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THE LANCET
Authors Sarah L Gorst, PhD * Nina Seylanova, MD * Susanna R Dodd, PhD Nicola L Harman, PhD Margaret O'Hara, PhD Prof Caroline B Terwee, PhD Prof Paula R Williamson, PhD † Prof Dale M Needham, PhD † Daniel Munblit, PhD † Timothy R Nicholson, thePC-COS study group
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THE NEW ENGLAND JOURNAL OF MEDICINE
Authors The REMAP-CAP Investigators
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 <1.2). RESULTS Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support–free days was 11 (interquartile range, −1 to 17) in the simvastatin group and 7 (interquartile range, −1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. CONCLUSIONS Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707. opens in new tab.) There have been more than
Authors Bruno Maranda*, Sébastien M Labbé*, Magali Lurquin, Pascal Brabant, Alexandre Fugère, Jean-François Larrivée, Djordje Grbic, Annie Leroux, Frédéric Leduc, Andrés Finzi, Simon Gaudreau, Yolandi Swart, on behalf of the IBIO-INH-001 Investigators†
JAMA
Authors Sarah Grantham-Hill, MBBS; Michael Eyre, MBBS, MRes; Athimalaipet V. Ramanan, MBBS; Neena Modi, MD; Saskia N. de Wildt, MD; Ming Lim
Authors Carolyn T Bramante, John B Buse, David M Liebovitz, Jacinda M Nicklas, Michael A Puskarich, Ken Cohen, Hrishikesh K Belani, Blake J Anderson, Jared D Huling, Christopher J Tignanelli, Jennifer L Thompson, Matthew Pullen, Esteban Lemus Wirtz, Lianne K Siegel, Jennifer L Proper, David J Odde, Nichole R Klatt, Nancy E Sherwood, Sarah M Lindberg, Amy B Karger, Kenneth B Beckman, Spencer M Erickson, Sarah L Fenno, Katrina M Hartman, Michael R Rose, Tanvi Mehta, Barkha Patel, Gwendolyn Griffiths, Neeta S Bhat, Thomas A Murray*, David R Boulware
THE BMJ
Authors Susana Monge, Roberto Pastor-Barriuso, Miguel A Hernán
NATURE
Authors Natalia Martin-Orozco, Noah Vale, Alan Mihic, Talya Amor, Lawrence Reiter, Yuko Arita, Reuben Samson, Queenie Hu, Anne-Claude Gingras, Bradley Thomas Sorenson, Eric Gates Marcusson & Piyush Patel
Abstract Access to vaccines against SARS-CoV-2 virus was limited in poor countries during the COVID-19 pandemic. Therefore, a low-cost mRNA vaccine, PTX-COVID19-B, was produced and evaluated in a Phase 1 trial. PTX-COVID19-B encodes Spike protein D614G variant without the proline-proline (986–987) mutation present in other COVID-19 vaccines. The aim of the study was to evaluate safety, tolerability, and immunogenicity of PTX-COVID19-B vaccine in healthy seronegative adults 18–64 years old. The trial design was observer-blinded, randomized, placebo-controlled, and tested ascending doses of 16-µg, 40-µg, or 100-µg in a total of 60 subjects who received two intramuscular doses, 4 weeks apart. Participants were monitored for solicited and unsolicited adverse events after vaccination and were provided with a Diary Card and thermometer to report any reactogenicity during the trial. Blood samples were collected on baseline, days 8, 28, 42, 90, and 180 for serum analysis of total IgG anti-receptor binding domain (RBD)/Spike titers by ELISA, and neutralizing antibody titers by pseudovirus assay. Titers in BAU/mL were reported as geometric mean and 95% CI per cohort. After vaccination, few solicited adverse events were observed and were mild to moderate and self-resolved within 48 h. The most common solicited local and systemic adverse event was pain at the injection site, and headache, respectively. Seroconversion was observed in all vaccinated participants, who showed high antibody titers against RBD, Spike, and neutralizing activity against the Wuhan strain. Neutralizing antibody titers were also detected against Alpha, Beta, and Delta variants of concerns in a dose dependent manner. All tested doses of PTX-COVID19-B were safe, well-tolerated, and provided a strong immunogenicity response. The 40-µg dose showed fewer adverse reactions than the 100-µg dose, and therefore was selected for a Phase 2 trial, which is currently ongoing.
Authors Djillali Annane*, Sean J Pittock*, Hrishikesh S Kulkarni, Brian W Pickering, Matt R Khoshnevis, Jason L Siegel, Charles A Powell, Pedro Castro, Tomoko Fujii, Derek Dunn, Keisha Smith, Sanjay Mitter, Shamsah Kazani, Austin Kulasekararaj
Authors Justin Z Chen*, Holly L Hoang*, Maryna Yaskina, Dima Kabbani, Karen E Doucette, Stephanie W Smith, Cecilia Lau, Jackson Stewart, Shahileen Remtulla, Karen Zurek, Morgan Schultz, Hiromi Koriyama-McKenzie, Carlos Cervera
Authors Adarsh Bhimraj, Jason C. Gallagher
Authors Matthew W. McCarthy, MD; Susanna Naggie, MD, MHS; David R. Boulware, MD, MPH; Christopher J. Lindsell, PhD; Thomas G. Stewart, PhD; G. Michael Felker, MD, MHS; Dushyantha Jayaweera, MD; Mark Sulkowski, MD; Nina Gentile, MD; Carolyn Bramante, MD, MPH; Upinder Singh, MD; Rowena J. Dolor, MD, MHS; Juan Ruiz-Unger, MD; Sybil Wilson, RN; Allison DeLong, BS; April Remaly, BA; Rhonda Wilder, MS; Sean Collins, MD, MSci; Sarah E. Dunsmore, PhD; Stacey J. Adam, PhD; Florence Thicklin; George Hanna, MD; Adit A. Ginde, MD, MPH; Mario Castro, MD, MPH; Kathleen McTigue, MD, MPH, MS; Elizabeth Shenkman, PhD; Adrian F. Hernandez, MD, MHS; for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators
Abstract Importance The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. Design, Setting, and Participants The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. Interventions Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. Main Outcomes and Measures The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Results Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. Conclusions and Relevance Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.
