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1. Simvastatin in Critically Ill Patients with Covid-19.

Author

Hills, Thomas, Lorenzi, Elizabeth, Berry, Lindsay, Shyamsundar, Murali, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Aryal, Diptesh, Au, Carly, Beane, Abigail, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Burrell, Aidan, Buxton, Meredith, Calfee, Carolyn, Cecconi, Maurizio, Cheng, Allen, Cove, Matthew, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goligher, Ewan, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Harrison, David, Hashmi, Madiha, Higgins, Alisa, Huang, David, Ichihara, Nao, Jayakumar, Deva, Kruger, Peter, Lamontagne, François, Lampro, Lamprini, Lawler, Patrick, Marshall, John, Mason, Alexina, McGlothlin, Anna, McGuinness, Shay, McQuilten, Zoe, McVerry, Bryan, Mouncey, Paul, Murthy, Srinivas, Neal, Matthew, Nichol, Alistair, OKane, Cecilia, Parke, Rachael, Parker, Jane, Rabindrarajan, Ebenezer, Reyes, Luis, Rowan, Kathryn, Saito, Hiroki, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Shankar-Hari, Manu, Sinha, Pratik, Thompson, B, Turgeon, Alexis, Turner, Anne, van de Veerdonk, Frank, Weis, Sebastian, Young, Ian, Zarychanski, Ryan, McArthur, Colin, Angus, Derek, Berry, Scott, Derde, Lennie, Webb, Steve, Gordon, Anthony, McAuley, Daniel, and Lewis, Roger

Subjects
Humans, Bayes Theorem, COVID-19, COVID-19 Drug Treatment, Critical Illness, Hospital Mortality, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Treatment Outcome
Abstract

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was

Published
2023

2. A blueprint for a multi-disease, multi-domain Bayesian adaptive platform trial incorporating adult and paediatric subgroups: the Staphylococcus aureus Network Adaptive Platform trial.

Author

Mahar, Robert, McGlothlin, Anna, Dymock, Michael, Lee, Todd, Lewis, Roger, Lumley, Thomas, Mora, Jocelyn, Price, David, Saville, Benjamin, Snelling, Tom, Turner, Rebecca, Webb, Steven, Davis, Joshua, Tong, Steven, and Marsh, Julie

Subjects
Adaptive, Bayesian, Platform, Randomised, Staphylococcus aureus, Trial, Adult, Child, Humans, Bayes Theorem, Sepsis, Staphylococcal Infections, Staphylococcus aureus
Abstract

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a multifactorial Bayesian adaptive platform trial that aims to improve the way that S. aureus bloodstream infection, a globally common and severe infectious disease, is treated. In a world first, the SNAP trial will simultaneously investigate the effects of multiple intervention modalities within multiple groups of participants with different forms of S. aureus bloodstream infection. Here, we formalise the trial structure, modelling approach, and decision rules that will be used for the SNAP trial. By summarising the statistical principles governing the design, our hope is that the SNAP trial will serve as an adaptable template that can be used to improve comparative effectiveness research efficiency in other disease areas.Trial registration NCT05137119 . Registered on 30 November 2021.

Published
2023

3. The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.

Author

Tong, Steven, Mora, Jocelyn, Bowen, Asha, Cheng, Matthew, Daneman, Nick, Goodman, Anna, Heriot, George, Lee, Todd, Lewis, Roger, Lye, David, Mahar, Robert, Marsh, Julie, McGlothlin, Anna, McQuilten, Zoe, Morpeth, Susan, Paterson, David, Price, David, Roberts, Jason, Robinson, J, van Hal, Sebastiaan, Walls, Genevieve, Webb, Steve, Whiteway, Lyn, Yahav, Dafna, and Davis, Joshua

Subjects
Staphylococcus aureus, adaptive platform, bacteremia, bloodstream infection, randomized controlled trial, Humans, Anti-Bacterial Agents, Bacteremia, Staphylococcal Infections, Staphylococcus aureus
Abstract

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this,

Published
2022

4. The design of a Bayesian adaptive clinical trial of tranexamic acid in severely injured children

Author

VanBuren, John M, Casper, T Charles, Nishijima, Daniel K, Kuppermann, Nathan, Lewis, Roger J, Dean, J Michael, and McGlothlin, Anna

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Clinical Trials and Supportive Activities, Pediatric, Physical Injury - Accidents and Adverse Effects, Clinical Research, Traumatic Head and Spine Injury, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Antifibrinolytic Agents, Bayes Theorem, Child, Double-Blind Method, Hemorrhage, Humans, Tranexamic Acid, Trauma Severity Indices, Wounds and Injuries, Bayesian statistics, Tranexamic acid, Pediatrics, Adaptive clinical trial design, Response-adaptive randomization, Dose-response, Trauma, TIC-TOC Collaborators of the Pediatric Emergency Care Applied Research Network, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, General & Internal Medicine, Clinical sciences, Epidemiology, Health services and systems
Abstract

BackgroundTrauma is the leading cause of death and disability in children in the USA. Tranexamic acid (TXA) reduces the blood transfusion requirements in adults and children during surgery. Several studies have evaluated TXA in adults with hemorrhagic trauma, but no randomized controlled trials have occurred in children with trauma. We propose a Bayesian adaptive clinical trial to investigate TXA in children with brain and/or torso hemorrhagic trauma.Methods/designWe designed a double-blind, Bayesian adaptive clinical trial that will enroll up to 2000 patients. We extend the traditional Emax dose-response model to incorporate a hierarchical structure so multiple doses of TXA can be evaluated in different injury populations (isolated head injury, isolated torso injury, or both head and torso injury). Up to 3 doses of TXA (15 mg/kg, 30 mg/kg, and 45 mg/kg bolus doses) will be compared to placebo. Equal allocation between placebo, 15 mg/kg, and 30 mg/kg will be used for an initial period within each injury group. Depending on the dose-response curve, the 45 mg/kg arm may open in an injury group if there is a trend towards increasing efficacy based on the observed relationship using the data from the lower doses. Response-adaptive randomization allows each injury group to differ in allocation proportions of TXA so an optimal dose can be identified for each injury group. Frequent interim stopping periods are included to evaluate efficacy and futility. The statistical design is evaluated through extensive simulations to determine the operating characteristics in several plausible scenarios. This trial achieves adequate power in each injury group.DiscussionThis trial design evaluating TXA in pediatric hemorrhagic trauma allows for three separate injury populations to be analyzed and compared within a single study framework. Individual conclusions regarding optimal dosing of TXA can be made within each injury group. Identifying the optimal dose of TXA, if any, for various injury types in childhood may reduce death and disability.

Published
2021

5. Association of Active Renin Content With Mortality in Critically Ill Patients: A Post hoc Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Trial*

Author

Busse, Laurence W., Schaich, Christopher L., Chappell, Mark C., McCurdy, Michael T., Staples, Erin M., Ten Lohuis, Caitlin C., Hinson, Jeremiah S., Sevransky, Jonathan E., Rothman, Richard E., Wright, David W., Martin, Greg S., Khanna, Ashish K., Hager, David N., Bernard, Gordon R., Brown, Samuel M., Buchman, Timothy G., Coopersmith, Craig M., DeWilde, Christine, Wesley Ely, E., Eyzaguirre, Lindsay M., Fowler, Alpha A., Gaieski, David F., Gong, Michelle N., Hall, Alex, Hooper, Michael H., Kelen, Gabor D., Khan, Akram, Levine, Mark A., Lewis, Roger J., Lindsell, Chris J., Marlin, Jessica S., McGlothlin, Anna, Moore, Brooks L., Nugent, Katherine L., Nwosu, Samuel, Polito, Carmen C., Rice, Todd W., Ricketts, Erin P., Rudolph, Caroline C., Sanfilippo, Fred, and Viele, Kert

Published
2024
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6. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Author

Arabi, Yaseen M, Gordon, Anthony C, Derde, Lennie PG, Nichol, Alistair D, Murthy, Srinivas, Beidh, Farah Al, Annane, Djillali, Swaidan, Lolowa Al, Beane, Abi, Beasley, Richard, Berry, Lindsay R, Bhimani, Zahra, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen, De Jong, Menno, Detry, Michelle A, Duffy, Eamon J, Estcourt, Lise J, Fitzgerald, Mark, Fowler, Rob, Girard, Timothy D, Goligher, Ewan C, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa M, Hills, Thomas E, Horvat, Christopher M, Huang, David T, King, Andrew J, Lamontagne, Francois, Lawler, Patrick R, Lewis, Roger, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Malakouti, Salim, McAuley, Daniel F, McGlothlin, Anna, Mcguinness, Shay, McVerry, Bryan J, Montgomery, Stephanie K, Morpeth, Susan C, Mouncey, Paul R, Orr, Katrina, Parke, Rachael, Parker, Jane C, Patanwala, Asad E, Rowan, Kathryn M, Santos, Marlene S, Saunders, Christina T, Seymour, Christopher W, Shankar-Hari, Manu, Tong, Steven YC, Turgeon, Alexis F, Turner, Anne M, Van de Veerdonk, Frank Leo, Zarychanski, Ryan, Green, Cameron, Berry, Scott, Marshall, John C, McArthur, Colin, Angus, Derek C, and Webb, Steven A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Comparative Effectiveness Research, Clinical Research, Clinical Trials and Supportive Activities, Good Health and Well Being, Adult, Antiviral Agents, Bayes Theorem, Critical Illness, Drug Combinations, Humans, Hydroxychloroquine, Lopinavir, Ritonavir, SARS-CoV-2, COVID-19 Drug Treatment, Adaptive platform trial, Intensive care, Pneumonia, Pandemic, COVID-19, Lopinavir-ritonavir, REMAP-CAP Investigators, Public Health and Health Services, Emergency & Critical Care Medicine, Clinical sciences
Abstract

PurposeTo study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).MethodsCritically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.ResultsWe randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).ConclusionAmong critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

Published
2021

7. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

Author

Gordon, Anthony, Mouncey, Paul, Al-Beidh, Farah, Rowan, Kathryn, Nichol, Alistair, Arabi, Yaseen, Annane, Djillali, Beane, Abi, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buzgau, Adrian, Cheng, Allen, Detry, Michelle, Duffy, Eamon, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa, Hills, Thomas, Horvat, Christopher, Lamontagne, Francois, Lawler, Patrick, Leavis, Helen, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, Mayr, Florian, McAuley, Daniel, McGlothlin, Anna, McGuinness, Shay, McVerry, Bryan, Montgomery, Stephanie, Morpeth, Susan, Murthy, Srinivas, Orr, Katrina, Parke, Rachael, Parker, Jane, Patanwala, Asad, Pettilä, Ville, Rademaker, Emma, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Shankar-Hari, Manu, Sligl, Wendy, Turgeon, Alexis, Turner, Anne, van de Veerdonk, Frank, Zarychanski, Ryan, Green, Cameron, Lewis, Roger, Angus, Derek, McArthur, Colin, Berry, Scott, Webb, Steve, and Derde, Lennie

Subjects
Adult, Aged, Antibodies, Monoclonal, Humanized, COVID-19, Critical Illness, Female, Hospital Mortality, Humans, Intensive Care Units, Male, Middle Aged, Odds Ratio, Receptors, Interleukin-6, Respiration, Artificial, COVID-19 Drug Treatment
Abstract

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Published
2021

8. The Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia (REMAP-CAP) Study: Rationale and Design

Author

Angus, Derek C, Berry, Scott, Lewis, Roger J, Al-Beidh, Farah, Arabi, Yaseen, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc, Broglio, Kristine, Brunkhorst, Frank, Cheng, Allen C, Chiche, Jean-Daniel, De Jong, Menno, Detry, Michelle, Goossens, Herman, Gordon, Anthony, Green, Cameron, Higgins, Alisa M, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Litton, Edward, Marshall, John, McGlothlin, Anna, McGuinness, Shay, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, O'Neill, Genevieve K, Parke, Rachael, Parker, Jane, Rohde, Gernot, Rowan, Kathryn, Turner, Anne, Young, Paul, Derde, Lennie, McArthur, Colin, and Webb, Steven A

Subjects
Influenza, Cancer, Clinical Research, Lung, Clinical Trials and Supportive Activities, Vaccine Related, Pneumonia & Influenza, Comparative Effectiveness Research, Patient Safety, Infectious Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Anti-Bacterial Agents, Antiviral Agents, Betacoronavirus, COVID-19, Community-Acquired Infections, Coronavirus Infections, Evidence-Based Medicine, Humans, Influenza, Human, Pandemics, Pneumonia, Pneumonia, Viral, Point-of-Care Systems, SARS-CoV-2, randomized clinical trial, Bayesian adaptive platform trial, master protocol, community-acquired pneumonia, coronavirus disease 2019, Bayesian adaptive, platform trial
Abstract

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Published
2020

9. The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design.

Author

Angus, Derek C, Berry, Scott, Lewis, Roger J, Al-Beidh, Farah, Arabi, Yaseen, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc, Broglio, Kristine, Brunkhorst, Frank, Cheng, Allen C, Chiche, Jean-Daniel, De Jong, Menno, Detry, Michelle, Goossens, Herman, Gordon, Anthony, Green, Cameron, Higgins, Alisa M, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Litton, Edward, Marshall, John, McGlothlin, Anna, McGuinness, Shay, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, O'Neill, Genevieve K, Parke, Rachael, Parker, Jane, Rohde, Gernot, Rowan, Kathryn, Turner, Anne, Young, Paul, Derde, Lennie, McArthur, Colin, and Webb, Steven A

Subjects
Humans, Community-Acquired Infections, Pneumonia, Viral, Coronavirus Infections, Pneumonia, Anti-Bacterial Agents, Antiviral Agents, Evidence-Based Medicine, Point-of-Care Systems, Influenza, Human, Pandemics, Betacoronavirus, COVID-19, SARS-CoV-2, Bayesian adaptive, community-acquired pneumonia, coronavirus disease 2019, master protocol, platform trial, randomized clinical trial, Bayesian adaptive platform trial, Respiratory System, Clinical Sciences
Abstract

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Published
2020

10. The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial

Author

McCreary, Erin K., Bariola, J. Ryan, Minnier, Tami E., Wadas, Richard J., Shovel, Judith A., Albin, Debbie, Marroquin, Oscar C., Kip, Kevin E., Collins, Kevin, Schmidhofer, Mark, Wisniewski, Mary Kay, Nace, David A., Sullivan, Colleen, Axe, Meredith, Meyers, Russell, Weissman, Alexandra, Garrard, William, Peck-Palmer, Octavia M., Wells, Alan, Bart, Robert D., Yang, Anne, Berry, Lindsay R., Berry, Scott, Crawford, Amy M., McGlothlin, Anna, Khadem, Tina, Linstrum, Kelsey, Montgomery, Stephanie K., Ricketts, Daniel, Kennedy, Jason N., Pidro, Caroline J., Haidar, Ghady, Snyder, Graham M., McVerry, Bryan J., Yealy, Donald M., Angus, Derek C., Nakayama, Anna, Zapf, Rachel L., Kip, Paula L., Seymour, Christopher W., and Huang, David T.

