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Background: The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date. Methods: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948. Findings: Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82-1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89-1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76-0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46-1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76-0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77-1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75-0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings. Interpretation: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both). Funding: WHO.
Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses
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J.;Gotuzzo E.;Alejandria M. M.;Maltez F. M. T.;Beaumont H.;Alotaibi A. O.;Asiri A.;Karim Q. A.;Nel J.;Rees H.;Portoles A.;Manuel O.;Rottingen J. -A.;Karim Q. A.;Alejandria M.;Garcia C. H.;Kieny M. P.;Malekzadeh R.;Murthy S.;Reddy K. S.;Periago M. R.;Swaminathan S.;Gjermeni N.;Meta E.;Balbuena J.;Castelli J. M.;Mykietiuk A.;Vizzotti C.;Aguila D.;Lupo S.;Chediack V.;Cunto E.;de Vedia L.;Dominguez C.;Fernandez J.;Lista N.;Rodriguez A.;Caimi S.;Delgado C.;Frare P.;Losso M.;Masciottra F.;Pachioli V.;Toibaro J.;Barletta J.;Carrillo J.;D'Amico N.;Hermida L.;Jaume M.;Luna C.;Padilla M. J.;Patroso J.;Blanco L. P.;Presas J. L.;Rolon M. J.;Sisto A. L.;Themines S.;Arce V.;Arribillaga P.;Ferreyra R. A.;Lescano M. L.;Tito F.;Veron L.;Chalco A.;Farina J.;Provenzano M.;Alonso I.;Alzola R.;Benedetti M.;Cervellino F.;Di Pilla D.;Aguiar P. D.;Ellero L.;Giudiche C.;Golikow M.;Jacobo M.;Laplume D.;Loiacono F.;Lopez A. 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C.;Rupali P.;Stanley N.;Thangakunam B.;Varghese G.;Viggeswarpu S.;Ahmed M. D.;Billa B.;Agrawal P.;Agrawal N.;Bhelekar S.;Faisal M.;Gomase P.;Gosavi P.;Sabu R.;Agrawal S.;Arathi G.;Jayashree G.;Meenakshi T.;Gomathi S.;Anuradha C. R.;Jayakumar M.;Praveen Kumar C.;Pravin Kumar R.;Ramesh Kumar T.;Sai Vishal S.;Subashree A.;Manimaran K. P.;Mehendale S.;Raju R.;Sunavala A.;Gupta B.;Beulah F.;Ramu S.;Govindarajan N.;Prasetyo E.;Fujiyanto F. N. K.;Adiwinate R.;Kristanto E.;Setiawan H. W.;Wulaningrum P. A.;Rosyid A. N.;Ramadhan N. A.;Purnamasidhi C. A. W.;Aryabiantara I. W.;Suyasa I. K.;Samatra D. P. G. P.;Bachtiar D.;Sastria E.;Rusmana M.;Yuliana E.;Otifa V.;Sabaan W.;Sumawan S.;Nopiasardani I.;Sitepu;Pratama R.;Siswandi S.;Parman P.;Mariana N.;Rusli