Authors Ronen Arbel, Ariel Hammerman, Ruslan Sergienko, Michael Friger, Alon Peretz, Doron Netzer, Shlomit Yaron
Abstract BACKGROUND The emergence of the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 and the reduced effectiveness over time of the BNT162b2 vaccine (Pfizer–BioNTech) led to a resurgence of coronavirus disease 2019 (Covid-19) cases in populations that had been vaccinated early. On July 30, 2021, the Israeli Ministry of Health approved the use of a third dose of BNT162b2 (booster) to cope with this resurgence. Evidence regarding the effectiveness of the booster in lowering mortality due to Covid-19 is still needed. METHODS We obtained data for all members of Clalit Health Services who were 50 years of age or older at the start of the study and had received two doses of BNT162b2 at least 5 months earlier. The mortality due to Covid-19 among participants who received the booster during the study period (booster group) was compared with that among participants who did not receive the booster (nonbooster group). A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of booster status with death due to Covid-19, with adjustment for sociodemographic factors and coexisting conditions. RESULTS A total of 843,208 participants met the eligibility criteria, of whom 758,118 (90%) received the booster during the 54-day study period. Death due to Covid-19 occurred in 65 participants in the booster group (0.16 per 100,000 persons per day) and in 137 participants in the nonbooster group (2.98 per 100,000 persons per day). The adjusted hazard ratio for death due to Covid-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% confidence interval, 0.07 to 0.14; P<0.001). CONCLUSIONS Participants who received a booster at least 5 months after a second dose of BNT162b2 had 90% lower mortality due to Covid-19 than participants who did not receive a booster.
Authors Scott A Halperin, Lingyun Ye, Donna MacKinnon-Cameron, Bruce Smith, Pedro E Cahn, Guillermo M Ruiz-Palacios, Aamer Ikram, Fernando Lanas, M Lourdes Guerrero, Sergio Raúl Muñoz Navarro, Omar Sued, Dmitry A Lioznov, Vitalina Dzutseva, Ghazala Parveen, Fengcai Zhu, Laura Leppan, Joanne M Langley, Luis Barreto, Jinbo Gou, Tao Zhu
Authors Gregory L. Fricchione, M.D., Aaron B. Paul, M.D., Zeina Chemali, M.D., M.P.H., and Michael D. Kritzer
Authors Danilo Buonsenso
Authors Katherine L. Hoffman, MS; Edward J. Schenck, MD, MS; Michael J. Satlin, MD; William Whalen, MD, MS; Di Pan, MD, MS; Nicholas Williams, MPH; Iván Díaz
Authors Jonathan D Casey, Laura M Beskow, Jeremy Brown, Samuel M Brown, Étienne Gayat, Michelle Ng Gong, Michael O Harhay, Samir Jaber, Jacob C Jentzer, Pierre-François Laterre, John C Marshall, Michael A Matthay, Todd W Rice, Yves Rosenberg, Alison E Turnbull, Lorraine B Ware, Wesley H Self, Alexandre Mebazaa, Sean P Collins
Authors James Welker, Juan D Pulido, Andrew T Catanzaro, Carlos D Malvestutto, Prof Zihai Li, Jonathan B Cohen, Eric D Whitman, Dana Byrne, Olivia K Giddings, Jordan E Lake, Joel V Chua, Ella Li, Jian Chen, Xiang Zhou, MPH Kun He, Davis Gates, PhD Amarjot Kaur, Jamie Chen, Hung-Yen Chou, Martin Devenport, Raymond Touomou, Shyamasundaran Kottilil, Yang Liu, Prof Pan Zheng
SCIENCE
Authors William A. Fischer II, Joseph J. Eron Jr, Wayne Holman, Myron S. Cohen, Lei Fang, Laura J. Szewczyk, Timothy P. Sheahan, Ralph Baric, Katie R. Mollan, Cameron R. Wolfe, Elizabeth R. Duke, Masoud M. Azizad, Katyna Borroto-Esoda, David A. Wohl, Robert W. Coombs, Amy James Loftis, Paul Alabanza, Felicia Lipansky, Wendy P. Painter
Abstract There is an urgent need for an effective, oral, direct-acting therapeutic to block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and prevent progression to severe coronavirus disease 2019 (COVID-19). In a phase 2a double-blind, placebo-controlled, randomized, multicenter clinical trial, we evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and symptom duration <7 days. Participants were randomized 1:1 to receive molnupiravir (200 mg) or placebo and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. Antiviral activity was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in nasopharyngeal swabs. Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR. Time to viral RNA clearance (primary endpoint) was decreased in the 800-mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank P value = 0.013). Of participants receiving 800 mg of molnupiravir, 92.5% achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks). Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800-mg molnupiravir group compared with 16.7% of the placebo group at day 3 of treatment (P = 0.016). At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg of molnupiravir compared with 11.1% of placebo recipients (P = 0.034 and 0.027, respectively). Molnupiravir was well tolerated across all doses.