Published
2022
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11. Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial

Author

Hergenroeder, Georgene W., Yokobori, Shoji, Choi, Huimahn Alex, Schmitt, Karl, Detry, Michelle A., Schmitt, Lisa H., McGlothlin, Anna, Puccio, Ava M., Jagid, Jonathan, Kuroda, Yasuhiro, Nakamura, Yukihiko, Suehiro, Eiichi, Ahmad, Faiz, Viele, Kert, Wilde, Elisabeth A., McCauley, Stephen R., Kitagawa, Ryan S., Temkin, Nancy R., Timmons, Shelly D., Diringer, Michael N., Dash, Pramod K., Bullock, Ross, Okonkwo, David O., Berry, Donald A., and Kim, Dong H.

Published
2022
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12. Whole-of-Life Inclusion in Bayesian Adaptive Platform Clinical Trials.

Author

Campbell, Anita J., Anpalagan, Keerthi, Best, Emma J., Britton, Philip N., Gwee, Amanda, Hatcher, James, Manley, Brett J., Marsh, Julie, Webb, Rachel H., Davis, Joshua S., Mahar, Robert K., McGlothlin, Anna, McMullan, Brendan, Meyer, Michael, Mora, Jocelyn, Murthy, Srinivas, Nourse, Clare, Papenburg, Jesse, Schwartz, Kevin L., and Scheuerman, Oded

Published
2024
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13. Does Adjunctive Clindamycin Have a Role in Staphylococcus aureus Bacteremia? A Protocol for the Adjunctive Treatment Domain of the Staphylococcus aureus Network Adaptive Platform (SNAP) Randomized Controlled Trial.

Author

Anpalagan, Keerthi, Dotel, Ravindra, MacFadden, Derek R, Smith, Simon, Voss, Lesley, Petersiel, Neta, Marks, Michael, Marsh, Julie, Mahar, Robert K, McGlothlin, Anna, Lee, Todd C, Goodman, Anna, Morpeth, Susan, Davis, Joshua S, Tong, Steven Y C, Bowen, Asha C, and Group, the Adjunctive Clindamycin Domain-Specific Working Group for the Staphylococcus aureus Network Adaptive Platform (SNAP) Trial

Subjects
STAPHYLOCOCCAL diseases, BACTEREMIA, STAPHYLOCOCCUS aureus, RANDOMIZED controlled trials, CLINDAMYCIN
Abstract

Background The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and it is recommended in many guidelines, but this is based on limited evidence. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leukocidins (eg, Panton-Valentine leukocidin, toxic shock syndrome toxin 1, exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. Methods and Analysis The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multicenter adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality rates. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either 5 days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard-of-care antibiotics. Most participants with SAB (within 72 hours of index blood culture and with no contraindications) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol, and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and Panton-Valentine leukocidin–positive isolate. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage

Author

Pradilla, Gustavo, primary, Ratcliff, Jonathan J., additional, Hall, Alex J., additional, Saville, Benjamin R., additional, Allen, Jason W., additional, Paulon, Giorgio, additional, McGlothlin, Anna, additional, Lewis, Roger J., additional, Fitzgerald, Mark, additional, Caveney, Angela F., additional, Li, Xiao T., additional, Bain, Mark, additional, Gomes, Joao, additional, Jankowitz, Brain, additional, Zenonos, Georgios, additional, Molyneaux, Bradley J., additional, Davies, Jason, additional, Siddiqui, Adnan, additional, Chicoine, Michael R., additional, Keyrouz, Salah G., additional, Grossberg, Jonathan A., additional, Shah, Mitesh V., additional, Singh, Ranjeet, additional, Bohnstedt, Bradley N., additional, Frankel, Michael, additional, Wright, David W., additional, and Barrow, Daniel L., additional

Published
2024
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16. Precision Promise (PrP) Bayesian platform trial for metastatic pancreatic cancer (mPDAC): Results of the first experimental arm, SM-88 as second line therapy.

Author

Oberstein, Paul Eliezer, primary, wang-gillam, Andrea, additional, Varghese, Anna M., additional, Ko, Andrew H., additional, Hendifar, Andrew Eugene, additional, Ocean, Allyson J., additional, McGlothlin, Anna, additional, Graves, Todd, additional, Berry, Scott M., additional, Detry, Michelle A., additional, Fitzgerald, Mark, additional, Bosse, Anna, additional, Moravek, Cassadie, additional, Feehan, Kelly, additional, Howland, Carrie Meghann, additional, Berry, Donald A., additional, Simeone, Diane M., additional, and Picozzi, Vincent J., additional

Published
2024
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17. In response: Letter on update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol

Author

Lindsell, Christopher J., McGlothlin, Anna, Nwosu, Samuel, Rice, Todd W., Hall, Alex, Bernard, Gordon R., Busse, Laurence W., Ely, E. Wesley, Fowler, Alpha A., Gaieski, David F., Hinson, Jeremiah S., Hooper, Michael H., Jackson, James C., Kelen, Gabor D., Levine, Mark, Martin, Greg S., Rothman, Richard E., Sevransky, Jonathan E., Viele, Kert, Wright, David W., and Hager, David N.

Published
2020
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18. Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial

Author

Lindsell, Christopher J., McGlothlin, Anna, Nwosu, Samuel, Rice, Todd W., Hall, Alex, Bernard, Gordon R., Busse, Laurence W., Ely, E. Wesley, Fowler, Alpha A., Gaieski, David F., Hinson, Jeremiah S., Hooper, Michael H., Jackson, James C., Kelen, Gabor D., Levine, Mark, Martin, Greg S., Rothman, Richard E., Sevransky, Jonathan E., Viele, Kert, Wright, David W., and Hager, David N.

Published
2019
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19. Results from the first four regimens of the HEALEY ALS Platform Trial (PL5.004)

Author

Paganoni, Sabrina, primary, Berry, James, additional, Quintana, Melanie, additional, Macklin, Eric, additional, Saville, Benjamin, additional, Andrews, Jinsy, additional, Shefner, Jeremy, additional, Fournier, Christina, additional, Babu, Suma, additional, Maragakis, Nicholas, additional, Oskarsson, Bjorn, additional, Detry, Michelle, additional, Chase, Marianne, additional, Sherman, Alex, additional, Yu, Hong, additional, Pothier, Lindsay, additional, Drake, Kristin, additional, Chibnik, Lori, additional, Bind, Marie-Abele, additional, Vestrucci, Matteo, additional, McGlothlin, Anna, additional, Marion, Joseph, additional, Duda, Petra, additional, Harvey, Brittany, additional, Qureshi, Irfan, additional, Donohue, Mary, additional, Granit, Volkan, additional, Grossman, Katheryn, additional, Glanzman, Robert, additional, Hotchkin, Michael, additional, Goldberg, Y Paul, additional, Leitner, Melanie, additional, Hayden, Michael, additional, and Cudkowicz, Merit, additional

Published
2023
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20. Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial

Author

Writing Committee for the REMAP-CAP Investigators, Lawler, Patrick R, Derde, Lennie PG, van de Veerdonk, Frank L, McVerry, Bryan J, Huang, David T, Berry, Lindsay R, Lorenzi, Elizabeth, van Kimmenade, Roland, Gommans, Frank, Vaduganathan, Muthiah, Leaf, David E, Baron, Rebecca M, Kim, Edy Y, Frankfurter, Claudia, Epelman, Slava, Kwan, Yvonne, Grieve, Richard, O'Neill, Stephen, Sadique, Zia, Puskarich, Michael, Marshall, John C, Higgins, Alisa M, Mouncey, Paul R, Rowan, Kathryn M, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Au, Carly, Beane, Abi, van Bentum-Puijk, Wilma, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Burrell, Aidan, Buzgau, Adrian, Buxton, Meredith, Cecconi, Maurizio, Cheng, Allen C, Cove, Matthew, Detry, Michelle A, Estcourt, Lise J, Ezekowitz, Justin, Fitzgerald, Mark, Gattas, David, Godoy, Lucas C, Goossens, Herman, Haniffa, Rashan, Harrison, David A, Hills, Thomas, Horvat, Christopher M, Ichihara, Nao, Lamontagne, Francois, Linstrum, Kelsey M, McAuley, Daniel F, McGlothlin, Anna, McGuinness, Shay P, McQuilten, Zoe, Murthy, Srinivas, Nichol, Alistair D, Owen, David RJ, Parke, Rachael L, Parker, Jane C, Pollock, Katrina M, Reyes, Luis Felipe, Saito, Hiroki, Santos, Marlene S, Saunders, Christina T, Seymour, Christopher W, Shankar-Hari, Manu, Singh, Vanessa, Turgeon, Alexis F, Turner, Anne M, Zarychanski, Ryan, Green, Cameron, Lewis, Roger J, Angus, Derek C, Berry, Scott, Gordon, Anthony C, McArthur, Colin J, Webb, Steve A, and Apollo - University of Cambridge Repository

Subjects
Male, Renin-Angiotensin System, Hospitalization, Angiotensin Receptor Antagonists, Critical Illness, Humans, COVID-19, Female, Angiotensin-Converting Enzyme Inhibitors, Bayes Theorem, Receptors, Chemokine, Middle Aged, COVID-19 Drug Treatment
Abstract

