Although convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited.
We conducted a ...randomized, double-blind, placebo-controlled trial among adults hospitalized with severe and critical COVID-19 at five sites in New York City (USA) and Rio de Janeiro (Brazil). Patients were randomized in a 2:1 ratio to receive a single transfusion of either convalescent plasma or placebo (normal control plasma). The primary outcome was clinical status at 28 days following randomization, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population.
Of 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to normal control plasma. At 28 days, no significant improvement in clinical status was observed in participants randomized to convalescent plasma (OR 1.50, 95% confidence interval (CI) 0.83-2.68, p=0.180). However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 12.6% versus 18/73 24.6%, OR 0.44, 95% CI 0.22-0.91, p=0.034). The median titer of anti-SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80-1:320). In a subset of nasopharyngeal swab samples from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected.
In adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in clinical status at day 28. However, a significant improvement in mortality was observed, which warrants further evaluation.
ClinicalTrials.gov, NCT04359810FUNDING. Amazon Foundation. Skoll Foundation.
Abstract
Objectives
The aim of this study is to evaluate the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in hospitalized adults with severe SARS-CoV-2 infection.
Trial Design
...This is a prospective, single-center, phase 2, randomized, controlled trial that is blinded to participants and clinical outcome assessor.
Participants
Eligible participants include adults (≥ 18 years) with evidence of SARS-CoV-2 infection by PCR test of nasopharyngeal or oropharyngeal swab within 14 days of randomization, evidence of infiltrates on chest radiography, peripheral capillary oxygen saturation (SpO2) ≤ 94% on room air, and/or need for supplemental oxygen, non-invasive mechanical ventilation, or invasive mechanical ventilation, who are willing and able to provide written informed consent prior to performing study procedures or who have a legally authorized representative available to do so. Exclusion criteria include participation in another clinical trial of anti-viral agent(s)* for coronavirus disease-2019 (COVID-19), receipt of any anti-viral agent(s)* with possible activity against SARS-CoV-2 <24 hours prior to plasma infusion, mechanical ventilation (including extracorporeal membrane oxygenation ECMO) for ≥ 5 days, severe multi-organ failure, history of allergic reactions to transfused blood products per NHSN/CDC criteria, known IgA deficiency, and pregnancy. Included participants will be hospitalized at the time of randomization and plasma infusion.
*Use of remdesivir as treatment for COVID-19 is permitted.
The study will be undertaken at Columbia University Irving Medical Center in New York, USA.
Intervention and comparator
The investigational treatment is anti-SARS-CoV-2 human convalescent plasma. To procure the investigational treatment, volunteers who recovered from COVID-19 will undergo testing to confirm the presence of anti-SARS-CoV-2 antibody to the spike trimer at a 1:400 dilution. Donors will also be screened for transfusion-transmitted infections (e.g. HIV, HBV, HCV, WNV, HTLV-I/II, T.
cruzi,
ZIKV). If donors have experienced COVID-19 symptoms within 28 days, they will be screened with a nasopharyngeal swab to confirm they are SARS-CoV-2 PCR-negative. Plasma will be collected using standard apheresis technology by the New York Blood Center. Study participants will be randomized in a 2:1 ratio to receive one unit (200 – 250 mL) of anti-SARS-CoV-2 plasma versus one unit (200 – 250 mL) of the earliest available control plasma. The control plasma cannot be tested for presence of anti-SARS-CoV-2 antibody prior to the transfusion, but will be tested for anti- SARS-CoV-2 antibody after the transfusion to allow for a retrospective per-protocol analysis.
Main outcomes
The primary endpoint is time to clinical improvement. This is defined as time from randomization to either discharge from the hospital or improvement by one point on the following seven-point ordinal scale, whichever occurs first.
1. Not hospitalized with resumption of normal activities
2. Not hospitalized, but unable to resume normal activities
3. Hospitalized, not requiring supplemental oxygen
4. Hospitalized, requiring supplemental oxygen
5. Hospitalized, requiring high-flow oxygen therapy or non-invasive mechanical ventilation
6. Hospitalized, requiring ECMO, invasive mechanical ventilation, or both
7. Death
This scale, designed to assess clinical status over time, was based on that recommended by the World Health Organization for use in determining efficacy end-points in clinical trials in hospitalized patients with COVID-19. A recent clinical trial evaluating the efficacy and safety of lopinavir- ritonavir for patients hospitalized with severe COVID-19 used a similar ordinal scale, as have recent clinical trials of novel therapeutics for severe influenza, including a post-hoc analysis of a trial evaluating immune plasma.
The primary safety endpoints are cumulative incidence of grade 3 and 4 adverse events and cumulative incidence of serious adverse events during the study period.