Authors AA.VV.
Authors Shipo Wu, Jianying Huang, Zhe Zhang, Jianyuan Wu, Jinlong Zhang, Hanning Hu, Tao Zhu, Jun Zhang, Lin Luo, Pengfei Fan, Busen Wang, Chang Chen, Yi Chen, Xiaohong Song, Yudong Wang, Weixue Si, Tianjian Sun, Xinghuan Wang, Lihua Hou, Wei Chen
Authors Jean-Claude Tardif, Nadia Bouabdallaoui, Philippe L L’Allier, Daniel Gaudet, Binita Shah, Michael H Pillinger, Jose Lopez-Sendon, Protasio da Luz, Lucie Verret, Sylvia Audet, Jocelyn Dupuis, André Denault, Martin Pelletier, Philippe A Tessier, Sarah Samson, Denis Fortin, Jean-Daniel Tardif, David Busseuil, Elisabeth Goulet, Chantal Lacoste, Anick Dubois, Avni Y Joshi, David D Waters, Priscilla Hsue, Norman E Lepor, Frédéric Lesage, Nicolas Sainturet, Eve Roy-Clavel, Zohar Bassevitch, Andreas Orfanos, Gabriela Stamatescu, Jean C Grégoire, Lambert Busque, Christian Lavallée, Pierre-Olivier Hétu, Jean-Sébastien Paquette, Spyridon G Deftereos, Sylvie Levesque, Mariève Cossette, Anna Nozza, Malorie Chabot-Blanchet, Marie-Pierre Dubé, Marie-Claude Guertin, Guy Boivin,
Authors Sanjay Ramakrishnan, Dan V Nicolau Jr, Beverly Langford, Mahdi Mahdi, Helen Jeffers, Christine Mwasuku, Karolina Krassowska, Robin Fox, Ian Binnian, Victoria Glover, Stephen Bright, Christopher Butler, Jennifer L Cane, Andreas Halner, Philippa C Matthews, Louise E Donnelly, Jodie L Simpson, Jonathan R Baker, Nabil T Fadai, Stefan Peterson, Thomas Bengtsson, Peter J Barnes, Richard E K Russell, Mona Bafadhel
EUROSURVEILLANCE
Authors Isabelle Sermet-Gaudelus, Sarah Temmam, Christèle Huon, Sylvie Behillil, Vincent Gajdos, Thomas Bigot, Thibaut Lurier, Delphine Chrétien, Marija Backovic, Agnès Delaunay-Moisan, Flora Donati, Mélanie Albert, Elsa Foucaud, Bettina Mesplées, Grégoire Benoist, Albert Faye, Marc Duval-Arnould, Célia Cretolle, Marina Charbit, Mélodie Aubart, Johanne Auriau, Mathie Lorrot, Dulanjalee Kariyawasam, Laura Fertitta, Gilles Orliaguet, Bénédicte Pigneur, Brigitte Bader-Meunier, Coralie Briand, Vincent Enouf, Julie Toubiana, Tiffany Guilleminot, Sylvie van der Werf, Marianne Leruez-Ville, Marc Eloit
Authors Katherine R W Emary, Tanya Golubchik, Parvinder K Aley, Cristina V Ariani, Brian Angus, Sagida Bibi, Beth Blane, David Bonsall, Paola Cicconi, Sue Charlton, Elizabeth A Clutterbuck, Andrea M Collins, Tony Cox, Thomas C Darton, Christina Dold, Alexander D Douglas, Christopher J A Duncan, Katie J Ewer, Amy L Flaxman, Saul N Faust, Daniela M Ferreira, Shuo Feng, Adam Finn, Pedro M Folegatti, Michelle Fuskova, Eva Galiza, Anna L Goodman, Catherine M Green, Christopher A Green, Melanie Greenland, Bassam Hallis, Paul T Heath, Jodie Hay, Helen C Hill, Daniel Jenkin, Simon Kerridge, Rajeka Lazarus, Vincenzo Libri, Patrick J Lillie, Catherine Ludden, Natalie G Marchevsky, Angela M Minassian, Alastair C McGregor, Yama F Mujadidi, Daniel J Phillips, Emma Plested, Katrina M Pollock, Hannah Robinson, Andrew Smith, Rinn Song, Matthew D Snape, Rebecca K Sutherland, Emma C Thomson, Mark Toshner, David P J Turner, Johan Vekemans, Tonya L Villafana, Christopher J Williams, Adrian V S Hill, Teresa Lambe, Sarah C Gilbert, Merryn Voysey, Maheshi N Ramasamy, Andrew J Pollard, on behalf of the COVID-19 Genomics UK consortium, the AMPHEUS Project, and the Oxford COVID-19 Vaccine Trial Group
UNIVERSITY OF OXFORD
Authors UNIVERSITY OF OXFORD
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Authors U.S. Department of Health & Human Services
Authors WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation
Authors Jeanne Lenzer
NIH (NATIONAL INSTITUTES OF HEALTH)
Authors NIH (NATIONAL INSTITUTES OF HEALTH)
Authors V.A. Simonovich, L.D. Burgos Pratx, P. Scibona, M.V. Beruto, M.G. Vallone, C. Vázquez, N. Savoy, D.H. Giunta, L.G. Pérez, M..L. Sánchez, A.V. Gamarnik, D.S. Ojeda, D.M. Santoro, P.J. Camino, S. Antelo, K. Rainero, G.P. Vidiella, E.A. Miyazaki, W. Cornistein, O.A. Trabadelo, F.M. Ross, M. Spotti, G. Funtowicz, W.E. Scordo, M.H. Losso, I. Ferniot, P.E. Pardo, E. Rodriguez, P. Rucci, J. Pasquali, N.A. Fuentes, M. Esperatti, G.A. Speroni, E.C. Nannini, A. Matteaccio, H.G. Michelangelo, D. Follmann, H.C. Lane, W.H. Belloso
Abstract BACKGROUND Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials. METHODS We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient’s clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. RESULTS A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200]. No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83 (95% confidence interval [CI], 0.52 to 1.35; P=0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of −0.46 percentage points (95% CI, −7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535. opens in new tab.)
