Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

A systematic review of non-surgical treatments for pancreatic neuroendocrine tumours

AbstractIntroductionPancreatic neuroendocrine tumours (pNETs) are rare and the majority of patients present with advanced disease. Such patients have limited treatment options. We conducted a systematic review of published clinical trials of non-surgical interventions in pNET, to understand the efficacy, safety and health related quality of life (HRQoL) outcomes from the current evidence base.MethodsElectronic databases and manual bibliographic searches were conducted to identify relevant studies. Data were extracted by two independent reviewers.ResultsForty seven clinical studies met the predefined inclusion criteria. The following interventions were included: targeted therapies (two RCTs and six single-arm studies), chemotherapy (two RCTs, one prospective nonrandomised, comparative study and 14 single-arm studies);somatostatin analogues (SSA) and radiolabeled SSA therapies (nine single-arm studies), liver-directed therapies (six single-arm studies), mixed treatment regimens (one RCT, four single-arm studies) and other interventions such as interferon and recombinant human endostatin (one single-arm study for each). The paucity of RCT data and lack of consistency in reporting validated study outcomes and differing patient inclusion criteria between studies made it difficult to compare the relative efficacy of therapies.DiscussionThe majority of published studies assessing treatment regimens for the management of pNET are single arm, non-randomised studies, often enrolling a small number of patients and not reporting clinically meaningful outcomes. However data from recently conducted studies assessing targeted therapies indicate that it is possible to conduct adequately powered RCTs reporting standardised oncological endpoints in this rare cancer. Further, similarly robust studies should be conducted to define the optimal treatment algorithm

The top six of 32 multinomial log-linear models analyzed.

<p>Models were ranked via a corrected Akaike’s Information Criterion (AICc) value. The K* column indicates the number of parameters for each model.</p

Forest unit categories and descriptions used to describe individual forest units.

<p>Forest unit categories and descriptions used to describe individual forest units.</p

The predicted probabilities of no infection (1None), infection with <i>B</i>. <i>burgdorferi</i> s. s. (2Bbss), or <i>B</i>. <i>bissettiae</i> (3Bbis) by month at the HVTR.

<p>Blue bars represent probabilities associated with Allen’s chipmunks (Ns, <i>Neotamias senex</i>) and gray bars represent probabilities associated with dusky-footed woodrats (Nf, <i>Neotoma fuscipes</i>).</p

Numbers of Allen’s chipmunks (<i>N</i>. <i>senex</i>), dusky-footed woodrats (<i>N</i>. <i>fuscipes</i>), California ground squirrels (<i>O</i>. <i>beecheyi</i>), and northern flying squirrels (<i>G</i>. <i>sabrinus</i>) trapped at the HVTR from June 2004 through May 2005 and infection prevalence with Bbss (<i>B</i>. <i>burgdorferi</i> s. s.), Bbis (<i>B</i>. <i>bissettiae</i>), or unclassified Bbsl (<i>B</i>. <i>burgdorferi</i> s. l.).

<p>Numbers of Allen’s chipmunks (<i>N</i>. <i>senex</i>), dusky-footed woodrats (<i>N</i>. <i>fuscipes</i>), California ground squirrels (<i>O</i>. <i>beecheyi</i>), and northern flying squirrels (<i>G</i>. <i>sabrinus</i>) trapped at the HVTR from June 2004 through May 2005 and infection prevalence with Bbss (<i>B</i>. <i>burgdorferi</i> s. s.), Bbis (<i>B</i>. <i>bissettiae</i>), or unclassified Bbsl (<i>B</i>. <i>burgdorferi</i> s. l.).</p

Spatial clustering of <i>Borrelia burgdorferi</i> sensu lato within populations of Allen's chipmunks and dusky-footed woodrats in northwestern California

<div><p>The ecology of Lyme borreliosis is complex in northwestern California, with several potential reservoir hosts, tick vectors, and genospecies of <i>Borrelia burgdorferi</i> sensu lato. The primary objective of this study was to determine the fine-scale spatial distribution of different genospecies in four rodent species, the California ground squirrel (<i>Otospermophilus beecheyi</i>), northern flying squirrel (<i>Glaucomys sabrinus</i>), dusky-footed woodrat (<i>Neotoma fuscipes</i>), and Allen’s chipmunk (<i>Neotamias senex</i>). Rodents were live-trapped between June 2004 and May 2005 at the Hoopa Valley Tribal Reservation (HVTR) in Humboldt County, California. Ear-punch biopsies obtained from each rodent were tested by polymerase chain reaction (PCR) and sequencing analysis. The programs ArcGIS and SaTScan were used to examine the spatial distribution of genospecies. Multinomial log-linear models were used to model habitat and host-specific characteristics and their effect on the presence of each borrelial genospecies. The Akaike information criterion (AICc) was used to compare models and determine model fit. <i>Borrelia burgdorferi</i> sensu stricto was primarily associated with chipmunks and <i>B</i>. <i>bissettiae</i> largely with woodrats. The top model included the variables “host species”, “month”, and “elevation” (weight = 0.84). Spatial clustering of <i>B</i>. <i>bissettiae</i> was detected in the northwestern section of the HVTR, whereas <i>B</i>. <i>burgdorferi</i> sensu stricto was clustered in the southeastern section. We conclude that the spatial distribution of these borreliae are driven at least in part by host species, time-of-year, and elevation.</p></div

Coefficients, associated standard errors, and relative risk ratios from the top multinomial log-linear model as ranked by AICc.

<p>The abbreviations Bbss and Bbis stand for <i>Borrelia burgdorferi</i> sensu stricto and <i>Borrelia bissettiae</i>, respectively. The term “Chipmunk” refers to the Allen’s Chipmunk (<i>N</i>. <i>senex</i>).</p

Locations of California ground squirrels (<i>O</i>. <i>beecheyi</i>), northern flying squirrels (<i>G</i>. <i>sabrinus</i>), dusky-footed woodrats (<i>N</i>. <i>fuscipes</i>), and Allen’s chipmunks (<i>N</i>. <i>senex</i>) captured and tested for the presence of <i>B</i>. <i>burgdorferi</i> s. l. within the HVTR from June 2004 to May 2005.

<p>Each location represents one to many individuals because of overlapping capture locations.</p