Randomization
Study participants will be randomized in a 2:1 ratio to receive anti-SARS-CoV-2 plasma versus control plasma using a web-based randomization platform. Treatment assignments will be generated using randomly permuted blocks of different sizes to minimize imbalance while also minimizing predictability.
Blinding (masking)
The study participants and the clinicians who will evaluate post-treatment outcomes will be blinded to group assignment. The blood bank and the clinical research team will not be blinded to group assignment.
Numbers to be randomized (sample size)
We plan to enroll 129 participants, with 86 in the anti-SARS-CoV-2 arm, and 43 in the control arm. Among the participants, we expect ~70% or n = 72 will achieve clinical improvement. This will yield an 80% power for a one-sided Wald test at 0.15 level of significance under the proportional hazards model with a hazard ratio of 1.5.
Trial Status
Protocol AAAS9924, Version 17APR2020, 4/17/2020
Start of recruitment: April 20, 2020
Recruitment is ongoing.
Trial registration
ClinicalTrials.gov: NCT04359810
Date of trial registration: April 24, 2020
Retrospectively registered
Full protocol
The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
South Africa has the highest national burden of HIV globally. Understanding drivers of HIV acquisition in recently completed, prospective studies in which HIV was an endpoint may help inform the ...strategy and investments in national HIV prevention efforts and guide the design of future HIV prevention trials. We assessed HIV incidence and correlates of incidence among women enrolled in ECHO (Evidence for Contraceptive Options and HIV Outcomes), a large, open-label randomized clinical trial that compared three highly effective. reversible methods of contraception and rates of HIV acquisition.
During December 2015 to October 2018, ECHO followed sexually active, HIV-seronegative women, aged 16-35 years, seeking contraceptive services and willing to be randomized to one of three contraceptive methods (intramuscular depot medroxyprogesterone acetate, copper intrauterine device, or levonorgestrel implant) for 12-18 months at nine sites in South Africa. HIV incidence based on prospectively observed HIV seroconversion events. Cox proportional hazards regression models were used to define baseline cofactors related to incident HIV infection.
5768 women were enrolled and contributed 7647 woman-years of follow-up. The median age was 23 years and 62.5% were ≤24 years. A total of 345 incident HIV infections occurred, an incidence of 4.51 per 100 woman-years (95%CI 4.05-5.01). Incidence was >3 per 100 woman-years at all sites. Age ≤24 years, baseline infection with sexually transmitted infections, BMI≤30, and having new or multiple partners in the three months prior to enrollment were associated with incident HIV.
HIV incidence was high among South African women seeking contraceptive services. Integration of diagnostic management of sexually transmitted infections alongside delivery of HIV prevention options in health facilities providing contraception services are needed to mitigate ongoing risks of HIV acquisition for this vulnerable population.
ClinicalTrials.gov, number NCT02550067 was the main Clinical Trial from which this secondary, non-randomized / observational analysis was derived with data limited to just South African sites.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Globally, women have higher herpes simplex virus type 2 (HSV-2) prevalence than men; data from observational studies suggest a possible association of HSV-2 acquisition with use of intramuscular ...depot medroxyprogesterone acetate (DMPA-IM).
Within a randomized trial of the effect of 3 contraceptive methods-DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant-on human immunodeficiency virus (HIV) acquisition, we assessed HSV-2 acquisition. HSV-2 and HIV seronegative women, aged 16-35 years, and seeking effective contraception were followed for 12-18 months at 12 sites in Eswatini, Kenya, South Africa, and Zambia from 2015 to 2018. HSV-2 serologic testing was done at enrollment and final study visits. Intention-to-treat analysis using Poisson regression with robust standard errors compared HSV-2 incidence by contraceptive method.
At baseline, 4062 randomized women were HSV-2 seronegative, of whom 3898 (96.0%) had a conclusive HSV-2 result at their final study visit. Of these, 614 (15.8%) acquired HSV-2, at an incidence of 12.4/100 person-years (p-y): 10.9/100 p-y among women assigned DMPA-IM, 13.7/100 p-y the copper IUD, and 12.7/100 p-y the LNG implant. Incidence rate ratios (IRR) for HSV-2 acquisition were 0.80 (95% confidence interval CI, .65-.97) for DMPA-IM compared with copper IUD, 0.86 (95% CI, .71-1.05) for DMPA-IM compared with LNG implant, and 1.08 (95% CI, .89-1.30) for copper IUD compared with LNG implant. HSV-2 acquisition risk was significantly increased among women who also acquired HIV during follow-up (IRR 3.55; 95% CI, 2.78-4.48).
In a randomized trial, we found no association between HSV-2 acquisition and use of 3 contraceptive methods.
ClinicalTrials.gov number NCT02550067.