THE UNION
Authors Giovanni Battista Migliori
Authors E.J. Anderson, N.G. Rouphael, A.T. Widge, L.A. Jackson, P.C. Roberts, M. Makhene, J.D. Chappell, M.R. Denison, L.J. Stevens, A.J. Pruijssers, A.B. McDermott, B. Flach, B.C. Lin, N.A. Doria-Rose, S. O’Dell, S.D. Schmidt, K.S. Corbett, P.A. Swanson II, M. Padilla, K.M. Neuzil, H. Bennett, B. Leav, M. Makowski, J. Albert, K. Cross, V.V. Edara, K. Floyd, M.S. Suthar, D.R. Martinez, R. Baric, W. Buchanan, C.J. Luke, V.K. Phadke, C.A. Rostad, J.E. Ledgerwood, B.S. Graham, J.H. Beigel
Abstract BACKGROUND Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age. METHODS We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart. RESULTS Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-μg dose, the anti–S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. CONCLUSIONS In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461. opens in new tab.)
Authors Denis Y Logunov, Inna V Dolzhikova, Olga V Zubkova, Amir I Tukhvatullin, Dmitry V Shcheblyakov, Alina S Dzharullaeva, Daria M Grousova, Alina S Erokhova, Anna V Kovyrshina, Andrei G Botikov, Fatima M Izhaeva, Olga Popova, Tatiana A Ozharovskaya, Ilias B Esmagambetov, Irina A Favorskaya, Denis I Zrelkin, Daria V Voronina, Dmitry N Shcherbinin, Alexander S Semikhin, Yana V Simakova, Elizaveta A Tokarskaya, Nadezhda L Lubenets, Daria A Egorova, Maksim M Shmarov, Natalia A Nikitenko, Lola F Morozova, Elena A Smolyarchuk, Evgeny V Kryukov, Vladimir F Babira, Sergei V Borisevich, Boris S Naroditsky, Alexander L Gintsburg
Authors Madhukar Pai
Authors The RECOVERY Collaborative Group
ABSTRACT BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. RESULTS A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). CONCLUSIONS In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936. opens in new tab; ISRCTN number, 50189673. opens in new tab.)
Authors Crystal M. North, Michael L. Dougan, Chana A. Sacks
WORLD HEALTH ORGANIZATION
Authors WORLD HEALTH ORGANIZATION
ISTITUTO SUPERIORE DI SANITA'
Authors Angela Giusti, Francesca Zambri, Francesca Marchetti
TAYLOR & FRANCIS ONLINE
Authors Peng Xu ,Xiangyu Xing, Keying Yu, Zhiguo Lv,Huijing Cui,Yuhang Shi,Tianying Chang,Dongmei Zhang,Yibin Zhang,Kai Wang,Jing Lu,Qingxia Huang,Xiangyan Li,Yingzi Cui,Li Shi,Tan Wang,Junqi Niu, Jian Wang
ABSTRACT The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health crisis since its initial reports in China. Since no effective vaccine or drug has been developed to treat and combat the COVID-19, the current approaches for clinical management focus on supportive care. There is a pressing need for evidence-based interventions to address the devastating clinical and public health effects of the COVID-19 pandemic. The Chinese scientists supported by private and government resources have adopted extensive efforts to identify effective drugs against the virus. To date, a large number of clinical trials addressing various aspects of COVID-19 have been registered in the Chinese Clinical Trial Registry (ChiCTR), including more than 200 interventional studies. Under such an urgent circumstance, the scope and quality of these clinical studies vary significantly. Hence, this review aims to make a comprehensive analysis on the profiles of COVID-19 clinical trials registered in the ChiCTR, including a wide range of characteristics. Our findings will provide a useful summary on these clinical studies, since most of these studies will encounter major challenges from the design to completion. It will be a long road for the outcomes of these studies to be published and international collaboration will help the ultimate goals of developing new vaccines and antiviral drugs.
