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3.
Can J Anaesth ; 2022 Feb 02.
Article in English | MEDLINE | ID: covidwho-1739440

ABSTRACT

PURPOSE: Numerous guideline recommendations for airway and perioperative management during the COVID-19 pandemic have been published. We identified, synthesized, and compared guidelines intended for anesthesiologists. SOURCE: Member society websites of the World Federation of Societies of Anesthesiologists and the European Society of Anesthesiologists were searched. Recommendations that focused on perioperative airway management of patients with proven or potential COVID-19 were included. Accelerated screening was used; data were extracted by one reviewer and verified by a second. Data were organized into themes based on perioperative phase of care. PRINCIPAL FINDINGS: Thirty unique sets of recommendations were identified. None reported methods for systematically searching or selecting evidence to be included. Four were updated following initial publication. For induction and airway management, most recommended minimizing personnel and having the most experienced anesthesiologist perform tracheal intubation. Significant congruence was observed among recommendations that discussed personal protective equipment. Of those that discussed tracheal intubation methods, most (96%) recommended videolaryngoscopy, while discordance existed regarding use of flexible bronchoscopy. Intraoperatively, 23% suggested specific anesthesia techniques and most (63%) recommended a specific operating room for patients with COVID-19. Postoperatively, a minority discussed extubation procedures (33%), or care in the recovery room (40%). Non-technical considerations were discussed in 27% and psychological support for healthcare providers in 10%. CONCLUSION: Recommendations for perioperative airway management of patients with COVID-19 overlap to a large extent but also show significant differences. Given the paucity of data early in the pandemic, it is not surprising that identified publications largely reflected expert opinion rather than empirical evidence. We suggest future efforts should promote coordinated responses and provide suggestions for studying and establishing best practices in perioperative patients. STUDY REGISTRATION: Open Science Framework ( https://osf.io/a2k4u/ ); date created, 26 March 2020.


RéSUMé: OBJECTIF: De nombreuses recommandations ont été publiées pour la prise en charge des voies aériennes et périopératoires pendant la pandémie de COVID-19. Nous avons identifié, synthétisé et comparé les lignes directrices destinées aux anesthésiologistes. SOURCES: Les sites internet des sociétés membres de la Fédération mondiale des sociétés d'anesthésiologistes et de la Société européenne d'anesthésiologie ont été consultés. Les recommandations axées sur la prise en charge périopératoire des voies aériennes des patients atteints de COVID-19 prouvée ou potentielle ont été incluses. Une sélection accélérée a été utilisée; les données ont été extraites par un examinateur et vérifiées par un second. Les données ont été thématiquement organisées en fonction de la phase périopératoire des soins. CONSTATATIONS PRINCIPALES: Trente ensembles uniques de recommandations ont été identifiés. Aucun de ces ensemble n'a fait état de méthodes de recherche ou de sélection systématiques des données probantes à inclure. Quatre ont été mis à jour après leur publication initiale. Pour l'induction et la prise en charge des voies aériennes, la plupart ont recommandé de minimiser le personnel et de demander à l'anesthésiologiste le plus expérimenté de réaliser l'intubation trachéale. Une congruence significative a été observée parmi les recommandations qui portaient sur les équipements de protection individuelle. Parmi les lignes directrices évoquant les méthodes d'intubation trachéale, la plupart (96 %) ont recommandé la vidéolaryngoscopie, alors qu'il existait une discordance concernant l'utilisation de bronchoscopes flexibles. En peropératoire, 23 % ont suggéré des techniques d'anesthésie spécifiques et la plupart (63 %) ont recommandé une salle d'opération spécifique pour les patients atteints de COVID-19. En postopératoire, une minorité a abordé le sujet des procédures d'extubation (33 %) ou des soins en salle de réveil (40 %). Les considérations non techniques ont été traitées dans 27 % des cas et le soutien psychologique aux fournisseurs de soins de santé dans 10 %. CONCLUSION: Les recommandations pour la prise en charge périopératoire des voies aériennes des patients atteints de COVID-19 se chevauchent dans une large mesure, mais montrent également des différences significatives. Compte tenu de la rareté des données au début de la pandémie, il n'est pas surprenant que les publications identifiées reflètent en grande partie l'opinion d'experts plutôt que de se fonder sur des données probantes empiriques. Nous suggérons que les efforts futurs soient déployés de manière à promouvoir des réponses coordonnées et proposer des suggestions pour étudier et établir les meilleures pratiques chez les patients en période périopératoire. ENREGISTREMENT DE L'éTUDE: Open Science Framework ( https://osf.io/a2k4u/ ); date de création, 26 mars 2020.