The effects of prenatal stress on cognition and behavioral fearfulness in infants are studied. The findings suggest that mechanisms by which mental development and fearfulness are affected by ...prenatal stress are different and do not present a consistent relation.
Wheat coleoptile tips generate superoxide radical as a part of the phototropic response to blue light, but the source of this free radical generation is not known. We evaluated the presence and ...involvement of homologs of neutrophil NADPH oxidase (NOX), including gp91phox, p22phox, p67phox, p47phox, and p40phox, in wheat coleoptiles using Western blot analysis and immunofluorescence microscopy. Blue light augmented the expression levels of all these subunits and targeted NOX subunits onto the plasma membrane and to the nucleus. gp91phox, p22phox, p67phox, and p40phox showed entry into the nucleus and exhibited physical closeness with DNA. CuZnSOD was also present in the coleoptile tip, which also showed a blue-light-dependent elevation in expression. Superoxide production and phototropic response were both abrogated by DPIC and staurosporine, indicating their cause-and-effect relationship. We conclude that blue light mediates a phototropic response in wheat coleoptiles through modulation of expression of NOX and SOD as well as the translocation of NOX subunits onto the plasma membrane and nuclear membrane. Thus, this study provides a mechanistic explanation for superoxide production during the photoresponse in wheat coleoptiles.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective To compare rates of a composite outcome of mortality or major morbidity in very-preterm/very low birth weight infants between 8 members of the International Network for Evaluating Outcomes. ...Study design We included 58 004 infants born weighing <1500 g at 240 –316 weeks' gestation from databases in Australia/New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the United Kingdom. We compared a composite outcome (mortality or any of grade ≥3 peri-intraventricular hemorrhage, periventricular echodensity/echolucency, bronchopulmonary dysplasia, or treated retinopathy of prematurity) between each country and all others by using standardized ratios and pairwise using logistic regression analyses. Results Despite differences in population coverage, included neonates were similar at baseline. Composite outcome rates varied from 26% to 42%. The overall mortality rate before discharge was 10% (range: 5% Japan-17% Spain). The standardized ratio (99% CIs) estimates for the composite outcome were significantly greater for Spain 1.09 (1.04-1.14) and the United Kingdom 1.16 (1.11-1.21), lower for Australia/New Zealand 0.93 (0.89-0.97), Japan 0.89 (0.86-0.93), Sweden 0.81 (0.73-0.90), and Switzerland 0.77 (0.69-0.87), and nonsignificant for Canada 1.04 (0.99-1.09) and Israel 1.00 (0.93-1.07). The adjusted odds of the composite outcome varied significantly in pairwise comparisons. Conclusions We identified marked variations in neonatal outcomes between countries. Further collaboration and exploration is needed to reduce variations in population coverage, data collection, and case definitions. The goal would be to identify care practices and health care organizational factors, which has the potential to improve neonatal outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
IntroductionSouth Africa has the highest national burden of HIV globally. Understanding drivers of HIV acquisition in recently completed, prospective studies in which HIV was an endpoint may help ...inform the strategy and investments in national HIV prevention efforts and guide the design of future HIV prevention trials. We assessed HIV incidence and correlates of incidence among women enrolled in ECHO (Evidence for Contraceptive Options and HIV Outcomes), a large, open-label randomized clinical trial that compared three highly effective. reversible methods of contraception and rates of HIV acquisition.MethodsDuring December 2015 to October 2018, ECHO followed sexually active, HIV-seronegative women, aged 16-35 years, seeking contraceptive services and willing to be randomized to one of three contraceptive methods (intramuscular depot medroxyprogesterone acetate, copper intrauterine device, or levonorgestrel implant) for 12-18 months at nine sites in South Africa. HIV incidence based on prospectively observed HIV seroconversion events. Cox proportional hazards regression models were used to define baseline cofactors related to incident HIV infection.Results5768 women were enrolled and contributed 7647 woman-years of follow-up. The median age was 23 years and 62.5% were ≤24 years. A total of 345 incident HIV infections occurred, an incidence of 4.51 per 100 woman-years (95%CI 4.05-5.01). Incidence was >3 per 100 woman-years at all sites. Age ≤24 years, baseline infection with sexually transmitted infections, BMI≤30, and having new or multiple partners in the three months prior to enrollment were associated with incident HIV.ConclusionsHIV incidence was high among South African women seeking contraceptive services. Integration of diagnostic management of sexually transmitted infections alongside delivery of HIV prevention options in health facilities providing contraception services are needed to mitigate ongoing risks of HIV acquisition for this vulnerable population.Clinical trial registrationClinicalTrials.gov, number NCT02550067 was the main Clinical Trial from which this secondary, non-randomized / observational analysis was derived with data limited to just South African sites.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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