AIFA
Authors Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
Authors AIFA
The Lancet
Authors Mandeep R Mehra, Frank Ruschitzka, Amit N Patel
OXFORD UNIVERSITY
Authors PETER HORBY, MARTIN LANDRAY
Authors Mandeep R. Mehra, Sapan S. Desai, SreyRam Kuy, Timothy D. Henry, Amit N. Patel
CCTU (CLINICAL CAMBRIDGE TRIALS UNIT)
Authors TACTIC
Authors Rita Rubin
Authors Arturo Casadevall, Michael J. Joyner, Liise-Anne Pirofski
ZENODO
SCIENCE DIRECT
Authors Shi-Hui Sun, Qi Chen, Hong-Jing Gu, Yu-Sen Zhou, Cheng-Feng Qin, You-Chun Wang
ELSEVIER
Authors EmiliaBagiella, Deepak L.Bhatt, MarioGaudino
DRUGS IN CONTEXT
Authors Matteo Bassetti MD, Paolo Pelosi, Chiara Robba, Antonio Vena MD, Daniele Roberto Giacobbe
ABSTRACT Randomized controlled trials (RCTs) are the best way to find effective and acceptable safe treatments for COVID-19 and any possible future outbreak. However, caution is needed when comparing the number of participants in RCTs with that of patients with COVID-19 treated with compassionate and/or off-label drugs to support the hypothesis that the latter are preferred by clinicians as an alternative to the former.
Authors David C. Kaslow
ABSTRACT Vaccines for 17 viral pathogens have been licensed for use in humans. Previously, two critical biological parameters of the pathogen and the host–pathogen interaction—incubation period and broadly protective, relative immunogenicity—were proposed to account for much of the past successes in vaccine development, and to be useful in estimating the “certainty of success” of developing an effective vaccine for viral pathogens for which a vaccine currently does not exist. In considering the “certainty of success” in development of human coronavirus vaccines, particularly SARS-CoV-2, a third, related critical parameter is proposed—infectious inoculum intensity, at an individual-level, and force of infection, at a population-level. Reducing the infectious inoculum intensity (and force of infection, at a population-level) is predicted to lengthen the incubation period, which in turn is predicted to reduce the severity of illness, and increase the opportunity for an anamnestic response upon exposure to the circulating virus. Similarly, successfully implementing individual- and population-based behaviors that reduce the infectious inoculum intensity and force of infection, respectively, while testing and deploying COVID-19 vaccines is predicted to increase the “certainty of success” of demonstrating vaccine efficacy and controlling SARS-CoV-2 infection, disease, death, and the pandemic itself.
Authors Feng-Cai Zhu, Yu-Hua Li, Xu-Hua Guan, Li-Hua Hou, Wen-Juan Wang, Jing-Xin Li, Shi-Po Wu, Bu-Sen Wang, Zhao Wang, Lei Wang, Si-Yue Jia, Hu-Dachuan Jiang, Ling Wang, Tao Jiang, Yi Hu, Jin-Bo Gou, Sha-Bei Xu, Jun-Jie Xu, Xue-Wen Wang, Wei Wang, Wei Chen
WILEY ONLINE LIBRARY
Authors Sergio Bonini, Giuseppe Maltese
ABSTRACT Despite the ferment aroused in the scientific community by the COVID‐19 outbreak and the over 11,000 papers listed in PubMed, published evidence on safe and effective drugs has not progressed yet at the same speed of the pandemic. However, clinical research is rapidly progressing, as shown by the hundreds of registered clinical trials on candidate drugs for COVID‐19. Unfortunately, information on protocols of individual studies differs from registry to registry. Furthermore, study designs, criteria for stratification of patients and choice of outcomes are quite heterogeneous. All this makes data sharing and secondary analysis difficult.At last, small single centre studies and the use of drugs on a compassionate basis should be replaced by highly powered, multi‐centre, multi‐arm clinical trials, in orderto provide the required evidence of safety and efficacy of novel or repurposed candidate drugs. Hopefully, the efforts of clinical researchers in the fight against the SARS Cov‐2 will result into the identification of effective treatments. To make this possible, clinical research should be oriented by guidelines for more harmonized high‐quality studies and by a united commitment of the scientific community to share personal knowledge and data. Allergists and clinical immunologists should have a leading role in this unprecedent challenge.