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Published
2023

21. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19

Author

Bradbury, Charlotte A., Lawler, Patrick R., Stanworth, Simon J., McVerry, Bryan J., McQuilten, Zoe, Higgins, Alisa M., Mouncey, Paul R., Al-Beidh, Farah, Rowan, Kathryn M., Berry, Lindsay R., Lorenzi, Elizabeth, Zarychanski, Ryan, Arabi, Yaseen M., Annane, Djillali, Beane, Abi, Van Bentum-Puijk, Wilma, Bhimani, Zahra, Bihari, Shailesh, Bonten, Marc J. M., Brunkhorst, Frank M., Buzgau, Adrian, Buxton, Meredith, Carrier, Marc, Cheng, Allen C., Cove, Matthew, Detry, Michelle A., Estcourt, Lise J., Fitzgerald, Mark, Girard, Timothy D., Goligher, Ewan C., Goossens, Herman, Haniffa, Rashan, Hills, Thomas, Huang, David T., Horvat, Christopher M., Hunt, Beverley J., Ichihara, Nao, Lamontagne, Francois, Leavis, Helen L., Linstrum, Kelsey M., Litton, Edward, Marshall, John C., McAuley, Daniel F., McGlothlin, Anna, McGuinness, Shay P., Middeldorp, Saskia, Montgomery, Stephanie K., Morpeth, Susan C., Murthy, Srinivas, Neal, Matthew D., Nichol, Alistair D., Parke, Rachael L., Parker, Jane C., Reyes, Luis, Saito, Hiroki, Santos, Marlene S., Saunders, Christina T., Serpa-Neto, Ary, Seymour, Christopher W., Shankar-Hari, Manu, Singh, Vanessa, Tolppa, Timo, Turgeon, Alexis F., Turner, Anne M., van de Veerdonk, Frank L., Green, Cameron, Lewis, Roger J., Angus, Derek C., McArthur, Colin J., Berry, Scott, Derde, Lennie P. G., Webb, Steve A., Gordon, Anthony C., Depuydt, Pieter, De Waele, Jan, De Bus, Liesbet, Fierens, Jan, Vermassen, Joris, REMAP-CAP Investigators, University of Bristol [Bristol], University Health Network, University of Toronto, University of Oxford, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Monash University [Melbourne], Imperial College London, University of Manitoba [Winnipeg], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), University Medical Center [Utrecht], St. Michael's Hospital, 215522, CS-2016-16-011, RP-2015-06-18, National Institutes of Health, NIH, U.S. Department of Defense, DOD, National Institute of General Medical Sciences, NIGMS, National Institute of Neurological Disorders and Stroke, NINDS, Gordon and Betty Moore Foundation, GBMF, Medtronic, Baxter International, Medical Center, University of Pittsburgh, CancerCare Manitoba Foundation, CCMF, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD, Wellcome Trust, WT, Health Research Board, HRB: CTN 2014-012, Horizon 2020 Framework Programme, H2020: 101003589, LAM Therapeutics, Canadian Institutes of Health Research, IRSC: 158584, Medical Research Council, MRC, National Institute for Health and Care Research, NIHR, European Commission, EC, National Heart and Lung Institute, NHLI, Queen's University Belfast, QUB: US8962032, National Health and Medical Research Council, NHMRC: APP1101719, National Medical Research Council, NMRC, Health Research Council of New Zealand, HRC: 16/631, Ministère des Affaires Sociales et de la Santé: PHRC-20-0147, Innovate UK, Horizon 2020, Pharmaceuticals Bayer, Swedish Orphan Biovitrum, NIHR Imperial Biomedical Research Centre, BRC, Minderoo Foundation, Funding/Support: This study was funded by the following: the Platform for European Preparedness Against (Re-)Emerging Epidemics (PREPARE) consortium of the European Union, FP7-HEALTH-2013-INNOVATION-1 (grant 602525), the Rapid European COVID-19 Emergency Research Response (RECOVER) consortium of the European Union’s Horizon 2020 Research and Innovation Programme (grant 101003589), the Australian National Health and Medical Research Council (grant APP1101719), the Health Research Council of New Zealand (grant 16/631), the Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program (grant 158584), the NIHR and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (grant CTN 2014-012), the University of Pittsburgh Medical Center (UPMC) Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (grant PHRC-20-0147), the Minderoo Foundation, and the Wellcome Trust Innovations Project (grant 215522). Dr Shankar-Hari is funded by an NIHR clinician scientist fellowship (grant CS-2016-16-011) and Dr Gordon is funded by an NIHR research professorship (grant RP-2015-06-18)., The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Clinical Trials Group, the Irish Critical Care Clinical Trials Network, the UK Critical Care Research Group and the International Forum of Acute Care Trialists., REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands, reported receipt of personal fees from Lilly, BMS-Pfizer, Bayer, Amgen, Novartis, Janssen, Portola, Ablynx, and Grifols. Dr Lawler reported receipt of personal fees from Novartis, CorEvitas, and Brigham and Women’s Hospital and royalties from McGraw-Hill Publishing. Dr McVerry reported receipt of grants from the National Heart, Lung, and Blood Institute and Bayer Pharmaceuticals and personal fees from Boehringer Ingelheim. Dr L. Berry reported being an employee of Berry Consultants, Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Lorenzi reported being an employee of Berry Consultants, Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Zarychanski reported receipt of grants from the Canadian Institutes of Health Research, LifeArc, Research Manitoba, the CancerCare Manitoba Foundation, Peter Munk Cardiac Centre, and the Thistledown Foundation and research operating support as the Lyonel G. Israels Research Chair in Hematology. Dr Bonten reported membership in international study steering committees, advisory boards, and independent data safety and monitoring committees funded by Janssen Vaccines, Merck Sharp & Dohme, AstraZeneca, Pfizer, and Sanofi Pasteur (all reimbursements to UMC Utrecht). Dr Brunkhorst reported receipt of grants from Jena University Hospital. Dr Buxton reported receipt of a gift from the Breast Cancer Research Foundation and contracts with Amgen and Eisai. Dr Carrier reported receipt of grants from BMS-Pfizer and personal fees from Bayer, Sanofi, Servier, Leo Phama, and BMS-Pfizer to his institution. Dr Cove reported receipt of grants from the National Medical Research Council and personal fees from Baxter and Medtronic. Dr Estcourt reported receipt of grants from the UK National Institute for Health Research (NIHR) and the European Union Horizon 2020 Research and Innovation Programme. Dr Haniffa reported receipt of grants from the UK Research and Innovation/Medical Research Council African Critical Care Registry Network. Dr Horvat reported receipt of grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Dr Ichihara reported being affiliated with the Department of Healthcare Quality Assessment, University of Tokyo, which is a social collaboration supported by the National Clinical Database, Johnson & Johnson, and Nipro Corporation. Dr Marshall reported receipt of personal fees from AM Pharma and Critical Care Medicine. Dr McAuley reported receipt of personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Lilly, Vir Biotechnology, Faron Pharmaceutical, and SOBI and grants from the NIHR, the Wellcome Trust, Innovate UK, the UK Medical Research Council, and the Northern Ireland Health and Social Care Research and Development Division, in addition, Dr McAuley had a Queen’s University Belfast patent for novel treatment for inflammatory disease (US8962032), was co-director of research at the Intensive Care Society until June 2021, and was director of the Efficacy and Mechanisms Evaluation Program for the UK Medical Research Council/NIHR. Dr Middeldorp reported receipt of personal fees from Daiichi Sankyo, Bayer, Pfizer, Boehringer Ingelheim, Portola/Alexion, AbbVie, BMS-Pfizer, Sanofi, and Viatris, all paid to his institution, and grants from Daiichi Sankyo, Bayer, Pfizer, and Boehringer Ingelheim. Dr Neal reported equity in Haima Therapeutics, receipt of personal fees from Janssen Pharma and Haemonetics, and receipt of grants from Instrumentation Laboratory, the National Institutes of Health, and the Department of Defense. Dr Nichol reported receipt of personal fees from AM Pharma, paid to his university, and grants from Baxter. Dr Parke reported receipt of grants from Fisher and Paykel Healthcare NZ. Dr Serpa-Neto reported receipt of personal fees from Drager and Endpoint Health. Dr Seymour reported receipt of grants from the Gordon and Betty Moore Foundation and the National Institutes of Health/National Institute of General Medical Sciences. Dr Lewis reported being senior medical scientist at Berry Consultants, Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr S. Berry reported being an employee with an ownership role at Berry Consultants, Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Derde reported being a coordinating committee member for the European Clinical Research Alliance on Infectious Diseases, a member of the Dutch Intensivists Task Force on Acute Infectious Threats, a member of the International Scientific Advisory Board for Sepsis Canada, and a member of the Dutch Academy of Sciences’ Pandemic Preparedness Plan committee. Dr Gordon reported receipt of personal fees from 30 Respiratory, paid to his institution. No other disclosures were reported., European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), Investigators, REMAP-CAP Writing Committee for the REMAP-CAP, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, and Intensive Care Medicine

Subjects
Adult, Male, Platelet Aggregation Inhibitors/adverse effects, Critical Illness, [SDV]Life Sciences [q-bio], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Hemorrhage, Aspirin/adverse effects, Hemorrhage/chemically induced, INFECTION, Humans, COAGULOPATHY, Aspirin, Anticoagulants, COVID-19, Bayes Theorem, Venous Thromboembolism, General Medicine, Middle Aged, Respiration, Artificial, COVID-19 Drug Treatment, Critical Illness/mortality, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Purinergic P2Y Receptor Antagonists/adverse effects, Purinergic P2Y Receptor Antagonists, COVID-19/complications, Female, Human medicine, Anticoagulants/adverse effects, Platelet Aggregation Inhibitors, Venous Thromboembolism/drug therapy
Abstract

Contains fulltext : 248713.pdf (Publisher’s version ) (Closed access) IMPORTANCE: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. MAIN OUTCOMES AND MEASURES: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. RESULTS: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). CONCLUSIONS AND RELEVANCE: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Published
2022

22. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial

Author

Hager, David N., Hooper, Michael H., Bernard, Gordon R., Busse, Laurence W., Ely, E. Wesley, Fowler, Alpha A., Gaieski, David F., Hall, Alex, Hinson, Jeremiah S., Jackson, James C., Kelen, Gabor D., Levine, Mark, Lindsell, Christopher J., Malone, Richard E., McGlothlin, Anna, Rothman, Richard E., Viele, Kert, Wright, David W., Sevransky, Jonathan E., and Martin, Greg S.

Published
2019
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23. Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer

Author

Infante, Jeffrey R., Patnaik, Amita, Verschraegen, Claire F., Olszanski, Anthony J., Shaheen, Montaser, Burris, Howard A., Tolcher, Anthony W., Papadopoulos, Kyriakos P., Beeram, Muralidhar, Hynes, Scott M., Leohr, Jennifer, Lin, Aimee Bence, Li, Lily Q., McGlothlin, Anna, Farrington, Daphne L., Westin, Eric H., and Cohen, Roger B.

Published
2017
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24. Effectiveness of Casirivimab-Imdevimab and Sotrovimab During a SARS-CoV-2 Delta Variant Surge

Author

Huang, David T., primary, McCreary, Erin K., additional, Bariola, J. Ryan, additional, Minnier, Tami E., additional, Wadas, Richard J., additional, Shovel, Judith A., additional, Albin, Debbie, additional, Marroquin, Oscar C., additional, Kip, Kevin E., additional, Collins, Kevin, additional, Schmidhofer, Mark, additional, Wisniewski, Mary Kay, additional, Nace, David A., additional, Sullivan, Colleen, additional, Axe, Meredith, additional, Meyers, Russell, additional, Weissman, Alexandra, additional, Garrard, William, additional, Peck-Palmer, Octavia M., additional, Wells, Alan, additional, Bart, Robert D., additional, Yang, Anne, additional, Berry, Lindsay R., additional, Berry, Scott, additional, Crawford, Amy M., additional, McGlothlin, Anna, additional, Khadem, Tina, additional, Linstrum, Kelsey, additional, Montgomery, Stephanie K., additional, Ricketts, Daniel, additional, Kennedy, Jason N., additional, Pidro, Caroline J., additional, Nakayama, Anna, additional, Zapf, Rachel L., additional, Kip, Paula L., additional, Haidar, Ghady, additional, Snyder, Graham M., additional, McVerry, Bryan J., additional, Yealy, Donald M., additional, Angus, Derek C., additional, and Seymour, Christopher W., additional

Published
2022
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25. PET-CR as a potential surrogate endpoint in untreated DLBCL: meta-analysis and implications for clinical trial design

Author

Broglio, Kristine, primary, Kostakoglu, Lale, additional, Ward, Carol, additional, Mattiello, Federico, additional, Sahin, Denis, additional, Nielsen, Tina, additional, McGlothlin, Anna, additional, Elliott, Corrine F., additional, Witzig, Thomas, additional, Sehn, Laurie H., additional, Trnĕný, Marek, additional, Vitolo, Umberto, additional, Martelli, Maurizio, additional, Foster, Margaret, additional, Wendelberger, Barbara, additional, Nowakowski, Grzegorz, additional, and Berry, Donald A., additional

Published
2022
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26. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Berry, Scott M, McArthur, Colin J, Neal, Matthew D, Hochman, Judith S, Webb, Steven A, Zarychanski, Ryan, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Kreuziger, Lisa Baumann, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, de Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Dzavik, Vladimir, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Kornblith, Aaron E, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Gregoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Lima, Felipe Gallego, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Lother, Sylvain A, Marten, Nicole, Marinez, Andrea Saud, Martinez, Mary, Garcia, Eduardo Mateos, Mavromichalis, Stavroula, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nicolau, Jose C, Nunez-Garcia, Brenda, Park, John J, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Pompilio, Mauricio, Quigley, John G, Rosenson, Robert S, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Santos, Mayler O, Satterwhite, Lewis, Saunders, Christina T, Schreiber, Jake, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Silva, Delcio G, Singhal, Aneesh B, Slutsky, Arthur S, Solvason, Dayna, Turner, Anne M, Van Bentum-Puijk, Wilma, van de Veerdonk, Frank L, van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zhong, Yongqi, Investigators, REMAP-CAP, Investigators, ACTIV-4a, Investigators, ATTACC, NIHR, National Institute for Health Research, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National Institutes of Health, NIH: 1OT2HL156812-01, AR7-162822, OTA-20-011, RP-2015-06-18, National Heart, Lung, and Blood Institute, NHLBI, Amgen, CancerCare Manitoba Foundation, CCMF, University of Manitoba, UM, Health Research Board, HRB: CTN 2014-012, Canadian Institutes of Health Research, CIHR: 158584, 447335, COVID-19, National Institute for Health Research, NIHR, European Commission, EC: 602525, FP7-HEALTH-2013-INNOVATION, National Health and Medical Research Council, NHMRC: APP1101719, APP1116530, Health Research Council of New Zealand, HRC: 16/631, Eisai, Ministère des Affaires Sociales et de la Santé: PHRC-20-0147, Université Pierre et Marie Curie, UPMC, Horizon 2020: 101003589, NIHR Imperial Biomedical Research Centre, BRC, Minderoo Foundation, REMAP-CAP was supported by the European Union through FP7-HEALTH-2013-INNOVATION: the Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium (grant 602525) and the Horizon 2020 research and innovation program: the Rapid European Covid-19 Emergency Research response (RECOVER) consortium (grant 101003589) and by grants from the Australian National Health and Medical Research Council (APP1101719 and APP1116530), the Health Research Council of New Zealand (16/631), the Canadian Institutes of Health Research (Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant 158584 and COVID-19 Rapid Research Operating Grant 447335), the U.K. National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Minderoo Foundation, Amgen, Eisai, the Global Coalition for Adaptive Research, and the Wellcome Trust Innovations Project (215522). The ATTACC platform was supported by grants from the Canadian Institutes of Health Research, LifeArc, Thistledown Foundation, Research Manitoba, CancerCare Manitoba Foundation, Victoria General Hospital Foundation, Ontario Ministry of Health, and the Peter Munk Cardiac Centre. The ACTIV-4a platform was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) and administered through OTA-20-011 and was supported in part by NIH agreement 1OT2HL156812-01. Dr. Goligher is the recipient of an Early Career Investigator award from the Canadian Institutes of Health Research (grant AR7-162822). Dr. Gordon is funded by an NIHR Research Professorship (RP-2015-06-18). Dr. Turgeon is funded by a Canada Research Chair-Tier 2. Dr. Zarychanski is the recipient of the Lyonel G. Israels Research Chair in Hematology (University of Manitoba)., Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, Investigators, REMAP-CAP, Investigators, ACTIV-4a, Investigators, ATTACC, REMAP-CAP Investigators, ACTIV-4a Investigators, and ATTACC Investigators

Subjects
Male, covid-19, anticoagulation, adaptive platform trial, [SDV]Life Sciences [q-bio], Critical Illness, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Hemorrhage, 030204 cardiovascular system & hematology, heparin, COVID-19/drug therapy, 03 medical and health sciences, 0302 clinical medicine, Medicine, General & Internal, Hemorrhage/chemically induced, General & Internal Medicine, Odds Ratio, thrombosis, covid-19, Humans, 030212 general & internal medicine, Hospital Mortality, Treatment Failure, Heparin/administration & dosage, anticoagulation, 11 Medical and Health Sciences, Aged, Anticoagulants/administration & dosage, Science & Technology, Thrombosis/prevention & control, Heparin, low molecular weight heparin, Anticoagulants, COVID-19, Thrombosis, General Medicine, Middle Aged, Respiration, Artificial, 3. Good health, COVID-19 Drug Treatment, critical care, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Logistic Models, ACTIV-4a Investigators, Female, Human medicine, ATTACC Investigators, REMAP-CAP Investigators, Covid-19, Life Sciences & Biomedicine
Abstract

BACKGROUNDThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.METHODSIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.RESULTSThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support–free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio CONCLUSIONSIn critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707. opens in new tab, NCT04505774. opens in new tab, NCT04359277. opens in new tab, and NCT04372589. opens in new tab.)