A.;Sundari T.;Rosamarlina R.;Suyastri S.;Tantular R.;Setyawan U. A.;Christanto A.;Ichsan N.;Kusmiati T.;Qibtiyah M.;Bachtiar A.;Febriani A.;Dewi Y. F.;Aphridasari J.;Adhiputri A.;Pramudyaningsih E.;Soeroto A. Y.;Andriyoko B.;Winarni R.;Chairunnisa N. H.;Sofro M. A. U.;Kholis F. N.;Farkhanah N.;Handoyo T.;Russilawati R.;Anggrainy A.;Ermayanti S.;Khairsyaf O.;Dayi F.;Riswiyanti A.;Trisnawati I.;Ananda N. R.;Nurulita A.;Ilyas M.;Lihawa N.;Tabri N. A.;Mayasari N.;Yudhorini L. T.;Nasarudin J.;Taufik M. A.;Utami L.;Muntasir M.;Agustina A.;Panjaitan D.;Ananda F. R.;Byantoro A. C.;Sutarto R.;Asmara A. S.;Kusumaeni T.;Kusumawardani I. A. J. D.;Candrawati N. W.;Arisanti N. L. P. E.;Utama I. M. S.;Susilo A.;Singh G.;Marini P.;Cesca M.;Bolcato I.;Scardoni L.;Paulauskas M.;Sakalauskiene U.;Alexandre M.;Berna M.;Diallo F.;Okello C.;Onwuchekwa U.;Marinkovikj S.;Petreska B.;Spasovska K.;Khan R.;Sohail A.;Rafique M.;Rehman A.;Hussain M.;Mustafa S.;Fernandez M. I. L.;de Leon M. L. F.;Dagwasi R. G.;Almero M. L.;Mercado M.;Vergara A.;Repunte F.;Tan S. O.;Ong-Tantuco M. K.;Reyes R. C.;Co P. L. G.;Gabriel-Chan A. L. G.;Reyes-Addatu A. O.;Li-Yu J. T.;Ang S. A.;Del Ayre K. I.;Santos S. M. A.;Torrico A.;Basobas H.;Del Rosario Z.;Taladua K. M.;Ricaforte-Docuyanan H. F.;Ramos-Precilla J. S.;Limson S. A.;Genaro R. C.;Nunez T. A. E.;Santiago A.;Cuevas T. R.;Montoya J. C.;Nala P.;Abaya R.;Mendoza G.;Arellano J.;Baniqued A. R.;Yabut A.;Cruz J. D.;Ligutan S. M.;Sibal E. A.;Dy-Arga G.;Enecilla R.;Villavicencio C. E.;David-Ona D.;Unson S.;Gargar J. D.;Samonte B. M.;Cumpas A. R.;Sumagaysay M. T. F.;Rozul C. D. A.;Tagle P.;Recana-Nieva M.;Bagano M.;Aquino G. M.;Bancat J. D.;Villaflor A. J.;Montalban M. H.;Jaen A. M.;Berame E. J.;Razon-Gonzales E. V.;Gacutan-Liwag A. A.;Altillero M.;Cruz P. V.;Duque F. T.;Vergeire M. R.;Domingo R. E.;Tonolete J. P.;Reotita D. J. D.;Ferreira M.;Luz F.;Alorayyidh N.;Moslmani R.;Abdurrahman A.;Bintaleb D.;Vorster E.;Mabuza L.;Kalambay D.;Lechuti W. B. T.;Koekemoer S.;Moosa S.;Morar T.;Matibela S.;Ramothwala V.;Shaku S.;Ma K.;Barker C.;Chellian J.;Ferreira J.;Kilian Y.;Knight M.;Koeberg L.;Naidoo S.;Rama A.;Strydom D.;Boikanya R.;Cornell S.;Docrat F.;Jacques A.;Moodley K.;Msomi T.;Criado Illana M. T.;Bachiller Luque P.;Carrero Gras A.;Gomez L. I.;Nunez P. G.;Cano V.;Largo Pau J.;Sepulveda M. A.;Carrillo A.;Chumbita M.;De La Mora L.;Etcheverry F.;Hernandez M.;Inciarte A.;Leal L.;Miro O.;Moreno E.;Puerta P.;Sola M.;Soriano A.;Tome A.;Alvarez V.;Astasio-Gonzalez O.;Bueno O.;BUrruezo I.;Garica-Gomez S.;Jimenez-Ortega A.;Martin-Sanchez F. J.;Perez-Ingidua