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Authors NATURE
Authors Paul P Glasziou
SCIENC
Authors Lawrence Corey, John R. Mascola, Anthony S. Fauci, Francis S. Collins
ABSTRACT There is an unprecedented need to manufacture and distribute enough safe and effective vaccine to immunize an extraordinarily large number of individuals in order to protect the entire global community from the continued threat of morbidity and mortality from severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The global need for vaccine and the wide geographic diversity of the pandemic require more than one effective vaccine approach. Collaboration will be essential among biotechnology and pharmaceutical companies, many of which are bringing forward a variety of vaccine approaches (1). The full development pathway for an effective vaccine for SARS-CoV-2 will require that industry, government, and academia collaborate in unprecedented ways, each adding their individual strengths. We discuss one such collaborative program that has recently emerged: the ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) public-private partnership. Spearheaded by the U.S. National Institutes of Health (NIH), this effort brings together the strengths of all sectors at this time of global urgency. We further discuss a collaborative platform for conducting harmonized, randomized controlled vaccine efficacy trials. This mechanism aims to generate essential safety and efficacy data for several candidate vaccines in parallel, so as to accelerate the licensure and distribution of multiple vaccine platforms and vaccines to protect against COVID-19 (coronavirus disease 2019). We currently know little about what constitutes a protective immune response against COVID-19. Data from SARS-CoV-1 patients as well as recently infected SARS-CoV-2 patients document relatively high levels of immune responses after infection, especially antibody responses to the surface (spike) protein that mediates entry into host cells. However, in vivo data on the type or level of immunity required to protect from subsequent re-infection, and the likely duration of that protection, are currently unknown. In animal models of SARS-CoV-1, immunization with recombinant subunit proteins and viral- and nucleic acid–vectored vaccines, as well as passive transfer of neutralizing antibodies to the spike protein, have been shown to be protective against experimental infection (2, 3). Endpoints vary from protection of infection to modification of viral replication and disease. These data bring optimism that a highly immunogenic vaccine will elicit the magnitude and quality of antibody responses required for protection. The role that T cell immunity plays in preventing acquisition or amelioration of early disease, either in animal challenge models or in human coronavirus disease, is unclear (4); this constitutes another reason why a diversity of vaccine approaches must be pursued. A high degree of safety is a primary goal for any widely used vaccine, and there is theoretical risk that vaccination could make subsequent SARS-CoV-2 infection more severe. This has been reported for feline coronaviruses and has been observed in some vaccine-challenge animal models of SARS-CoV-1 (5). These preclinical data suggest that the syndrome of vaccine-associated enhanced respiratory disease results from a combination of poorly protective antibodies that produce immune complex deposition together with a T helper cell 2 (TH2)–biased immune response. The potential mechanism behind vaccine-induced immune enhancement and the means to minimize this risk have recently been reviewed (6). It will be important to construct conformationally correct antigens to elicit functionally effective antibodies—a lesson learned from vaccine-induced enhanced lower respiratory illness among infants receiving a formalin-inactivated respiratory syncytial virus (RSV) vaccine. Animal models of SARS-CoV-2 infection are currently being developed, and these models can be used to better understand the immune responses associated with protection (7).
THE JOURNAL OF CLINICAL INVESTIGATION
Authors Evelyne Bischof, Jeannette Wolfe, and Sabra L. Klein
ABSTRACT This Viewpoint calls on investigators that are developing and testing therapeutic and prophylactic approaches for COVID-19 to design studies that are inclusive of male-female differences.
National Institutes of Health (NIH)
Authors National Institutes of Health (NIH)
SPRINGER LINK
Authors Sylvain A. Lother, Mahsa Abassi, Alyssa Agostinis, Ananta S. Bangdiwala, Matthew P. Cheng, Glen Drobot, Nicole Engen, Kathy H. Hullsiek, Lauren E. Kelly, Todd C. Lee, FIDSA, Sarah M. Lofgren, Lauren J. MacKenzie, Nicole Marten RN, Emily G. McDonald, Elizabeth C. Okafor, Katelyn A. Pastick, Matthew F. Pullen , Radha Rajasingham, Ilan Schwartz, Caleb P. Skipper, Alexis F. Turgeon, Ryan Zarychanski, David R. Boulware
ABSTRACT Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 causing the coronavirus disease (COVID-19) pandemic. Currently, there is a lack of evidence-based therapies to prevent COVID-19 following exposure to the virus, or to prevent worsening of symptoms following confirmed infection. We describe the design of a clinical trial of hydroxychloroquine for post-exposure prophylaxis (PEP) and pre-emptive therapy (PET) for COVID-19. Methods We will conduct two nested multicentre international double-blind randomized placebo-controlled clinical trials of hydroxychloroquine for: 1) PEP of asymptomatic household contacts or healthcare workers exposed to COVID-19 within the past four days, and 2) PET for symptomatic outpatients with COVID-19 showing symptoms for less than four days. We will recruit 1,500 patients each for the PEP and PET trials. Participants will be randomized 1:1 to receive five days of hydroxychloroquine or placebo. The primary PEP trial outcome will be the incidence of symptomatic COVID-19. The primary PET trial outcome will be an ordinal scale of disease severity (not hospitalized, hospitalized without intensive care, hospitalization with intensive care, or death). Participant screening, informed consent, and follow-up will be exclusively internet-based with appropriate regulatory and research ethics board approvals in Canada and the United States. Discussion These complementary randomized-controlled trials are innovatively designed and adequately powered to rapidly answer urgent questions regarding the effectiveness of hydroxychloroquine to reduce virus transmission and disease severity of COVID-19 during a pandemic. In-person participant follow-up will not be conducted to facilitate social distancing strategies and reduce risks of exposure to study personnel. Innovative trial approaches are needed to urgently assess therapeutic options to mitigate the global impact of this pandemic.