Published
2021

27. Association of Subcutaneous or Intravenous Administration of Casirivimab and Imdevimab Monoclonal Antibodies With Clinical Outcomes in Adults With COVID-19

Author

McCreary, Erin K., primary, Bariola, J. Ryan, additional, Wadas, Richard J., additional, Shovel, Judith A., additional, Wisniewski, Mary Kay, additional, Adam, Michelle, additional, Albin, Debbie, additional, Minnier, Tami, additional, Schmidhofer, Mark, additional, Meyers, Russell, additional, Marroquin, Oscar C., additional, Collins, Kevin, additional, Garrard, William, additional, Berry, Lindsay R., additional, Berry, Scott, additional, Crawford, Amy M., additional, McGlothlin, Anna, additional, Linstrum, Kelsey, additional, Nakayama, Anna, additional, Montgomery, Stephanie K., additional, Snyder, Graham M., additional, Yealy, Donald M., additional, Angus, Derek C., additional, Kip, Paula L., additional, Seymour, Christopher W., additional, Huang, David T., additional, and Kip, Kevin E., additional

Published
2022
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28. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Author

Lawler, Patrick R, Golighe, Ewan C, Berge, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kah, Susan RN, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Angus, Derek C, McArthur, Colin J, Webb, Steven A, Farkouh, Michael E, Hochman, Judith S, Zarychanski, Ryan, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Kreuziger, Lisa Baumann, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadzw, Tamta, Coiffard, Benjamin, Costantini, Todd W, de Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Dzavik, Vladimir, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Garcia-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, Kin, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Krishnan, Vidya, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Gregoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Lima, Felipe Gallego, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Moreno, Jose L Lopez-Sendon, Lother, Sylvain A, Malhotra, Saurabh, Marcos, Miguel, Marinez, Andrea Saud, Marshall, John C, Marten, Nicole, Matthay, Michael A, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Moore, Steven C, Guerreor, Raquel Morillo, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nunez-Garcia, Brenda, Pandey, Ambarish, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Gonzalez, Yessica S Perez, Pompilio, Mauricio, Prekker, Matthew E, Quigley, John G, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Santos, Mayler Olombrada, Satterwhite, Lewis, Saunders, Christina T, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Jr, Silva Delcio G, Shankar-Hari, Manu, Sheehan, John P, Singhal, Aneesh B, Solvaso, Dayna, Stanworth, Simon J, Tritschler, Tobias, Turner, Anne M, Van Bentum-Puijk, Wilma, van de Veerdonk, Frank L, van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Wells, Bryan J, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zampieri, Fernando G, Investigators, ATTACC, Investigators, ACTIV-4a, Investigators, REMAP-CAP, Investigators, ATTACC, Investigators, ACTIV-4a, Investigators, REMAP-CAP, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 215522, AR7-162822, CS-2016-16-011, RP-2015-06-18, National Institutes of Health, NIH: 1OT2HL156812-01, OTA-20-011, UL1TR001445, National Heart, Lung, and Blood Institute, NHLBI, Breast Cancer Research Foundation, BCRF, National Center for Advancing Translational Sciences, NCATS, New York University, NYU, Medical Center, University of Pittsburgh, CancerCare Manitoba Foundation, CCMF, University of Manitoba, UM, Health Research Board, HRB: CTN 2014-012, Canadian Institutes of Health Research, CIHR, National Institute for Health Research, NIHR, European Commission, EC: 602525, FP7-HEALTH-2013-INNOVATION, National Health and Medical Research Council, NHMRC: APP1101719, APP1116530, Health Research Council of New Zealand, HRC: 158584, 16/631, 447335, Canada Research Chairs, Eisai, Ministère des Affaires Sociales et de la Santé: PHRC-20-0147, Horizon 2020: 101003589, NIHR Imperial Biomedical Research Centre, BRC, Minderoo Foundation, The ATTACC platform was supported by grants from the Canadian Institutes of Health Research, LifeArc Foundation, Thistledown Foundation, Research Manitoba, Ontario Ministry of Health, Peter Munk Cardiac Centre, CancerCare Manitoba Foundation, and Victoria General Hospital Foundation. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) (grant numbers, OTA-20-011 and 1OT2HL156812-01). The pilot program (PROTECT) was funded in part by a grant (UL1TR001445) from the New York University Clinical and Translational Science Award program, supported by the National Center for Advancing Translational Sciences of the NIH. The REMAP-CAP platform was supported by the European Union through FP7-HEALTH-2013-INNOVATION: the Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium (602525) and the Horizon 2020 research and innovation program: the Rapid European Covid-19 Emergency Research response (RECOVER) consortium (101003589), by the Australian National Health and Medical Research Council (APP1101719 and APP1116530), the Health Research Council of New Zealand (16/631), the Canadian Institutes of Health Research (Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant [158584] and Covid-19 Rapid Research Operating Grant [447335]), the U.K. National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the Learning While Doing Program at the University of Pittsburgh Medical Center, the Breast Cancer Research Foundation, the French Ministry of Health (PHRC-20-0147), the Minderoo Foundation, Am-gen, Eisai, the Global Coalition for Adaptive Research, and the Wellcome Trust Innovations Project (215522). Dr. Goligher is the recipient of an Early Career Investigator award from the Canadian Institutes of Health Research (grant AR7-162822). Dr. Gordon is supported by an NIHR Research Professorship (RP-2015-06-18), Dr. Shankar-Hari by an NIHR Clinician Scientist Fellowship (CS-2016-16-011), and Dr. Turgeon by a Canada Research Chair (Tier 2). Dr. Zarychanski is the recipient of the Lyonel G. Israels Research Chair in Hematology (University of Manitoba)., Listed are data that were included in the analysis involving patients with moderate severity of coronavirus disease 2019 (Covid-19). The denominators of patients in the anticoagulation group and the thrombophylaxis group are un-equal owing to response-adaptive randomization. The baseline characteristics of the patients according to d-dimer level are provided in Table S2 in the Supplementary Appendix. To convert the values for creatinine to micromoles per liter, multiply by 88.4. ULN denotes upper limit of the normal range. † Race or ethnic group was reported by the patients. ‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. § Severe cardiovascular disease was defined as a baseline history of heart failure, myocardial infarction, coronary artery disease, peripheral arterial disease, or cerebrovascular disease (stroke or transient ischemic attack) in the ATTACC (Antithrombotic Therapy to Ameliorate Complications of Covid-19) and ACTIV-4a (A Multicenter, Adaptive, Ran-domized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19) platforms and as a baseline history of New York Heart Association class IV symptoms in the REMAP-CAP platform (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia). ¶ Chronic respiratory disease was defined as a baseline history of asthma, chronic obstructive pulmonary disease, bron-chiectasis, interstitial lung disease, primary lung cancer, pulmonary hypertension, active tuberculosis, or the receipt of home oxygen therapy. ‖ Not listed are 74 patients who were coenrolled in the REMAP-CAP Antiplatelet Domain (39 in the anticoagulation group and 35 in the thromboprophylaxis group). ** In REMAP-CAP, levels of oxygen support (including no support) below the level of high-flow nasal cannula were not reported. †† The relative proportion of patients who were randomly assigned in each platform was imbalanced owing to imple-mentation of response-adaptive randomization in ATTACC on December 15, 2020. ‡‡ A total of 215 patients who were enrolled in the ATTACC platform were funded by the ACTIV4a platform by the National Heart, Lung, and Blood Institute. §§ Other participating countries were Mexico, Nepal, Australia, the Netherlands, and Spain., ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, Lawler, Patrick R [0000-0001-5155-5071], Neal, Matthew D [0000-0001-8931-6236], McVerry, Bryan J [0000-0002-1175-4874], Carrier, Marc [0000-0001-8296-2972], Escobedo, Jorge [0000-0003-1942-7402], Huang, David T [0000-0001-7649-1633], Bradbury, Charlotte A [0000-0001-5248-8165], Houston, Brett L [0000-0002-8776-4083], Kornblith, Lucy Z [0000-0002-1861-9691], Kim, Keri S [0000-0002-8480-4801], Gordon, Anthony C [0000-0002-0419-547X], Higgins, Alisa M [0000-0001-8295-7559], Aday, Aaron W [0000-0001-6243-3432], Aryal, Diptesh [0000-0002-1431-8293], Baumann Kreuziger, Lisa [0000-0002-1171-0548], Beane, Abi [0000-0001-7046-1580], Coiffard, Benjamin [0000-0002-8896-5346], Derde, Lennie PG [0000-0002-3577-5629], Detry, Michelle A [0000-0002-2794-1439], Estcourt, Lise J [0000-0003-4309-9162], Everett, Brendan M [0000-0002-6331-5224], Galen, Benjamin T [0000-0001-8172-258X], Girard, Timothy D [0000-0002-9833-4871], Godoy, Lucas C [0000-0001-6171-1269], Greenstein, Yonatan Y [0000-0002-5718-4408], Haniffa, Rashan [0000-0002-8288-449X], Hanna, George [0000-0001-8737-3843], Hegde, Sheila M [0000-0001-8157-8899], Hendrickson, Carolyn M [0000-0003-4662-2385], Hite, R Duncan [0000-0002-2625-8750], Hindenburg, Alexander A [0000-0002-1232-2168], Horvat, Christopher M [0000-0002-1593-2252], Jacobson, Jeffrey R [0000-0001-8929-994X], Kim, Yuri [0000-0001-5978-5779], King, Andrew J [0000-0002-9809-0563], Kutcher, Matthew E [0000-0003-4566-5359], Lima, Felipe Gallego [0000-0003-1204-5743], Lopez-Sendon Moreno, Jose L [0000-0001-9414-3990], Marcos, Miguel [0000-0003-1269-4487], McGlothlin, Anna [0000-0002-9079-6166], Mouncey, Paul R [0000-0002-8510-8517], Nunez-Garcia, Brenda [0000-0002-0355-4557], Parnia, Sam [0000-0002-6158-4404], Quigley, John G [0000-0003-3116-4545], Saunders, Christina T [0000-0003-4325-9568], Shankar-Hari, Manu [0000-0002-5338-2538], Sheehan, John P [0000-0002-4328-2613], Tritschler, Tobias [0000-0002-8775-0511], Yuriditsky, Eugene [0000-0003-2263-9297], Zampieri, Fernando G [0000-0001-9315-6386], Angus, Derek C [0000-0002-7026-5181], Apollo - University of Cambridge Repository, NIHR, and National Institute for Health Research

Subjects
Male, covid-19, anticoagulation, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, heparin, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Hemorrhage/chemically induced, 030212 general & internal medicine, Hospital Mortality, Heparin/administration & dosage, anticoagulation, 11 Medical and Health Sciences, Anticoagulants/administration & dosage, Thrombosis/prevention & control, low molecular weight heparin, General Medicine, Heparin, Middle Aged, Thrombosis, Patient Discharge, 3. Good health, Coagulation, Original Article, Female, ATTACC Investigators, medicine.symptom, Covid-19, Life Sciences & Biomedicine, medicine.drug, Adult, medicine.medical_specialty, medicine.drug_class, adaptive platform trial, Low molecular weight heparin, Inflammation, Hemorrhage, COVID-19/drug therapy, 03 medical and health sciences, Medicine, General & Internal, General & Internal Medicine, medicine, Humans, Intensive care medicine, Survival analysis, Aged, Science & Technology, business.industry, SARS-CoV-2, Anticoagulants, COVID-19, Odds ratio, Heparin, Low-Molecular-Weight, medicine.disease, Survival Analysis, COVID-19 Drug Treatment, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Heparin, Low-Molecular-Weight/therapeutic use, ACTIV-4a Investigators, Human medicine, REMAP-CAP Investigators, business
Abstract

BACKGROUNDThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.METHODSIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.RESULTSThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.CONCLUSIONSIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589. opens in new tab, NCT04505774. opens in new tab, NCT02735707. opens in new tab, and NCT04359277. opens in new tab.)