4.
Cytotherapy ; 2022 Jan 31.
Article in English | MEDLINE | ID: covidwho-1729893

ABSTRACT

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic, and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. METHODS AND FINDINGS: All English-language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients), four of which were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random-effects meta-analysis. MSCs decreased the risk of death at study endpoint compared with controls (risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.74; P = .02; I2 = 0%), although follow-up differed. Among secondary outcomes, interleukin-6 levels were most commonly reported and were decreased compared with controls (standardized mean difference, -0.69; 95% CI, -1.15 to -0.22; P = .004; I2 = 0%) (n = 3 studies). Other outcomes were not reported consistently, and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low. In two of nine studies, RoB analysis revealed a low to moderate risk of bias in controlled studies, and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. CONCLUSION: Use of MSCs to treat COVID-19 appears promising; however, few studies were identified, and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects.

5.
BMJ Open ; 12(3): e057024, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1723817

ABSTRACT

INTRODUCTION: COVID-19 has caused morbidity, hospitalisations and deaths worldwide. Despite four approved vaccines for COVID-19 in Canada, there is still a need for effective treatments, especially for people in the community. Vaccine efficacy is not 100% and long-term efficacy is still unknown. Furthermore, there are challenges to herd immunity including vaccine hesitancy and underlying conditions preventing vaccination. We aim to explore if the nutrients vitamin C, vitamin D, vitamin K2 and zinc are an effective treatment option for outpatients diagnosed with COVID-19. The primary outcome is the difference in participant-reported overall health; secondary outcomes include the effect on health status, symptom severity and duration, frequency and length of hospitalisations and mortality. METHODS AND ANALYSIS: This study is a two-arm, parallel-group, double-blind, placebo-controlled, phase III randomised controlled trial. 200 patients will be recruited remotely from COVID-19 test centres in Ottawa, Canada associated with The Ottawa Hospital. Overall health will be measured using the EuroQol Visual Assessment Scale; health status will be measured using the EuroQol 5-dimension 5-level questionnaire; symptom severity and duration will be measured using an independently developed questionnaire; analyses will use an area under the curve approach and compare mean scores using unadjusted t tests. Study data will be recorded on electronic case report forms using the Research Electronic Data Capture platform. An independent data safety and monitoring board will perform ongoing review of the study for feasibility and safety. ETHICS AND DISSEMINATION: This study has received ethical approval from the research ethics boards of the Canadian College of Naturopathic Medicine and the Ottawa Health Sciences Network, as well as regulatory approval from the Therapeutic Products Directorate and Natural and Non-Prescription Health Products Directorate of Health Canada. Results will be published in a peer-reviewed scientific journal with open access. TRIAL REGISTRATION NUMBER: NCT04780061.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , COVID-19 Vaccines , Canada , Dietary Supplements , Humans , Randomized Controlled Trials as Topic , Treatment Outcome
7.
JAMA ; 326(17): 1690-1702, 2021 Nov 02.
Article in English | MEDLINE | ID: covidwho-1525402

ABSTRACT

IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group. CONCLUSIONS AND RELEVANCE: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.


Subject(s)
COVID-19/therapy , ABO Blood-Group System , Adult , Aged , Critical Illness/therapy , Female , Hospital Mortality , Humans , Immunization, Passive , Length of Stay , Logistic Models , Male , Middle Aged , Respiration, Artificial/statistics & numerical data , Treatment Failure , Vasoconstrictor Agents/therapeutic use
8.
Nat Med ; 27(11): 2012-2024, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526091

ABSTRACT

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.


Subject(s)
COVID-19/therapy , Adult , Aged , Aged, 80 and over , Brazil/epidemiology , COVID-19/epidemiology , Canada/epidemiology , Female , Hospitalization/statistics & numerical data , Humans , Immunization, Passive , Intention to Treat Analysis , Male , Middle Aged , SARS-CoV-2/immunology , Treatment Outcome , United States/epidemiology
9.
J Extracell Vesicles ; 10(12): e12141, 2021 10.
Article in English | MEDLINE | ID: covidwho-1451869