Authors ZhongrenMa, JiayeLiu, QiuweiPan
Authors Robin Foà Massimiliano Bonifacio Sabina Chiaretti Antonio Curti Anna Candoni Carmen Fava Maria Ciccone Giovanni Pizzolo Felicetto Ferrara
BMJ
Authors C Raina MacIntyre, Holly Seale, Tham Chi Dung, Nguyen Tran Hien, Phan Thi Nga, Abrar Ahmad Chughtai, Bayzidur Rahman, Dominic E Dwyer, Quanyi Wang
ABSTRACT Objective: The aim of this study was to compare the efficacy of cloth masks to medical masks in hospital healthcare workers (HCWs). The null hypothesis is that there is no difference between medical masks and cloth masks. Setting: 14 secondary-level/tertiary-level hospitals in Hanoi, Vietnam. Participants: 1607 hospital HCWs aged ≥18 years working full-time in selected high-risk wards. Intervention: Hospital wards were randomised to: medical masks, cloth masks or a control group (usual practice, which included mask wearing). Participants used the mask on every shift for 4 consecutive weeks. Main outcome measure: Clinical respiratory illness (CRI), influenza-like illness (ILI) and laboratory- confirmed respiratory virus infection. Results: The rates of all infection outcomes were highest in the cloth mask arm, with the rate of ILI statistically significantly higher in the cloth mask arm (relative risk (RR)=13.00, 95% CI 1.69 to 100.07) compared with the medical mask arm. Cloth masks also had significantly higher rates of ILI compared with the control arm. An analysis by mask use showed ILI (RR=6.64, 95% CI 1.45 to 28.65) and laboratory- confirmed virus (RR=1.72, 95% CI 1.01 to 2.94) were significantly higher in the cloth masks group compared with the medical masks group. Penetration of cloth masks by particles was almost 97% and medical masks 44%. Conclusions: This study is the first RCT of cloth masks, and the results caution against the use of cloth masks. This is an important finding to inform occupational health and safety. Moisture retention, reuse of cloth masks and poor filtration may result in increased risk of infection. Further research is needed to inform the widespread use of cloth masks globally. However, as a precautionary measure, cloth masks should not be recommended for HCWs, particularly in high-risk situations, and guidelines need to be updated.
Authors Howard Bauchner; Phil B. Fontanarosa
Authors Giuseppe Mancia, Federico Rea, Monica Ludergnani, Giovanni Apolone,,and Giovanni Corrao,
ABSTRACT A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. METHODS We carried out a population-based case–control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. RESULTS Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. CONCLUSIONS In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.
Authors Kristian Thorlund, Louis Dron, Jay Park, Grace Hsu, Jamie I Forrest, Edward J Mills
BMC
Authors Anitra C. Carr
Authors RECOVERY STAFF
Background: In early 2020, as this protocol was being developed, there were no approved treatments for COVID-19, a disease induced by the novel coronavirus SARSCoV-2 that emerged in China in late 2019. The UK New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) advised that several possible treatments should be evaluated, including Lopinavir-Ritonavir, low-dose corticosteroids, and hydroxychloroquine. These groups also advised that other treatments will soon emerge that require evaluation. A World Health Organization (WHO) expert group issued broadly similar advice.
Authors COVID-19 Clinical Research Coalition
GOVERNMENT OF CANADA
Authors GOVERNMENT OF CANADA
UK REMAP
Authors REMAP-CAP
UK Oxford Vaccine Trial
The BMJ
Authors Elisabeth Mahase
U.S NATIONAL LIBRARY OF MEDICINE
Authors U.S NATIONAL LIBRARY OF MEDICINE
NULL
Authors Francesco Perrone, Paolo Ascierto, Anna Maria Marata, Roberto Parrella, Patrizia Popoli, Maria Carmela Piccirillo, Luigi Atripaldi, Marco Cascella, Massimo Costantini, Giovanni Dolci, Nicola Facciolongo, Fiorentino Fragranza, Marco Massari, Vincenzo Montesarchio, Cristina Mussini,Emanuele Alberto Negri
Titolo dello studio Studio multicentrico su efficacia e sicurezza di Tocilizumab nel trattamento di pazienti affetti da polmonite da COVID-19 Sigla dello studio TOCIVID-19 Obiettivo dello studio Valutare l’efficacia e la sicurezza di Tocilizumab in pazienti affetti da polmonite da COVID-19 Background - la polmonite rappresenta la complicanza più frequente e grave in corso di infezione da coronavirus - IL-6 è uno dei mediatori dell’infiammazione che consegue alla risposta immunitaria contro il virus che si realizza a livello degli alveoli polmonari; tale risposta immunitaria e la conseguente “tempesta citochinica” finiscono con il produrre un significativo danno al parenchima polmonare con una interstiziopatia che riduce notevolmente la funzionalità respiratoria - Tocilizumab è un anticorpo monoclonale ricombinante umanizzato diretto contro il recettore dell’IL-6 - In una esperienza resa nota dai ricercatori Cinesi (Xiaoling Xu, Mingfeng Han, Tiantian Li et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. chinaXiv: 202003.00026v1) il tocilizumab ha prodotto incoraggianti benefici clinici e nei parametri di laboratorio in una casistica di 21 pazienti affetti da polmonite severa o critica COVID-19 - Tali risultati hanno dato luogo al disegno di una sperimentazione randomizzata (tocilizumab vs controllo) che dovrebbe chiudersi entro la metà del mese di maggio 2020. Obiettivo primario Ridurre la mortalità in corso di polmonite da COVID-19 Disegno del progetto di studio Questo progetto è stato scritto al momento della pandemia da coronavirus e mentre in Italia il numero di persone che si infettano o sono ricoverate in ospedale per complicanze respiratorie è drammaticamente in aumento. Pertanto, lo scenario clinico e operativo è estremamente variabile e si prevede che rimarrà tale per un tempo imprevedibile. Inoltre, sono disponibili pochissime prove concrete sul decorso della malattia e molti endpoint intermedi prima dell'uso del farmaco sperimentale. Pertanto, è accettato in anticipo che il presente protocollo