Published
2021

29. Effectiveness of casirivimab and imdevimab, and sotrovimab during Delta variant surge: a prospective cohort study and comparative effectiveness randomized trial

Author

Huang, David T., primary, McCreary, Erin K., additional, Bariola, J. Ryan, additional, Minnier, Tami E., additional, Wadas, Richard J., additional, Shovel, Judith A., additional, Albin, Debbie, additional, Marroquin, Oscar C., additional, Kip, Kevin E., additional, Collins, Kevin, additional, Schmidhofer, Mark, additional, Wisniewski, Mary Kay, additional, Nace, David A., additional, Sullivan, Colleen, additional, Axe, Meredith, additional, Meyers, Russell, additional, Weissman, Alexandra, additional, Garrard, William, additional, Peck-Palmer, Octavia M., additional, Wells, Alan, additional, Bart, Robert D., additional, Yang, Anne, additional, Berry, Lindsay R., additional, Berry, Scott, additional, Crawford, Amy M., additional, McGlothlin, Anna, additional, Khadem, Tina, additional, Linstrum, Kelsey, additional, Montgomery, Stephanie K., additional, Ricketts, Daniel, additional, Kennedy, Jason N., additional, Pidro, Caroline J., additional, Zapf, Rachel L., additional, Kip, Paula L., additional, Haidar, Ghady, additional, Snyder, Graham M., additional, McVerry, Bryan J., additional, Yealy, Donald M., additional, Angus, Derek C., additional, and Seymour, Christopher W., additional

Published
2021
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30. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author

Writing Committee for the REMAP-CAP Investigators, Estcourt, Lise J, Turgeon, Alexis F, McQuilten, Zoe K, McVerry, Bryan J, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Arnold, Donald M, Beane, Abigail, Bégin, Philippe, van Bentum-Puijk, Wilma, Berry, Lindsay R, Bhimani, Zahra, Birchall, Janet E, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Buxton, Meredith, Callum, Jeannie L, Chassé, Michaël, Cheng, Allen C, Cove, Matthew E, Daly, James, Derde, Lennie, Detry, Michelle A, De Jong, Menno, Evans, Amy, Fergusson, Dean A, Fish, Matthew, Fitzgerald, Mark, Foley, Claire, Goossens, Herman, Gordon, Anthony C, Gosbell, Iain B, Green, Cameron, Haniffa, Rashan, Harvala, Heli, Higgins, Alisa M, Hills, Thomas E, Hoad, Veronica C, Horvat, Christopher, Huang, David T, Hudson, Cara L, Ichihara, Nao, Laing, Emma, Lamikanra, Abigail A, Lamontagne, François, Lawler, Patrick R, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, MacLennan, Sheila, Marshall, John, McAuley, Daniel F, McDyer, John F, McGlothlin, Anna, McGuinness, Shay, Miflin, Gail, Montgomery, Stephanie, Mouncey, Paul R, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane C, Priddee, Nicole, Purcell, Damian FJ, Reyes, Luis F, Richardson, Peter, Robitaille, Nancy, Rowan, Kathryn M, Rynne, Jennifer, Saito, Hiroki, Santos, Marlene, Saunders, Christina T, Serpa Neto, Ary, Seymour, Christopher W, Silversides, Jon A, Tinmouth, Alan A, Triulzi, Darrell J, Turner, Anne M, van de Veerdonk, Frank, Walsh, Timothy S, Wood, Erica M, Berry, Scott, Lewis, Roger J, Menon, David K, McArthur, Colin, Zarychanski, Ryan, Angus, Derek C, Webb, Steve A, Roberts, David J, Shankar-Hari, Manu, Menon, David [0000-0002-3228-9692], Apollo - University of Cambridge Repository, Investigators, Writing Committee for the REMAP-CAP, Writing Comm REMAP-CAP Investigators, Hôpital Raymond Poincaré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National Institutes of Health, NIH, National Institute of Child Health and Human Development, NICHD, Pittsburgh Foundation, Breast Cancer Research Foundation, BCRF, Bristol-Myers Squibb, BMS, GlaxoSmithKline, GSK, Medtronic, Baxter International, Manitoba Medical Service Foundation, MMSF, CancerCare Manitoba Foundation, CCMF, Wellcome Trust, WT, University of Manitoba, UM, Health Research Board, HRB: PHRC-20-0147, National Blood Authority, NBA, Llywodraeth Cymru, Translational Breast Cancer Research Consortium, TBCRC, Canadian Institutes of Health Research, IRSC: 158584, CTN 2014-012, Medical Research Council, MRC, National Institute for Health Research, NIHR, Department of Health and Social Care, DH, European Commission, EC: APP194811, National Heart and Lung Institute, NHLI, National Health and Medical Research Council, NHMRC: 2015-06-18, 2016-16-011, APP1101719, APP2002132, Health Research Council of New Zealand, HRC: 16/631, 447335, Monash University, MU, Ministère des Affaires Sociales et de la Santé: 215522, Seventh Framework Programme, FP7, Université Pierre et Marie Curie, UPMC, Innovate UK, Horizon 2020, Pharmaceuticals Bayer, Minderoo Foundation, Dr Fitzgerald reported receiving grants from the PREPARE Network and the European Commission. Dr Gordon reported receiving grants from the National Institute for Health Research and receiving personal fees from 30 Respiratory, GlaxoSmithKline, and Bristol Myers Squibb. Dr Gosbell reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Haniffa reported receiving grants from the Wellcome Trust Innovations Project, the Minderoo Foundation, and the UK Research and Innovation African Critical Care Registry Network. Dr Higgins reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the National Blood Authority. Dr Hills reported receiving grants from the Health Research Council of New Zealand. Dr Hoad reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Horvat reported receiving grants from the National Institute of Child Health and Human Development. Dr Huang reported receiving grants from the Breast Cancer Research Foundation. Dr Lamontagne reported receiving grants from the Canadian Institutes of Health Research. Dr Lawler reported receiving consulting fees from Novartis, Coronna LLC, and Brigham and Women’s Hospital, receiving royalties from McGraw-Hill Publishing, and receiving grants from the Canadian Institutes of Health Research, the LifeArc Foundation, the National Institutes of Health, the Peter Munk Cardiac Centre, the Ted Rogers Centre for Heart Research, the Thistledown Foundation, and the province of Ontario. Dr Lorenzi reported receiving personal fees from Berry Consultants. Dr Marshall reported receiving personal fees from AM-Pharma (data and safety monitoring board chair) and Critical Care Medicine (associate editor). Dr McAuley reported receiving personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, Vir Biotechnology, Faron Pharmaceuticals, and Sobi, receiving grants from the National Institute for Health Research, Wellcome Trust, Innovate UK, the Medical Research Council, and the Northern Ireland Health and Social Care Research and Development Division, and holding a patent for an anti-inflammatory treatment that was issued to Queen’s University Belfast. Dr McGlothlin reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Mr Mouncey reported receiving grants from the European Union, the PREPARE Network, the National Institute for Health Research, and European Union Horizon 2020. Dr Nichol reported receiving grants from the Health Research Board of Ireland and Baxter and receiving personal fees from AM-Pharma. Dr Parke reported receiving grants from Fisher and Paykel Healthcare Ltd. Ms Parker reported receiving grants from Monash University. Mr Richardson reported receiving funding from the Welsh government. Dr Rowan reported receiving grants from the European Commission and the National Institute for Health Research. Dr Saunders reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Dr Serpa Neto reported receiving personal fees from Drager and Endpoint Health. Dr Tinmouth reported receiving grants and personal fees from the Canadian Blood Services. Ms Turner reported receiving grants from the Health Research Council of New Zealand. Dr van de Veerdonk reported receiving personal fees from Gilead, Sobi, and GlaxoSmithKline. Dr Wood reported receiving grants from the Australian Medical Research Future Fund. Dr S. Berry reported being an employee of Berry Consultants with an ownership role. Dr Lewis reported being an employee of Berry Consultants. Dr Menon reported receiving grants from the National Institute for Health Research. Dr McArthur reported receiving grants from the Health Research Council of New Zealand. Dr Zarychanski reported receiving grants from the Canadian Institutes of Health Research, the University of Manitoba, LifeArc, the Thistledown Foundation, Research Manitoba, the CancerCare Manitoba Foundation, the Victoria General Hospital Foundation, the Peter Munk Cardiac Centre, and the Manitoba Medical Services Foundation. Dr Webb reported receiving grants from the National Health and Medical Research Council and the Minderoo Foundation. Dr Shankar-Hari reported receiving grants from the National Institute for Clinical Research. No other disclosures were reported., nonprofit sponsors: Monash University, Melbourne, Australia (Australasian sponsor), Utrecht Medical Center, Utrecht, the Netherlands (European sponsor), St Michael’s Hospital, Toronto, Ontario, Canada (Canadian sponsor), and the Global Coalition for Adaptive Research, San Francisco, California (US sponsor). This study was additionally funded by grant 602525 FP7-health-2013-innovation-1 from the European Union Platform for European Preparedness Against Reemerging Epidemics, grants APP1101719 and APP1116530 from the Australian National Health and Medical Research Council, grant APP2002132 from the Australian Medical Research Future Fund, grant 16/631 from the New Zealand Health Research Council, grant 447335 from the Canadian Institutes of Health Research COVID-19 Rapid Research, grant 158584 from the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program, grant CTN 2014-012 from the Health Research Board of Ireland, grant PHRC-20-0147 from the French Ministry of Health, and grant 215522 from the Wellcome Trust Innovations Project and funding from the National Institute for Health Research, the Department of Health and Social Care, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the National Institute for Health Research, the National Institute for Health Research Imperial Biomedical Research Centre, the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the Pittsburgh Foundation, and the Minderoo Foundation. The Australian government funds the Australian Red Cross Lifeblood for the provision of blood products and services. The collection of plasma in the United Kingdom was funded by European Union SoHo grants from the Department of Health and Social Care. Dr Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Dr McQuilten is supported by emerging leader fellowship APP194811 from the National Health and Medical Research Council. Dr Gordon is funded by research professorship 2015-06-18 from the National Institute for Health Research. Dr Shankar-Hari is funded by clinician scientist fellowship 2016-16-011 from the National Institute for Health Research., In Canada, the trial has been funded by the Canadian Institute of Health Research, Strategy for Patient-Oriented Research (CIHR-SPOR) Innovative Clinical Trials Program Grant (no. 158584) for CAD $1,497,200, for the recruitment of 300 patients., The Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium is funded by the European Union (FP7-HEALTH-2013-INNOVATION-1, grant number 602525). Within the PREPARE consortium, the trial has funding for the recruitment of approximately 4000 patients., REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands (RCC-Net)., Funding sources for the REMAP-CAP trial are specified in the core protocol documents. This domain has received domain-specific funding from the Australian Medical Research Future Fund (MRFF)., reported receiving grants from the National Institute for Health Research and European Union Horizon 2020. Dr Turgeon reported receiving grants from the Canadian Institutes of Health Research. Dr McQuilten reported receiving grants from the Australian Medical Research Future Fund. Dr McVerry reported receiving grants from the Pittsburgh Foundation, the Translational Breast Cancer Research Consortium, UPMC Learning While Doing Program, National Heart, Lung, and Blood Institute, and Bayer Pharmaceuticals and receiving personal fees from Boehringer Ingelheim. Dr Annane reported receiving grants from the French Ministry of Health and Solidarity. Dr Arnold reported receiving grants from the Canadian Institutes of Health Research. Ms Beane reported receiving grants and salary support from Wellcome Trust. Ms Bentum-Puijk reported receiving grants from the European Commission and the European Union. Dr L. Berry reported receiving grants from Berry Consultants. Dr Bradbury reported receiving personal fees from Lilly, Bristol Myers Squibb, Pfizer, Bayer, Amgen, Novartis, Janssen, Portola Advisors, and Ablynx. Dr Buxton reported receiving personal fees from the Breast Cancer Research Foundation, Amgen, and Eisai. Dr Callum reported receiving grants from the Canadian Blood Services and Octapharma. Dr Cove reported receiving grants from National University Health System, receiving consulting fees from Medtronic and Baxter, and holding a US patent for removal of carbon dioxide via dialysis. Dr Daly reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Derde reported receiving grants from University Medical Center Utrecht, being a member of the COVID-19 guideline committee of the Surviving Sepsis Campaign/ European Society of Intensive Care Medicine and European Society of Intensive Care Medicine COVID-19 taskforce, and serving as chair of the Dutch intensivists taskforce acute infectious threats. Dr Detry reported receiving grants from the European Union Platform for European Preparedness Against Reemerging Epidemics (PREPARE) consortium, the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the UPMC Learning While Doing Program. Dr De Jong reported receiving personal fees from Roche Scientific, Shionogi Scientific, and Janssen., The current regions are: x Europe, with funding from a European Union FP7 grant (FP7-HEALTH-2013-INNOVATION-1, grant number 602525), to support the enrollment of 4000 participants. This funding terminates in 2021. x Australia and New Zealand. In Australia the project has received funding from a NHMRC Project Grant (APP1101719), to support the enrollment of 2000 participants. This funding terminates in December 2021, although some extension may be feasible. In New Zealand the project has received funding from a HRC Programme Grant (16/631), to support the enrollment of 800 participants. This funding terminates in November 2021. x Canada. In Canada the project has received funding for a CIHR grant (158584), to support the enrollment of 300 participants. This funding terminates in 2022. x United States. In the US, funding has been received from UPMC health system for recruitment internally at all UPMC hospitals (>40) and to support a US regional coordinating center. Philanthropic support is being provided through GCAR. Additional funds are being pursued., The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Trials Group, the Irish Critical Care, European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), NIHR, National Institute for Health Research, Medical Microbiology and Infection Prevention, AII - Infectious diseases, and Intensive Care Medicine

Subjects
Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, Logistic regression, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Critical Illness/therapy, Vasoconstrictor Agents, 030212 general & internal medicine, Hospital Mortality, Treatment Failure, 11 Medical and Health Sciences, Original Investigation, Mortality rate, General Medicine, Middle Aged, Intensive care unit, Writing Committee for the REMAP-CAP Investigators, 3. Good health, Female, Life Sciences & Biomedicine, COVID-19/therapy, Adult, medicine.medical_specialty, Randomization, Respiration, Artificial/statistics & numerical data, Critical Illness, ABO Blood-Group System, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, General & Internal Medicine, medicine, Humans, Adverse effect, COVID-19 Serotherapy, Aged, Mechanical ventilation, Science & Technology, business.industry, Immunization, Passive, Vasoconstrictor Agents/therapeutic use, COVID-19, Odds ratio, Length of Stay, Respiration, Artificial, Logistic Models, Human medicine, business
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 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

Published
2021

33. Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.

