double‐anonymous review) to ...reduce these biases. However, the effectiveness of double‐blind peer review in eliminating biases is uncertain because few randomized trials have manipulated blinding of author identities for journal submissions and those that have are generally small or provide few insights on how it influences reviewer biases.
In 2019, Functional Ecology began a large, randomized trial, using real manuscript submissions, to evaluate the various consequences of shifting to double‐blind peer review. Research papers submitted to the journal were randomly assigned to be reviewed with author identities blinded to reviewers (double‐blind review) or with authors identified to reviewers (single‐blind review). In this paper, we explore the effect of blinding on the outcomes of peer review, examining reviewer ratings and editorial decisions, and ask whether author gender and/or location mediate the effects of review type.
Double‐blind review reduced the average success of manuscripts in peer review; papers reviewed with author identities blinded received on average lower ratings from reviewers and were less likely to be invited for revision or resubmission. However, the effect of review treatment varied with the author's location.
Papers with first authors residing in countries with a higher human development index (HDI) and/or higher average English proficiency fared much better than those from countries with a lower HDI and lower English proficiency, but only when author identities were known to reviewers; outcomes were similar between demographic groups when author identities were not known to reviewers.
Blinding author identities had no effect on gender differences in reviewer ratings or editor decisions.
Our data provide strong evidence that authors from higher income and/or English‐speaking countries receive significant benefits (a large positive bias) to being identified to reviewers during the peer review process and that anonymizing author‐identities (e.g. double‐blind review) reduces this bias, making the peer review process more equitable. We suggest that offering optional blinding of author identities, as some journals allow, is unlikely to substantially reduce the biases that exist because authors from higher‐income and English‐speaking countries are the least likely to choose to be reviewed with their identity anonymized.
Read the free Plain Language Summary for this article on the Journal blog.
摘要
大量证据表明系统性偏见会影响学术同行评议过程。许多学者提倡双盲同行评议(或称双重匿名评议)以减少这些偏见。 然而，双盲同行评议在消除偏见方面的有效性尚不清楚，因为极少有随机试验在期刊投稿过程中隐藏作者身份，且隐去身份的试验通常规模较小或很少提出双盲如何影响审稿偏见作用的见解。
2019 年，《Functional Ecology》杂志启动了一项大型随机试验，使用真实提交的稿件来评估双盲同行评议的各种影响。 在这个实验中，提交给期刊的研究论文被随机分配成双盲审稿(对审稿人不公开作者身份)或单盲审稿(对审稿人公开作者身份)。在本文中，我们探讨了上述处理对同行评议结果的影响，考察了审稿人评分和编辑决策，并询问了作者性别和/或背景(国别、工作单位等)是否会影响评议结果。
双盲评议降低了稿件在同行评议中的平均成功率；隐藏作者身份的论文审稿得到的评分较低，且不太可能被邀请进行修改或重新提交。然而，双盲评议的效果因作者背景而异。
如果第一作者居住在人类发展指数 (Human Development Index, HDI) 较高和/或平均英语水平较高的国家，其论文的表现比来自HDI较低和英语水平较低的国家的论文要好得多，但前提是审稿人知道作者的身份 ; 当审稿人不知道作者身份时，上述分组之间的结果相似。
在性别差异上，隐藏作者身份对审稿人评分或编辑决定没有影响。
我们的数据提供了强有力的证据，表明来自高收入和/或英语国家的作者，如果公开身份，在同行评议过程中表现出显著的益处(很大的正偏差)，隐匿作者身份(如双盲审)则减少了这种偏见，使同行评议过程更加公平。我们认为杂志提供隐藏作者身份的选项(正如一些杂志所作的那样)，不太可能显著减少已有的偏见，因为来自高收入和英语国家的作者最不可能选择匿名审阅。
Existe mucha evidencia de que sesgos sistémicos influyen en el proceso de revisión por pares académicos. Muchos académicos han apoyado la revisión por pares ‘doble ciego’ (también conocida como revisión doblemente anónima) para reducir estos sesgos. Sin embargo, la efectividad de la revisión por pares doble ciego en eliminar los sesgos es incierta porque pocos estudios han puesto a prueba sus efectos de forma sistematizada, y los que lo han hecho son generalmente pequeños o brindan poco conocimiento sobre cómo influye los sesgos de los revisores.
En 2019, Functional Ecology comenzó un gran ensayo aleatorio, utilizando envíos de manuscritos reales, para evaluar las diversas consecuencias del sistema doble ciego de revisión por pares. Los trabajos de investigación enviados a la revista se asignaron aleatoriamente para ser revisados con las identidades de los autores no disponibles para los revisores (revisión doble ciego) o con los autores identificados para los revisores (revisión simple ciego). En este artículo, exploramos el efecto del sistema de revisión por pares, examinando las calificaciones de los revisores y las decisiones editoriales, y preguntamos si el género y/o la ubicación del autor impactan la revisión.