potrebbe richiedere ripetute modifiche per conformarsi all'evoluzione delle conoscenze sulla pandemia, sul tasso di complicanze e sullo scenario terapeutico per i pazienti che sviluppano polmonite. Si prevede quindi un elevato grado di adattamento, che sarà discusso rigorosamente con il comitato indipendente di monitoraggio dei dati che sarà nominato subito dopo l'approvazione del protocollo. Disegno dello studio Al suo concepimento, il progetto di studio include uno studio di fase 2 a braccio singolo e uno studio di coorte osservazionale parallelo, che arruolano pazienti con polmonite COVID-19. Studio di fase 2 Questo è uno studio multicentrico, a braccio singolo, in aperto, di fase 2. Tutti i pazienti arruolati sono trattati con tocilizumab. Il tasso di mortalità a un mese è l'endpoint primario. Dai dati disponibili, si può presumere che la mortalità a 1 mese per la popolazione definita dai criteri di selezione sia di circa il 15 % (P0). Per verificare l'ipotesi che il farmaco sperimentale possa dimezzare il tasso di mortalità (dal 15% al 7,5%, P1), sono necessari 330 pazienti per verificare l'ipotesi con una potenza del 99% e un errore alfa bilaterale del 5%. Studio di coorte osservazionale Questa coorte di osservazione prospettica / retrospettiva includerà pazienti che non sono eleggibili per lo studio di fase 2 perché: a) condizioni di emergenza o limiti infrastrutturali o operativi hanno impedito la registrazione prima della somministrazione del farmaco sperimentale o b) erano stati intubati più di 24 ore prima della registrazione. Le stesse informazioni pianificate per la coorte di fase 2 sono in linea di principio richieste anche per lo studio di coorte osservazionale. La dimensione del campione dello studio osservazionale non è definita a priori e la coorte si chiuderà alla fine del progetto complessivo. Dimensione del campione Nella coorte di fase 2 verranno arruolati 330 pazienti. Nella coorte osservazionale il campione non è definito a priori. Popolazione oggetto di studio Popolazione in studio: pazienti con polmonite da COVID-19 con deficit di saturazione dell’ossigeno e che richiedono assistenza in regime di ricovero. Principali criteri di inclusione 1. Qualsiasi genere 2. Nessun limite di età 3. Consenso informato per la partecipazione allo studio (NB. il consenso può essere orale se non è possibile esprimere un consenso scritto. Se il soggetto non è in grado di fornire un consenso informato e un rappresentante autorizzato non è disponibile in tempi molto brevi, il che, a giudizio dell'Investigatore, comprometterebbe il potenziale effetto salvavita del trattamento, il trattamento stesso può essere somministrato senza consenso. Il consenso a rimanere nella ricerca dovrebbe essere richiesto non appena le condizioni del paziente lo consentiranno) 4. Diagnosi virologica dell'infezione da Sars-CoV2 (real-time PCR) 5. Ricoverato in ospedale a causa della diagnosi clinica/strumentale di polmonite 6. Saturazione di ossigeno a riposo in aria ambiente ≤93% (valida per pazienti non intubati e sia per lo studio di fase 2 che per la coorte osservazionale) 7. Intubato meno di 24 ore prima della registrazione (eleggibile solo per la fase 2 - il criterio nr. 6 non si applica in questo caso) 8. Intubato più di 24 ore prima della registrazione (eleggibile solo per la coorte osservazione - il criterio nr. 6 non si applica in questo caso) 9. I pazienti già trattati con tocilizumab prima della registrazione sono eleggibili per la coorte osservazionale solo se è valido un criterio tra i nr. 6, 7, 8
Authors X. Jin, B. Pang, J. Zhang et al.
ABSTRACT Since its outbreak in December 2019, a series of clinical trials on Coronavirus Disease 2019 (COVID-19) have been registered or carried out. However, the significant heterogeneity and less critical outcomes of such trials may be leading to a waste of research resources. This study aimed to develop a core outcome set (COS) for clinical trials on COVID-19 in order to tackle the outcome issues. The study was conducted according to the Core Outcome Measures in Effectiveness Trials (COMET) handbook (version 1.0), a guideline for COS development. A research group was set up that included experts in respiratory and critical medicine, traditional Chinese medicine, evidence-based medicine, clinical pharmacology, and statistics, in addition to medical journal editors. Clinical trial registry websites (chictr.org.cn and clinicaltrials.gov) were searched to retrieve clinical trial protocols and outcomes in order to form an outcome pool. A total of 78 clinical trial protocols on COVID-19 were included and 259 outcomes were collected. After standardization, 132 outcomes were identified within seven different categories, of which 58 were selected to develop a preliminary outcome list for further consensus. After two rounds of Delphi survey and one consensus meeting, the most important outcomes for the different clinical classifications of COVID-19 were identified and determined to constitute the COS for clinical trials on COVID-19 (COS-COVID). The COS-COVID includes one outcome for the mild type (time to 2019-nCoV reverse transcription-polymerase chain reaction (RT-PCR) negativity), four outcomes for the ordinary type (length of hospital stay, composite events, score of clinical symptoms, and time to 2019-nCoV RT-PCR negativity), five outcomes for the severe type (composite events, length of hospital stay, arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2), duration of mechanical ventilation, and time to 2019-nCoV RT-PCR negativity), one outcome for critical type (all-cause mortality), and one outcome for rehabilitation period (pulmonary function). The COS-COVID is currently the most valuable and practical clinical outcome set for the evaluation of intervention effect, and is useful for evidence assessment and decision-making. With a deepening understanding of COVID-19 and application feedback, the COS-COVID should be continuously updated.
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