Author

Tong, Steven Y C, Mora, Jocelyn, Bowen, Asha C, Cheng, Matthew P, Daneman, Nick, Goodman, Anna L, Heriot, George S, Lee, Todd C, Lewis, Roger J, Lye, David C, Mahar, Robert K, Marsh, Julie, McGlothlin, Anna, McQuilten, Zoe, Morpeth, Susan C, Paterson, David L, Price, David J, Roberts, Jason A, Robinson, J Owen, and Hal, Sebastiaan J van

Subjects
CLINICAL trials, HUMAN research subjects, COMMUNICABLE diseases, MEDICAL protocols, STAPHYLOCOCCAL diseases, STATISTICAL sampling
Abstract

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%–30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes. [ABSTRACT FROM AUTHOR]

Published
2022
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34. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, de Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Grégoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Gallego Lima, Felipe, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Lother, Sylvain A, Marten, Nicole, Saud Marinez, Andréa, Martinez, Mary, Mateos Garcia, Eduardo, Mavromichalis, Stavroula, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nicolau, Jose C, Nunez-Garcia, Brenda, Park, John J, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Pompilio, Mauricio, Quigley, John G, Rosenson, Robert S, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Santos, Mayler O, Satterwhite, Lewis, Saunders, Christina T, Schreiber, Jake, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Silva, Delcio G, Singhal, Aneesh B, Slutsky, Arthur S, Solvason, Dayna, Stanworth, Simon J, Turner, Anne M, van Bentum-Puijk, Wilma, van de Veerdonk, Frank L, van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zhong, Yongqi, Berry, Scott M, McArthur, Colin J, Neal, Matthew D, Hochman, Judith S, Webb, Steven A, Zarychanski, Ryan, Bradbury, Charlotte A [0000-0001-5248-8165], McVerry, Bryan J [0000-0002-1175-4874], Lawler, Patrick R [0000-0001-5155-5071], Carrier, Marc [0000-0001-8296-2972], Kim, Keri S [0000-0002-8480-4801], Houston, Brett L [0000-0002-8776-4083], Cushman, Mary [0000-0002-7871-6143], Tritschler, Tobias [0000-0002-8775-0511], Godoy, Lucas C [0000-0001-6171-1269], Gordon, Anthony C [0000-0002-0419-547X], Ahuja, Tania [0000-0003-1833-4124], Aryal, Diptesh [0000-0002-1431-8293], Baumann Kreuziger, Lisa [0000-0002-1171-0548], Beane, Abi [0000-0001-7046-1580], Coiffard, Benjamin [0000-0002-8896-5346], Detry, Michelle A [0000-0002-2794-1439], Escobedo, Jorge [0000-0003-1942-7402], Estcourt, Lise J [0000-0003-4309-9162], Everett, Brendan M [0000-0002-6331-5224], Fu, Zhuxuan [0000-0002-9190-195X], Galen, Benjamin T [0000-0001-8172-258X], Girard, Timothy D [0000-0002-9833-4871], Greenstein, Yonatan Y [0000-0002-5718-4408], Haniffa, Rashan [0000-0002-8288-449X], Hegde, Sheila M [0000-0001-8157-8899], Hendrickson, Carolyn M [0000-0003-4662-2385], Higgins, Alisa M [0000-0001-8295-7559], Hindenburg, Alexander A [0000-0002-1232-2168], Horvat, Christopher M [0000-0002-1593-2252], Huang, David T [0000-0001-7649-1633], Jacobson, Jeffrey R [0000-0001-8929-994X], Kim, Yuri [0000-0001-5978-5779], King, Andrew J [0000-0002-9809-0563], Kutcher, Matthew E [0000-0003-4566-5359], Leifer, Eric S [0000-0001-6888-8307], Litton, Edward [0000-0002-5125-6829], Mateos Garcia, Eduardo [0000-0002-0904-4056], Mouncey, Paul R [0000-0002-8510-8517], Nunez-Garcia, Brenda [0000-0002-0355-4557], Parnia, Sam [0000-0002-6158-4404], Quigley, John G [0000-0003-3116-4545], Saunders, Christina T [0000-0003-4325-9568], Yuriditsky, Eugene [0000-0003-2263-9297], Zhong, Yongqi [0000-0002-4042-7450], Neal, Matthew D [0000-0001-8931-6236], and Apollo - University of Cambridge Repository

Subjects
Male, Heparin, Critical Illness, Anticoagulants, COVID-19, Hemorrhage, Thrombosis, Middle Aged, Respiration, Artificial, COVID-19 Drug Treatment, Logistic Models, Odds Ratio, Humans, Female, Hospital Mortality, Treatment Failure, Aged
Abstract

BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

Published
2021

35. Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial

Author

Hergenroeder, Georgene W., primary, Yokobori, Shoji, additional, Choi, Huimahn Alex, additional, Schmitt, Karl, additional, Detry, Michelle A., additional, Schmitt, Lisa H., additional, McGlothlin, Anna, additional, Puccio, Ava M., additional, Jagid, Jonathan, additional, Kuroda, Yasuhiro, additional, Nakamura, Yukihiko, additional, Suehiro, Eiichi, additional, Ahmad, Faiz, additional, Viele, Kert, additional, Wilde, Elisabeth A., additional, McCauley, Stephen R., additional, Kitagawa, Ryan S., additional, Temkin, Nancy R., additional, Timmons, Shelly D., additional, Diringer, Michael N., additional, Dash, Pramod K., additional, Bullock, Ross, additional, Okonkwo, David O., additional, Berry, Donald A., additional, and Kim, Dong H., additional

Published
2021
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36. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report

Author

Gordon, Anthony C., Mouncey, Paul R., Al-Beidh, Farah, Rowan, Kathryn M., Nichol, Alistair D., Arabi, Yaseen M., Annane, Djillali, Beane, Abi, van Bentum-Puijk, Wilma, Berry, Lindsay R., Bhimani, Zahra, Bonten, Marc J.M., Bradbury, Charlotte A., Brunkhorst, Frank M., Buzgau, Adrian, Cheng, Allen C., Detry, Michelle A., Duffy, Eamon J., Estcourt, Lise J., Fitzgerald, Mark, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa M., Hills, Thomas E., Horvat, Christopher M., Lamontagne, Francois, Lawler, Patrick R., Leavis, Helen L., Linstrum, Kelsey M., Litton, Edward, Lorenzi, Elizabeth, Marshall, John C., Mayr, Florian B., McAuley, Danny, McGlothlin, Anna, McGuinness, Shay P, McVerry, Bryan J., Montgomery, Stephanie K., Morpeth, Susan C., Murthy, Srinivas, Orr, Katrina, Parke, Rachael L., Parker, Jane C., Patanwala, Asad E., Pettilä, Ville, Rademaker, Emma, Santos, Marlene S., Saunders, Christina T., Seymour, Christopher W., Shankar-Hari, Manu, Sligl, Wendy I., Turgeon, Alexis F., Turner, Anne M., van de Veerdonk, Frank L., Zarychanski, Ryan, Green, Cameron, Lewis, Roger J., Angus, Derek C., McArthur, Colin J., Berry, Scott, Webb, Steve A., and Derde, Lennie P.G.

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, COVID-19, Odds ratio, Intensive care unit, law.invention, Coronavirus, Sarilumab, chemistry.chemical_compound, Tocilizumab, chemistry, Interquartile range, law, Intensive care, Internal medicine, Interleukin-6 receptor, Medicine, business
Abstract

BackgroundThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.MethodsWe evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility.ResultsTocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] −1, 16), 11 (IQR 0, 16) and 0 (IQR −1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists.ConclusionsIn critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.govnumber:NCT02735707)

Published
2021

39. Sutureless versus conventional bioprostheses for aortic valve replacement in severe symptomatic aortic valve stenosis

Author

Fischlein, Theodor, primary, Folliguet, Thierry, additional, Meuris, Bart, additional, Shrestha, Malakh L., additional, Roselli, Eric E., additional, McGlothlin, Anna, additional, Kappert, Utz, additional, Pfeiffer, Steffen, additional, Corbi, Pierre, additional, Lorusso, Roberto, additional, Fabre, Olivier, additional, Pinaud, Frederic, additional, Troise, Giovanni, additional, Kueri, Sami, additional, Siepe, Matthias, additional, Bonaros, Nikolaos, additional, Tan, Erwin, additional, Andreas, Martin, additional, García-Puente, Julio, additional, Voisine, Pierre, additional, Rega, Filip, additional, Girdauskas, Evaldas, additional, Berastegui, Elisabet, additional, Hanke, Thorsten, additional, Kats, Suzanne, additional, Blasio, Andrea, additional, Muneretto, Claudio, additional, Repossini, Alberto, additional, Tribastone, Salvatore, additional, De Kerchove, Laurent, additional, Mikus, Elisa, additional, Solinas, Marco, additional, Rambaldini, Manfredo, additional, Chocron, Sidney, additional, De Bock, Dina, additional, Wang, Shaohua, additional, Grabenwoeger, Martin, additional, Raanani, Ehud, additional, Glauber, Mattia, additional, Maluenda, Gabriel, additional, Ramlawi, Basel, additional, Bouchard, Denis, additional, Johnston, Douglas, additional, Diegeler, Anno, additional, Bitran, Daniel, additional, Teoh, Kevin, additional, Vincentelli, André, additional, Castillo, José Cuenca, additional, Albat, Bernard, additional, Oberwalder, Peter, additional, Ramchandani, Mahesh, additional, and Heimansohn, David, additional

Published
2021
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40. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19:The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