La revisión doble ciego redujo el éxito promedio de los manuscritos en la revisión por pares; los artículos revisados con las identidades de los autores ocultadas recibieron en promedio calificaciones más bajas de los revisores y tuvieron menos probabilidades de ser invitados para revisión o reenvío. Sin embargo, el efecto del tratamiento de la revisión varió según la ubicación del autor.
Los artículos cuyos primeros autores residían en países con un índice de desarrollo humano (IDH) más alto y/o un dominio promedio del inglés más alto obtuvieron mejores resultados que los de países con un IDH más bajo y un dominio del inglés más bajo, pero solo cuando los revisores conocían las identidades de los autores. Los resultados fueron similares entre los grupos demográficos cuando los revisores no conocían las identidades de los autores.
El ocultamiento de las identidades de los autores no tuvo efecto sobre diferencias de género en las calificaciones de los revisores ni en decisiones de los editores.
Nuestros datos proporcionan pruebas sólidas de que los autores de países de mayores ingresos y/o de habla inglesa reciben beneficios significativos (un fuerte sesgo positivo) al ser identificados ante los revisores durante el proceso de revisión por pares, y que ocultar las identidades de los autores (p. ej. revisión ciega) reduce este sesgo, haciendo que el proceso de revisión por pares sea más equitativo. Sugerimos que es muy poco probable que ofrecer el sistema doble ciego de revisión de forma opcional, como lo permiten algunas revistas, reduzca sustancialmente los sesgos que existen porque los autores de países de habla inglesa y de ingresos más altos son los que tienen menos probabilidades de optar por esta alternativa.
Read the free Plain Language Summary for this article on the Journal blog.
Storm phobia in companion dogs is a common disorder that significantly impacts dogs' welfare. Gabapentin, the action of which is only partially understood, is widely used for its antiepileptic and ...analgesic properties. Only recently, the veterinary community began to use gabapentin to address phobia and anxiety in dogs. This study tested gabapentin to lower fear responses of dogs during a thunderstorm event.
Eighteen dogs suffering from storm phobia completed our double-blind, placebo-controlled crossover trial. Each dog's behaviour was evaluated twice by his owner: once under placebo, once under gabapentin. The treatment was orally administered at least 90 min before the exposure. Gabapentin was given at a dose ranging from 25 to 30 mg/kg.
Our results indicate a significant reduction of the fear responses of dogs under gabapentin. The adverse effects were rare, and the most frequent amongst them was ataxia.
In this trial, gabapentin appears to be an efficient and safe molecule that should be considered as part of the treatment plan of storm phobia in dogs.
There are limited efficacious treatments for Alzheimer disease.
To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.
Multicenter (277 medical ...research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).
Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.
The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.
Among 1736 randomized participants (mean age, 73.0 years; 996 57.4% women; 1182 68.1% with low/medium tau pathology and 552 31.8% with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 95% CI, 1.88-4.62; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 95% CI, 1.51-4.33; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 95% CI, -0.95 to -0.40; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 95% CI, -0.95 to -0.45; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.
Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.
ClinicalTrials.gov Identifier: NCT04437511.
Due to its significant applications in many relevant fields, light detection in the solar‐blind deep‐ultraviolet (DUV) wavelength region is a subject of great interest for both scientific and ...industrial communities. The rapid advances in preparing high‐quality ultrawide‐bandgap (UWBG) semiconductors have enabled the realization of various high‐performance DUV photodetectors (DUVPDs) with different geometries, which provide an avenue for circumventing numerous disadvantages in traditional DUV detectors. This article presents a comprehensive review of the applications of inorganic UWBG semiconductors for solar‐blind DUV light detection in the past several decades. Different kinds of DUVPDs, which are based on varied UWBG semiconductors including Ga2O3, MgxZn1−xO, III‐nitride compounds (AlxGa1−xN/AlN and BN), diamond, etc., and operate on different working principles, are introduced and discussed systematically. Some emerging techniques to optimize device performance are addressed as well. Finally, the existing techniques are summarized and future challenges are proposed in order to shed light on development in this critical research field.
Recent advances in developing solar‐blind deep ultraviolet light (DUV) photodetectors based on various inorganic ultrawide‐bandgap semiconductors are reviewed, such as Ga2O3, MgxZn1−xO, III‐nitride compounds (AlxGa1−xN/AlN and BN), and diamonds.
The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear.
We performed a randomized, ...double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses.
We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval CI, 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo.
Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).
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