ABSTRACT

Preclinical studies suggest mesenchymal stromal cell extracellular vesicles (MSC-EVs) reduce inflammation and improve organ function in lung diseases; however, an objective analysis of all available data is needed prior to translation. Using rigorous meta-research methods, we determined the effectiveness of MSC-EVs for preclinical respiratory diseases and identified experimental conditions that may further refine this therapy. A systematic search of MEDLINE/Embase identified 1167 records. After screening, 52 articles were included for data extraction and evaluated for risk of bias and quality of reporting in study design. A random effects meta-analysis was conducted for acute lung injury (ALI; N = 23), bronchopulmonary dysplasia (BPD; N = 8) and pulmonary arterial hypertension (PAH; N = 7). Subgroup analyses identified EV methods/characteristics that may be associated with improved efficacy. Data is presented as standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). For ALI, MSC-EVs markedly reduced lung injury (SMD -4.33, CI -5.73 to -2.92), vascular permeability (SMD -2.43, CI -3.05 to -1.82), and mortality (RR 0.39, CI 0.22 to 0.68). Small EVs were more consistently effective than large EVs whereas no differences were observed between tissue sources, immunocompatibility or isolation techniques. For BPD, alveolarization was improved by MSC-EVs (SMD -1.45, CI -2.08 to -0.82) with small EVs more consistently beneficial then small/large EVs. In PAH, right ventricular systolic pressure (SMD -4.16, CI -5.68 to -2.64) and hypertrophy (SMD -2.80, CI -3.68 to -1.91) were significantly attenuated by EVs. In BPD and PAH, EVs isolated by ultracentrifugation demonstrated therapeutic benefit whereas tangential flow filtration (N = 2) displayed minimal efficacy. Lastly, risk of bias and quality of reporting for experimental design were consistently unclear across all studies. Our findings demonstrate clear potential of MSC-EVs to be developed as therapy for acute and chronic lung diseases. However, greater transparency in research design and direct comparisons of isolation technique and EV subtypes are needed to generate robust evidence to guide clinical translation. Protocol Registration: PROSPERO CRD42020145334.


Subject(s)
Extracellular Vesicles/metabolism , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Respiration Disorders/therapy , Acute Disease , Animals , Chronic Disease , Disease Models, Animal , Humans
10.
Syst Rev ; 10(1): 249, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1412799

ABSTRACT

BACKGROUND: Mesenchymal stromal cells (MSCs) have significant immunomodulatory and tissue repair capabilities, mediated partly by conditioned media or through secreted extracellular vesicles (MSC-EVs). Infection with SARS-CoV-2 can cause mild to life-threatening illness due to activated immune responses that may be dampened by MSCs or their secretome. Many clinical studies of MSCs have been launched since the beginning of the global pandemic, however, few have been completed and most lack power to assess efficacy. Repeated systematic searches and meta-analyses are needed to understand, in real time, the extent of potential benefit in different patient populations as the evidence emerges. METHODS: This living systematic review will be maintained to provide up-to-date information as the pandemic evolves. A systematic literature search of Embase, MEDLINE, and Cochrane Central Register of Controlled Trials databases will be performed. All clinical studies (e.g., randomized, pseudorandomized and non-randomized controlled trials, uncontrolled trials, and case series) employing MSCs or their secretome as a therapeutic intervention for COVID-19 will be included. Patients must have confirmed SARS-CoV-2 infection. Study screening and data extraction will be performed in duplicate. Information concerning interventions, patient populations, methods of MSC isolation and characterization, primary and secondary clinical and/or laboratory outcomes, and adverse events will be extracted. Key clinical outcomes will be pooled through random-effects meta-analysis to determine the efficacy of MSCs and their secreted products for COVID-19. DISCUSSION: Our systematic review and subsequent updates will inform the scientific, medical, and health policy communities as the pandemic evolves to guide decisions on the appropriate use of MSC-related products to treat COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD 42021225431.


Subject(s)
COVID-19 , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Humans , Meta-Analysis as Topic , Pandemics , SARS-CoV-2 , Systematic Reviews as Topic
11.
Nat Med ; 27(11): 2012-2024, 2021 11.
Article in English | MEDLINE | ID: covidwho-1402107

ABSTRACT

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.


Subject(s)
COVID-19/therapy , Adult , Aged , Aged, 80 and over , Brazil/epidemiology , COVID-19/epidemiology , Canada/epidemiology , Female , Hospitalization/statistics & numerical data , Humans , Immunization, Passive , Intention to Treat Analysis , Male , Middle Aged , SARS-CoV-2/immunology , Treatment Outcome , United States/epidemiology
12.
Trials ; 22(1): 323, 2021 May 04.
Article in English | MEDLINE | ID: covidwho-1273249

ABSTRACT

BACKGROUND: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection. METHODS: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600). DISCUSSION: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification. TRIAL REGISTRATION: Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.


Subject(s)
COVID-19 , Coronavirus Infections , Adult , Bisoprolol , COVID-19/therapy , Humans , Immunization, Passive , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
13.
Trials ; 22(1): 323, 2021 May 04.
Article in English | MEDLINE | ID: covidwho-1216923

ABSTRACT

BACKGROUND: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection. METHODS: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600). DISCUSSION: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification. TRIAL REGISTRATION: Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.