Author

Angus, Derek C, Derde, Lennie, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Beane, Abigail, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen C, de Jong, Menno, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Higgins, Alisa M, Horvat, Christopher, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Lawler, Patrick R, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, McAuley, Daniel, McGlothin, Anna, McGuinness, Shay, McVerry, Bryan, Montgomery, Stephanie, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane, Rowan, Kathryn, Sanil, Ashish, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Turner, Anne, van de Veerdonk, Frank, Venkatesh, Balasubramanian, Zarychanski, Ryan, Berry, Scott, Lewis, Roger J, McArthur, Colin, Webb, Steven A, Gordon, Anthony C, Writing Committee for the REMAP-CAP Investigators, Angus, Derek, Cheng, Allen, De Jong, Menno, Gordon, Anthony, Lawler, Patrick, Webb, Steve, Campbell, Lewis, Forbes, Andrew, Gattas, David, Heritier, Stephane, Higgins, Lisa, Peake, Sandra, Presneill, Jeffrey, Seppelt, Ian, Trapani, Tony, Young, Paul, Bagshaw, Sean, Daneman, Nick, Ferguson, Niall, Misak, Cheryl, Hullegie, Sebastiaan, Pletz, Mathias, Rohde, Gernot, Rowan, Kathy, Alexander, Brian, Basile, Kim, Girard, Timothy, Huang, David, Vates, Jennifer, Beasley, Richard, Fowler, Robert, McGloughlin, Steve, Morpeth, Susan, Paterson, David, Venkatesh, Bala, Uyeki, Tim, Baillie, Kenneth, Duffy, Eamon, Fowler, Rob, Hills, Thomas, Orr, Katrina, Patanwala, Asad, Tong, Steve, Netea, Mihai, Bihari, Shilesh, Carrier, Marc, Fergusson, Dean, Goligher, Ewan, Haidar, Ghady, Hunt, Beverley, Kumar, Anand, Laffan, Mike, Lawless, Patrick, Lother, Sylvain, McCallum, Peter, Middeldopr, Saskia, McQuilten, Zoe, Neal, Matthew, Pasi, John, Schutgens, Roger, Stanworth, Simon, Turgeon, Alexis, Weissman, Alexandra, Adhikari, Neill, Anstey, Matthew, Brant, Emily, de Man, Angelique, Lamonagne, Francois, Masse, Marie-Helene, Udy, Andrew, Arnold, Donald, Begin, Phillipe, Charlewood, Richard, Chasse, Michael, Coyne, Mark, Cooper, Jamie, Daly, James, Gosbell, Iain, Harvala-Simmonds, Heli, Hills, Tom, MacLennan, Sheila, Menon, David, McDyer, John, Pridee, Nicole, Roberts, David, Shankar-Hari, Manu, Thomas, Helen, Tinmouth, Alan, Triulzi, Darrell, Walsh, Tim, Wood, Erica, Calfee, Carolyn, O’Kane, Cecilia, Shyamsundar, Murali, Sinha, Pratik, Thompson, Taylor, Young, Ian, Bihari, Shailesh, Hodgson, Carol, Laffey, John, McAuley, Danny, Orford, Neil, Neto, Ary, Lewis, Roger, McGlothlin, Anna, Miller, Eliza, Singh, Vanessa, Zammit, Claire, van Bentum Puijk, Wilma, Bouwman, Wietske, Mangindaan, Yara, Parker, Lorraine, Peters, Svenja, Rietveld, Ilse, Raymakers, Kik, Ganpat, Radhika, Brillinger, Nicole, Markgraf, Rene, Ainscough, Kate, Brickell, Kathy, Anjum, Aisha, Lane, Janis-Best, Richards-Belle, Alvin, Saull, Michelle, Wiley, Daisy, Bion, Julian, Connor, Jason, Gates, Simon, Manax, Victoria, van der Poll, Tom, Reynolds, John, van Beurden, Marloes, Effelaar, Evelien, Schotsman, Joost, Boyd, Craig, Harland, Cain, Shearer, Audrey, Wren, Jess, Clermont, Giles, Garrard, William, Kalchthaler, Kyle, King, Andrew, Ricketts, Daniel, Malakoutis, Salim, Marroquin, Oscar, Music, Edvin, Quinn, Kevin, Cate, Heidi, Pearson, Karen, Collins, Joanne, Hanson, Jane, Williams, Penny, Jackson, Shane, Asghar, Adeeba, Dyas, Sarah, Sutu, Mihaela, Murphy, Sheenagh, Williamson, Dawn, Mguni, Nhlanhla, Potter, Alison, Porter, David, Goodwin, Jayne, Rook, Clare, Harrison, Susie, Williams, Hannah, Campbell, Hilary, Lomme, Kaatje, Williamson, James, Sheffield, Jonathan, van’t Hoff, Willian, McCracken, Phobe, Young, Meredith, Board, Jasmin, Mart, Emma, Knott, Cameron, Smith, Julie, Boschert, Catherine, Affleck, Julia, Ramanan, Mahesh, D’Souza, Ramsy, Pateman, Kelsey, Shakih, Arif, Cheung, Winston, Kol, Mark, Wong, Helen, Shah, Asim, Wagh, Atul, Simpson, Joanne, Duke, Graeme, Chan, Peter, Cartner, Brittney, Hunter, Stephanie, Laver, Russell, Shrestha, Tapaswi, Regli, Adrian, Pellicano, Annamaria, McCullough, James, Tallott, Mandy, Kumar, Nikhil, Panwar, Rakshit, Brinkerhoff, Gail, Koppen, Cassandra, Cazzola, Federica, Brain, Matthew, Mineall, Sarah, Fischer, Roy, Biradar, Vishwanath, Soar, Natalie, White, Hayden, Estensen, Kristen, Morrison, Lynette, Smith, Joanne, Cooper, Melanie, Health, Monash, Shehabi, Yahya, Al-Bassam, Wisam, Hulley, Amanda, Whitehead, Christina, Lowrey, Julie, Gresha, Rebecca, Walsham, James, Meyer, Jason, Harward, Meg, Venz, Ellen, Williams, Patricia, Kurenda, Catherine, Smith, Kirsy, Smith, Margaret, Garcia, Rebecca, Barge, Deborah, Byrne, Deborah, Byrne, Kathleen, Driscoll, Alana, Fortune, Louise, Janin, Pierre, Yarad, Elizabeth, Hammond, Naomi, Bass, Frances, Ashelford, Angela, Waterson, Sharon, Wedd, Steve, McNamara, Robert, Buhr, Heidi, Coles, Jennifer, Schweikert, Sacha, Wibrow, Bradley, Rauniyar, Rashmi, Myers, Erina, Fysh, Ed, Dawda, Ashlish, Mevavala, Bhaumik, Litton, Ed, Ferrier, Janet, Nair, Priya, Buscher, Hergen, Reynolds, Claire, Santamaria, John, Barbazza, Leanne, Homes, Jennifer, Smith, Roger, Murray, Lauren, Brailsford, Jane, Forbes, Loretta, Maguire, Teena, Mariappa, Vasanth, Smith, Judith, Simpson, Scott, Maiden, Matthew, Bone, Allsion, Horton, Michelle, Salerno, Tania, Sterba, Martin, Geng, Wenli, Depuydt, Pieter, De Waele, Jan, De Bus, Liesbet, Fierens, Jan, Bracke, Stephanie, Reeve, Brenda, Dechert, William, Chassé, Michaël, Carrier, François Martin, Boumahni, Dounia, Benettaib, Fatna, Ghamraoui, Ali, Bellemare, David, Cloutier, Ève, Francoeur, Charles, Lamontagne, François, D’Aragon, Frédérick, Carbonneau, Elaine, Leblond, Julie, Vazquez-Grande, Gloria, Marten, Nicole, Wilson, Maggie, Albert, Martin, Serri, Karim, Cavayas, Alexandros, Duplaix, Mathilde, Williams, Virginie, Rochwerg, Bram, Karachi, Tim, Oczkowski, Simon, Centofanti, John, Millen, Tina, Duan, Erick, Tsang, Jennifer, Patterson, Lisa, English, Shane, Watpool, Irene, Porteous, Rebecca, Miezitis, Sydney, McIntyre, Lauralyn, Brochard, Laurent, Burns, Karen, Sandhu, Gyan, Khalid, Imrana, Binnie, Alexandra, Powell, Elizabeth, McMillan, Alexandra, Luk, Tracy, Aref, Noah, Andric, Zdravko, Cviljevic, Sabina, Đimoti, Renata, Zapalac, Marija, Mirković, Gordan, Baršić, Bruno, Kutleša, Marko, Kotarski, Viktor, Vujaklija Brajković, Ana, Babel, Jakša, Sever, Helena, Dragija, Lidija, Kušan, Ira, Vaara, Suvi, Pettilä, Leena, Heinonen, Jonna, Kuitunen, Anne, Karlsson, Sari, Vahtera, Annukka, Kiiski, Heikki, Ristimäki, Sanna, Azaiz, Amine, Charron, Cyril, Godement, Mathieu, Geri, Guillaume, Vieillard-Baron, Antoine, Pourcine, Franck, Monchi, Mehran, Luis, David, Mercier, Romain, Sagnier, Anne, Verrier, Nathalie, Caplin, Cecile, Siami, Shidasp, Aparicio, Christelle, Vautier, Sarah, Jeblaoui, Asma, Fartoukh, Muriel, Courtin, Laura, Labbe, Vincent, Leparco, Cécile, Muller, Grégoire, Nay, Mai-Anh, Kamel, Toufik, Benzekri, Dalila, Jacquier, Sophie, Mercier, Emmanuelle, Chartier, Delphine, Salmon, Charlotte, Dequin, PierreFrançois, Schneider, Francis, Morel, Guillaume, L’Hotellier, Sylvie, Badie, Julio, Berdaguer, Fernando Daniel, Malfroy, Sylvain, Mezher, Chaouki, Bourgoin, Charlotte, Megarbane, Bruno, Voicu, Sebastian, Deye, Nicolas, Malissin, Isabelle, Sutterlin, Laetitia, Guitton, Christophe, Darreau, Cédric, Landais, Mickaël, Chudeau, Nicolas, Robert, Alain, Moine, Pierre, Heming, Nicholas, Maxime, Virginie, Bossard, Isabelle, Nicholier, Tiphaine Barbarin, Colin, Gwenhael, Zinzoni, Vanessa, Maquigneau, Natacham, Finn, André, Kreß, Gabriele, Hoff, Uwe, Friedrich Hinrichs, Carl, Nee, Jens, Hagel, Stefan, Ankert, Juliane, Kolanos, Steffi, Bloos, Frank, Petros, Sirak, Pasieka, Bastian, Kunz, Kevin, Appelt, Peter, Schütze, Bianka, Kluge, Stefan, Nierhaus, Axel, Jarczak, Dominik, Roedl, Kevin, Weismann, Dirk, Frey, Anna, Klinikum Neukölln, Vivantes, Reill, Lorenz, Distler, Michael, Maselli, Astrid, Bélteczki, János, Magyar, István, Fazekas, Ágnes, Kovács, Sándor, Szőke, Viktória, Szigligeti, Gábor, Leszkoven, János, Collins, Daniel, Breen, Patrick, Frohlich, Stephen, Whelan, Ruth, McNicholas, Bairbre, Scully, Michael, Casey, Siobhan, Kernan, Maeve, Doran, Peter, O’Dywer, Michael, Smyth, Michelle, Hayes, Leanne, Hoiting, Oscar, Peters, Marco, Rengers, Els, Evers, Mirjam, Prinssen, Anton, Bosch Ziekenhuis, Jeroen, Simons, Koen, Rozendaal, Wim, Polderman, F, de Jager, P, Moviat, M, Paling, A, Salet, A, Rademaker, Emma, Peters, Anna Linda, de Jonge, E, Wigbers, J, Guilder, E, Butler, M, Cowdrey, Keri-Anne, Newby, Lynette, Chen, Yan, Simmonds, Catherine, McConnochie, Rachael, Ritzema Carter, Jay, Henderson, Seton, Van Der Heyden, Kym, Mehrtens, Jan, Williams, Tony, Kazemi, Alex, Song, Rima, Lai, Vivian, Girijadevi, Dinu, Everitt, Robert, Russell, Robert, Hacking, Danielle, Buehner, Ulrike, Williams, Erin, Browne, Troy, Grimwade, Kate, Goodson, Jennifer, Keet, Owen, Callender, Owen, Martynoga, Robert, Trask, Kara, Butler, Amelia, Schischka, Livia, Young, Chelsea, Lesona, Eden, Olatunji, Shaanti, Robertson, Yvonne, José, Nuno, Amaro dos Santos Catorze, Teodoro, de Lima Pereira, Tiago Nuno Alfaro, Neves Pessoa, Lucilia Maria, Castro Ferreira, Ricardo Manuel, Pereira Sousa Bastos, Joana Margarida, Aysel Florescu, Simin, Stanciu, Delia, Zaharia, Miahela Florentina, Kosa, Alma Gabriela, Codreanu, Daniel, Marabi, Yaseen, Al Qasim, Eman, Moneer Hagazy, Mohamned, Al Swaidan, Lolowa, Arishi, Hatim, Muñoz-Bermúdez, Rosana, Marin-Corral, Judith, Salazar Degracia, Anna, Parrilla Gómez, Francisco, Mateo López, Maria Isabel, Rodriguez Fernandez, Jorge, Cárcel Fernández, Sheila, Carmona Flores, Rosario, León López, Rafael, de la Fuente Martos, Carmen, Allan, Angela, Polgarova, Petra, Farahi, Neda, McWilliam, Stephen, Hawcutt, Daniel, Rad, Laura, O’Malley, Laura, Whitbread, Jennifer, Kelsall, Olivia, Wild, Laura, Thrush, Jessica, Wood, Hannah, Austin, Karen, Donnelly, Adrian, Kelly, Martin, O’Kane, Sinéad, McClintock, Declan, Warnock, Majella, Johnston, Paul, Gallagher, Linda Jude, Mc Goldrick, Clare, Mc Master, Moyra, Strzelecka, Anna, Jha, Rajeev, Kalogirou, Michael, Ellis, Christine, Krishnamurthy, Vinodh, Deelchand, Vashish, Silversides, Jon, McGuigan, Peter, Ward, Kathryn, O’Neill, Aisling, Finn, Stephanie, Phillips, Barbara, Mullan, Dee, Oritz-Ruiz de Gordoa, Laura, Thomas, Matthew, Sweet, Katie, Grimmer, Lisa, Johnson, Rebekah, Pinnell, Jez, Robinson, Matt, Gledhill, Lisa, Wood, Tracy, Morgan, Matt, Cole, Jade, Hill, Helen, Davies, Michelle, Antcliffe, David, Templeton, Maie, Rojo, Roceld, Coghlan, Phoebe, Smee, Joanna, Mackay, Euan, Cort, Jon, Whileman, Amanda, Spencer, Thomas, Spittle, Nick, Kasipandian, Vidya, Patel, Amit, Allibone, Suzanne, Genetu, Roman Mary, Ramali, Mohamed, Ghosh, Alison, Bamford, Peter, London, Emily, Cawley, Kathryn, Faulkner, Maria, Jeffrey, Helen, Smith, Tim, Brewer, Chris, Gregory, Jane, Limb, James, Cowton, Amanda, O’Brien, Julie, Nikitas, Nikitas, Wells, Colin, Lankester, Liana, Pulletz, Mark, Birch, Jenny, Wiseman, Sophie, Horton, Sarah, Alegria, Ana, Turki, Salah, Elsefi, Tarek, Crisp, Nikki, Allen, Louise, McCullagh, Iain, Robinson, Philip, Hays, Carole, Babio-Galan, Maite, Stevenson, Hannah, Khare, Divya, Pinder, Meredith, Selvamoni, Selvin, Gopinath, Amitha, Pugh, Richard, Menzies, Daniel, Mackay, Callum, Allan, Elizabeth, Davies, Gwyneth, Puxty, Kathryn, McCue, Claire, Cathcart, Susanne, Hickey, Naomi, Ireland, Jane, Yusuff, Hakeem, Isgro, Graziella, Brightling, Chris, Bourne, Michelle, Craner, Michelle, Watters, Malcolm, Prout, Rachel, Davies, Louisa, Pegler, Suzannah, Kyeremeh, Lynsey, Arbane, Gill, Wilson, Karen, Gomm, Linda, Francia, Federica, Brett, Stephen, Sousa Arias, Sonia, Elin Hall, Rebecca, Budd, Joanna, Small, Charlotte, Birch, Janine, Collins, Emma, Henning, Jeremy, Bonner, Stephen, Hugill, Keith, Cirstea, Emanuel, Wilkinson, Dean, Karlikowski, Michal, Sutherland, Helen, Wilhelmsen, Elva, Woods, Jane, North, Julie, Sundaran, Dhinesh, Hollos, Laszlo, Coburn, Susan, Walsh, Joanne, Turns, Margaret, Hopkins, Phil, Smith, John, Noble, Harriet, Depante, Maria Theresa, Clarey, Emma, Laha, Shondipon, Verlander, Mark, Williams, Alexandra, Huckle, Abby, Hall, Andrew, Cooke, Jill, Gardiner-Hill, Caroline, Maloney, Carolyn, Qureshi, Hafiz, Flint, Neil, Nicholson, Sarah, Southin, Sara, Nicholson, Andrew, Borgatta, Barbara, Turner-Bone, Ian, Reddy, Amie, Wilding, Laura, Chamara Warnapura, Loku, Agno Sathianathan, Ronan, Golden, David, Hart, Ciaran, Jones, Jo, Bannard-Smith, Jonathan, Henry, Joanne, Birchall, Katie, Pomeroy, Fiona, Quayle, Rachael, Makowski, Arystarch, Misztal, Beata, Ahmed, Iram, KyereDiabour, Thyra, Naiker, Kevin, Stewart, Richard, Mwaura, Esther, Mew, Louise, Wren, Lynn, Willams, Felicity, Innes, Richard, Doble, Patricia, Hutter, Joanne, Shovelton, Charmaine, Plumb, Benjamin, Szakmany, Tamas, Hamlyn, Vincent, Hawkins, Nancy, Lewis, Sarah, Dell, Amanda, Gopal, Shameer, Ganguly, Saibal, Smallwood, Andrew, Harris, Nichola, Metherell, Stella, Lazaro, Juan Martin, Newman, Tabitha, Fletcher, Simon, Nortje, Jurgens, Fottrell-Gould, Deirdre, Randell, Georgina, Zaman, Mohsin, Elmahi, Einas, Jones, Andrea, Hall, Kathryn, Mills, Gary, Ryalls, Kim, Bowler, Helen, Sall, Jas, Bourne, Richard, Borrill, Zoe, Duncan, Tracey, Lamb, Thomas, Shaw, Joanne, Fox, Claire, Moreno Cuesta, Jeronimo, Xavier, Kugan, Purohit, Dharam, Elhassan, Munzir, Bakthavatsalam, Dhanalakshmi, Rowland, Matthew, Hutton, Paula, Bashyal, Archana, Davidson, Neil, Hird, Clare, Chhablani, Manish, Phalod, Gunjan, Kirkby, Amy, Archer, Simon, Netherton, Kimberley, Reschreiter, Henrik, Camsooksai, Julie, Patch, Sarah, Jenkins, Sarah, Pogson, David, Rose, Steve, Daly, Zoe, Brimfield, Lutece, Claridge, Helen, Parekh, Dhruv, Bergin, Colin, Bates, Michelle, Dasgin, Joanne, McGhee, Christopher, Sim, Malcolm, Hay, Sophie Kennedy, Henderson, Steven, Phull, Mandeep-Kaur, Zaidi, Abbas, Pogreban, Tatiana, Rosaroso, Lace Paulyn, Harvey, Daniel, Lowe, Benjamin, Meredith, Megan, Ryan, Lucy, Hormis, Anil, Walker, Rachel, Collier, Dawn, Kimpton, Sarah, Oakley, Susan, Rooney, Kevin, Rodden, Natalie, Hughes, Emma, Thomson, Nicola, McGlynn, Deborah, Walden, Andrew, Jacques, Nicola, Coles, Holly, Tilney, Emma, Vowell, Emma, Schuster-Bruce, Martin, Pitts, Sally, Miln, Rebecca, Purandare, Laura, Vamplew, Luke, Spivey, Michael, Bean, Sarah, Burt, Karen, Moore, Lorraine, Day, Christopher, Gibson, Charly, Gordon, Elizabeth, Zitter, Letizia, Keenan, Samantha, Baker, Evelyn, Cherian, Shiney, Cutler, Sean, Roynon-Reed, Anna, Harrington, Kate, Raithatha, Ajay, Bauchmuller, Kris, Ahmad, Norfaizan, Grecu, Irina, Trodd, Dawn, Martin, Jane, Wrey Brown, Caroline, Arias, Ana-Marie, Craven, Thomas, Hope, David, Singleton, Jo, Clark, Sarah, Rae, Nicola, Welters, Ingeborg, Hamilton, David Oliver, Williams, Karen, Waugh, Victoria, Shaw, David, Puthucheary, Zudin, Martin, Timothy, Santos, Filipa, Uddin, Ruzena, Somerville, Alastair, Tatham, Kate Colette, Jhanji, Shaman, Black, Ethel, Dela Rosa, Arnold, Howle, Ryan, Tully, Redmond, Drummond, Andrew, Dearden, Joy, Philbin, Jennifer, Munt, Sheila, Vuylsteke, Alain, Chan, Charles, Victor, Saji, Matsa, Ramprasad, Gellamucho, Minerva, Creagh-Brown, Ben, Tooley, Joe, Montague, Laura, De Beaux, Fiona, Bullman, Laetitia, Kersiake, Ian, Demetriou, Carrie, Mitchard, Sarah, Ramos, Lidia, White, Katie, Donnison, Phil, Johns, Maggie, Casey, Ruth, Mattocks, Lehentha, Salisbury, Sarah, Dark, Paul, Claxton, Andrew, McLachlan, Danielle, Slevin, Kathryn, Lee, Stephanie, Hulme, Jonathan, Joseph, Sibet, Kinney, Fiona, Senya, Ho Jan, Oborska, Aneta, Kayani, Abdul, Hadebe, Bernard, Orath Prabakaran, Rajalakshmi, Nichols, Lesley, Thomas, Matt, Worner, Ruth, Faulkner, Beverley, Gendall, Emma, Hayes, Kati, Hamilton-Davies, Colin, Chan, Carmen, Mfuko, Celina, Abbass, Hakam, Mandadapu, Vineela, Leaver, Susannah, Forton, Daniel, Patel, Kamal, Paramasivam, Elankumaran, Powell, Matthew, Gould, Richard, Wilby, Elizabeth, Howcroft, Clare, Banach, Dorota, Fernández de Pinedo Artaraz, Ziortza, Cabreros, Leilani, White, Ian, Croft, Maria, Holland, Nicky, Pereira, Rita, Zaki, Ahmed, Johnson, David, Jackson, Matthew, Garrard, Hywel, Juhaz, Vera, Roy, Alistair, Rostron, Anthony, Woods, Lindsey, Cornell, Sarah, Pillai, Suresh, Harford, Rachel, Rees, Tabitha, Ivatt, Helen, Sundara Raman, Ajay, Davey, Miriam, Lee, Kelvin, Barber, Russell, Chablani, Manish, Brohi, Farooq, Jagannathan, Vijay, Clark, Michele, Purvis, Sarah, Wetherill, Bill, Dushianthan, Ahilanandan, Cusack, Rebecca, de Courcy-Golder, Kim, Smith, Simon, Jackson, Susan, Attwood, Ben, Parsons, Penny, Page, Valerie, Zhao, Xiao Bei, Oza, Deepali, Rhodes, Jonathan, Anderson, Tom, Morris, Sheila, Xia Le Tai, Charlotte, Thomas, Amy, Keen, Alexandra, Digby, Stephen, Cowley, Nicholas, Southern, David, Reddy, Harsha, Campbell, Andy, Watkins, Claire, Smuts, Sara, Touma, Omar, Barnes, Nicky, Alexander, Peter, Felton, Tim, Ferguson, Susan, Sellers, Katharine, Bradley-Potts, Joanne, Yates, David, Birkinshaw, Isobel, Kell, Kay, Marshall, Nicola, Carr-Knott, Lisa, Writing Committee for the REMAP-CAP Investigators, Menon, David [0000-0002-3228-9692], Apollo - University of Cambridge Repository, Medical Microbiology and Infection Prevention, and AII - Infectious diseases