Subject(s)
COVID-19 , Coronavirus Infections , Adult , Bisoprolol , COVID-19/therapy , Humans , Immunization, Passive , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
14.
Clin Trials ; 17(5): 491-500, 2020 10.
Article in English | MEDLINE | ID: covidwho-724657

ABSTRACT

BACKGROUND: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Heparin/administration & dosage , Pneumonia, Viral/drug therapy , Thrombosis/prevention & control , Adolescent , Adult , Anticoagulants/administration & dosage , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Dose-Response Relationship, Drug , Female , Humans , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Thrombosis/etiology , Treatment Outcome , Young Adult
15.
Transfus Med Rev ; 34(3): 158-164, 2020 07.
Article in English | MEDLINE | ID: covidwho-654280

ABSTRACT

Many parallel studies of convalescent plasma with modest enrolment projections have been launched for the treatment of COVID-19. By pooling data from multiple parallel studies that are similar, we can increase the effective sample size and achieve enough statistical power to determine effectiveness more quickly through meta-analysis. A scoping review of registered clinical trials of convalescent plasma for COVID-19 was conducted to assess the feasibility of performing a rapid and timely meta-analysis that will support accelerated review for approval and implementation. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized convalescent plasma to treat or prevent COVID-19. Forty-eight registered trials (projected to enroll more than 5000 subjects) of convalescent plasma were identified and included for analysis. The majority of studies (33 studies with 4440 projected enrolment) will address the treatment of severe and/or critical cases of COVID-19. Twenty-nine studies are controlled and 17 of these are reported as actively recruiting. The combined enrolment of patients from similar studies should be sufficient to determine meaningful improvements in mortality, rates of admission to intensive care and need for mechanical ventilation by the end of 2020-sooner than any individual study could determine effectiveness. Accessing supplemental outcome data from investigators may be needed; however, to align reporting of some outcomes from these studies. Heterogeneity in product potency due to different antibody titers is anticipated and studies using conventional treatment as controls instead of placebo may complicate our understanding of efficacy. Convalescent plasma is being tested in ongoing controlled studies, largely to treat severe and/or critical cases of COVID-19. Sufficient combined power to detect clinically important reductions in multiple outcomes, including mortality, is expected by September 2020. Regulatory approval, funding and implementation by blood operators could be accelerated by planned meta-analysis as study results become available.


Subject(s)
Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Betacoronavirus , COVID-19 , Clinical Trials as Topic , Critical Care , Global Health , Humans , Immunization, Passive , Pandemics , Registries , Reproducibility of Results , Research Design , Respiration, Artificial , SARS-CoV-2 , Sample Size , Treatment Outcome
16.
Transfus Med Rev ; 34(3): 165-171, 2020 07.
Article in English | MEDLINE | ID: covidwho-628007

ABSTRACT

The urgent need for safe and effective treatments for COVID-19 has fueled the launch of many parallel complex studies of cellular therapies with small to modest enrolment projections. By pooling data from multiple studies that are similar, we can increase the ability to achieve sufficient power to determine effectiveness more quickly through meta-analysis. A scoping review of registered clinical trials using cell-based interventions for COVID-19 was conducted to identify candidate studies for meta-analysis that could support an accelerated regulatory review. ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized cell or cell-derived products to treat or prevent COVID-19. Fifty-four registered cellular therapy trials were identified and included for analysis. Studies of mesenchymal stromal cells (MSCs; 41 studies; 1129 subjects projected to receive cells) and natural killer (NK) cells (5 studies; 135 projected to received cells) were observed most commonly. A subset of studies are controlled (34 studies, or 63%), including 27 studies of MSCs and 3 of NK cells. While heterogeneity in study design exists, the cumulative projected enrolment of patients from similar studies appears sufficient to allow the detection of meaningful differences in clinically important outcomes such as mortality, admission to intensive care and need for mechanical ventilation by September 2020-sooner than any individual study could determine effectiveness. MSCs are the predominant cell type in registered trials for severe or critical COVID-19 and represent the most promising candidates for future meta-analysis. Sufficient pooled sample size to detect clinically important reductions in multiple outcomes, including mortality, is anticipated by September 2020, but may require accessing supplementary data to align outcome reporting. Regulatory approval, funding and implementation by cell manufacturing partners will be accelerated by our framework for rapid meta-analysis.


Subject(s)
Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Betacoronavirus , COVID-19 , Clinical Trials as Topic , Critical Care , Global Health , Humans , Immunization, Passive , Killer Cells, Natural/metabolism , Mesenchymal Stem Cells/metabolism , Pandemics , Registries , Reproducibility of Results , Research Design , Respiration, Artificial , SARS-CoV-2 , Sample Size , Treatment Outcome
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