Subjects
Male, Hydrocortisone, Anti-Inflammatory Agents, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 01 natural sciences, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Adrenal Cortex Hormones, Clinical endpoint, Medicine, 030212 general & internal medicine, Hydrocortisone/administration & dosage, Original Investigation, 2. Zero hunger, Mortality rate, Shock, Covid19, General Medicine, Middle Aged, Intensive care unit, 3. Good health, Intensive Care Units, Treatment Outcome, Early Termination of Clinical Trials, Corticosteroid, Female, Coronavirus Infections, medicine.drug, Adult, medicine.medical_specialty, Respiration, Artificial/statistics & numerical data, medicine.drug_class, Anti-Inflammatory Agents/administration & dosage, Pneumonia, Viral, UNCOVER, Adrenal Cortex Hormones/therapeutic use, 03 medical and health sciences, Betacoronavirus, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Humans, 0101 mathematics, Adverse effect, Pandemics, business.industry, SARS-CoV-2, 010102 general mathematics, COVID-19, Odds ratio, Coronavirus Infections/drug therapy, Pneumonia, Viral/drug therapy, Respiration, Artificial, COVID-19 Drug Treatment, Shock/drug therapy, Human medicine, business
Abstract

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Published
2020

41. The remap-cap (Randomized embedded multifactorial adaptive platform for community-acquired pneumonia) Study rationale and design: Rationale and Design

Author

Epi Infectieziekten, MMB, Infection & Immunity, JC onderzoeksprogramma Infectieziekten, Medische Staf Intensive Care, Angus, Derek C, Berry, Scott, Lewis, Roger J, Al-Beidh, Farah, Arabi, Yaseen, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc, Broglio, Kristine, Brunkhorst, Frank, Cheng, Allen C, Chiche, Jean-Daniel, De Jong, Menno, Detry, Michelle, Goossens, Herman, Gordon, Anthony, Green, Cameron, Higgins, Alisa M, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Litton, Edward, Marshall, John, McGlothlin, Anna, McGuinness, Shay, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, O'Neill, Genevieve K, Parke, Rachael, Parker, Jane, Rohde, Gernot, Rowan, Kathryn, Turner, Anne, Young, Paul, Derde, Lennie, McArthur, Colin, Webb, Steven A, Epi Infectieziekten, MMB, Infection & Immunity, JC onderzoeksprogramma Infectieziekten, Medische Staf Intensive Care, Angus, Derek C, Berry, Scott, Lewis, Roger J, Al-Beidh, Farah, Arabi, Yaseen, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc, Broglio, Kristine, Brunkhorst, Frank, Cheng, Allen C, Chiche, Jean-Daniel, De Jong, Menno, Detry, Michelle, Goossens, Herman, Gordon, Anthony, Green, Cameron, Higgins, Alisa M, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Litton, Edward, Marshall, John, McGlothlin, Anna, McGuinness, Shay, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, O'Neill, Genevieve K, Parke, Rachael, Parker, Jane, Rohde, Gernot, Rowan, Kathryn, Turner, Anne, Young, Paul, Derde, Lennie, McArthur, Colin, and Webb, Steven A

Published
2020

43. Patient-Level Meta-Analysis of End-of-Therapy PET-CR as a Surrogate Endpoint for PFS and OS in Patients with Previously Untreated DLBCL: Implications for Clinical Trial Design

Author

Berry, Donald, primary, Broglio, Kristine, additional, Ward, Carol, additional, Mattiello, Federico, additional, Sahin, Deniz, additional, Nielsen, Tina G, additional, McGlothlin, Anna, additional, Elliott, Corrine, additional, Witzig, Thomas E., additional, Sehn, Laurie H, additional, Trněný, Marek, additional, Vitolo, Umberto, additional, Martelli, Maurizio, additional, Kostakoglu, Lale, additional, and Nowakowski, Grzegorz, additional

Published
2019
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47. Optimizing Sample Size Allocation and Power in a Bayesian Two-Stage Drop-the-Losers Design.

Author

Karanevich, Alex, Meier, Richard, Graw, Stefan, McGlothlin, Anna, and Gajewski, Byron

Subjects
SAMPLE size (Statistics), STATISTICAL power analysis, STATISTICAL sampling, GRAPHICAL user interfaces
Abstract

When a researcher desires to test several treatment arms against a control arm, a two-stage adaptive design can be more efficient than a single-stage design where patients are equally allocated to all treatment arms and the control. We see this type of approach in clinical trials as a seamless Phase II–Phase III design. These designs require more statistical support and are less straightforward to plan and analyze than a standard single-stage design. To diminish the barriers associated with a Bayesian two-stage drop-the-losers design, we built a user-friendly point-and-click graphical user interface with R Shiny to aid researchers in planning such designs by allowing them to easily obtain trial operating characteristics, estimate statistical power and sample size, and optimize patient allocation in each stage to maximize power. We assume that endpoints are distributed normally with unknown but common variance between treatments. We recommend this software as an easy way to engage statisticians and researchers in two-stage designs as well as to actively investigate the power of two-stage designs relative to more traditional approaches. The software is freely available at . [ABSTRACT FROM AUTHOR]

Published
2021
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48. Comparison of methods for control allocation in multiple arm studies using response adaptive randomization.

Author

Viele, Kert, Broglio, Kristine, McGlothlin, Anna, and Saville, Benjamin R

Subjects
PATIENT selection, RESOURCE allocation, CLINICAL trials, STATISTICAL sampling, HUMAN research subjects, DESCRIPTIVE statistics, EXPERIMENTAL design, SIMULATION methods in education
Abstract

Background/Aims: Response adaptive randomization has many polarizing properties in two-arm settings comparing control to a single treatment. The generalization of these features to the multiple arm setting has been less explored, and existing comparisons in the literature reach disparate conclusions. We investigate several generalizations of two-arm response adaptive randomization methods relating to control allocation in multiple arm trials, exploring how critiques of response adaptive randomization generalize to the multiple arm setting. Methods: We perform a simulation study to investigate multiple control allocation schemes within response adaptive randomization, comparing the designs on metrics such as power, arm selection, mean square error, and the treatment of patients within the trial. Results: The results indicate that the generalization of two-arm response adaptive randomization concerns is variable and depends on the form of control allocation employed. The concerns are amplified when control allocation may be reduced over the course of the trial but are mitigated in the methods considered when control allocation is maintained or increased during the trial. In our chosen example, we find minimal advantage to increasing, as opposed to maintaining, control allocation; however, this result reflects an extremely limited exploration of methods for increasing control allocation. Conclusion: Selection of control allocation in multiple arm response adaptive randomization has a large effect on the performance of the design. Some disparate comparisons of response adaptive randomization to alternative paradigms may be partially explained by these results. In future comparisons, control allocation for multiple arm response adaptive randomization should be chosen to keep in mind the appropriate match between control allocation in response adaptive randomization and the metric or metrics of interest. [ABSTRACT FROM AUTHOR]

Published
2020
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49. Abstract A86: A phase 1 study of LY2523355, an Eg5 inhibitor, administered on Days 1, 2, and 3 with or without pegfilgrastim in patients with advanced malignancy (NCT01214629).

Author

Verschraegen, Claire, primary, Cohen, Roger B., additional, Olszanski, Anthony J., additional, Shaheen, Montaser, additional, Nishida, Yuko, additional, Bauman, Julie, additional, Li, Lily, additional, Brandt, John T., additional, Nasir, Aejaz, additional, Hynes, Scott M., additional, Leohr, Jennifer K., additional, McGlothlin, Anna, additional, and Westin, Eric H., additional

Published
2011
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