C.;Perez-Macias N.;Tellez M. J.;Uribe-Lopez D.;de la Rica M.;Diez-Galan L.;Pena Villanueva P.;Algarra Vento J.;Perez D. R.;Marcia Paredes A.;Pelleja Munne D.;Razskeivicz A.;Sabate Frias N.;Valero Rovira S.;Ortega P.;Sanz F.;Tamarit J.;Elices-Calzon M. I.;Gonzalez-Cervera J.;Lopez-Larramona G.;Maestre-Muniz M. M.;Martin-Toledano M.;Masegosa-Casanova S.;Ruiz-Chicote A. M.;Agea I.;Boix V.;Garcia R.;Gil J.;Llorens P.;Reus S.;Sanchez R.;Torrus-Tendero D.;Masia M.;Padilla S.;Aldamiz T.;Diez P.;Gutierrez I.;Miguens I.;Perez-Latorre L.;Ramirez M.;Borobia A.;Torres R. M.;Adolfo Centeno G.;Cabalero Bermejo A. F.;Diaz De Santiago A.;Fernandez Cruz A.;Pintos Pascual I.;Ramos Martinez A.;Lopez-Carmona M. D.;Perez-Camacho I.;Perez-Ordono L.;Alvarez Lavin M. M.;Baraiaetxaburu Artetxe J. M.;De La Pena Trigueros M.;De Miguel Landiribar J.;Erburu Iriarte M.;Ferrero Beneitez O.;Ibarra Ugarte S.;Intxausti Urrutibeaskoa M.;Larruscain Zorroza J. I.;Lombide Aguirre I.;Lopez Martinez M.;Martinez de Bourio Uriarte R.;Moreno Munoz C.;Ramiz Martinez M.;Rodriguez Miguel M.;Sagarna Aguirrezabala A.;Torre Salaberri I.;Zubero Sulibarria M.;Arrebola Benitez J. D. D.;Castanar Jover A. M.;Nogales Munoz M. N.;Basterretxea Ozamiz A.;Blanco Vidal M. J.;Del Alamo Martinez M.;Garcia de Vicuna Melendez A.;Ibarrola Hierro M.;Isasi Otaolea J.;Nieto Arana J.;Aranda Rife E.;Balado Rico M.;Conde Senovilla E.;Del Cerro Saelices M.;Herrera Rodriguez A.;Lopez Munoz N.;Manzone E.;Martinez Cifre B.;Munoz Flores M.;Odeh Santana S.;Perez Caballero G.;Barbero Hernandez M. J.;Herrero Rodriguez C.;Horno Urena F.;La Rosa Salas F. J.;Garcia Criado J.;Marcos Martin M.;Agirre E.;Alvarez I.;Andueza M. C.;Berroeta A.;Bustinduy M. J.;Camino X.;Couto A.;Fuertes A.;Goenaga M. A.;Kortajarena X.;Zubeldia J. J.;Zubelzzu B.;Zufiaurre A.;Martinez-Simon J. J.;Martin-Segarra O.;Pablo-Esteban A.;Sierra-Torres G.;Alvaro-Alonso E.;Fortuny-Esterri I.;Garcia-Caballero R.;Llorente Guitierrez J.;Mansilla Paco C.;Navarro Jimenez G.;Nogales-Garcia A.;Sanchez-Rivero I.;Vazquez-Ronda M. A.;Asensio J.;Fullana M. I.;Ramon L.;Jimenez-Lopez R.;Sanchez-Lora J.;Sanchez-Yanez E.;Gutierrez-Moreno M.;Jimenez-Varo I.;Palacios-Baena Z.;Palazon-Carrion N.;Retamar P.;Salamanca-Rivera E.;Sevillano M.;Valiente-Mendez A.;Vicente-Baz D.;Berrocal Gil P.;Aranda Garcia Y.;Borque P.;Comeche B.;Diaz Garcia N.;Escudero-Sanchez R.;Giogia F.;Moreno Guillen S.;Ron Gonzalez R.;Vizcarra P.;Lobo-Acosta M. A.;Rosso-Acosta C. M.;Groen C.;Evison J.;Savet M.;Luyet A.;Bartschi K.;Friedl A.;Rutz F.;Rochat P.;Hackman P.;Wiesli P.;Kistler A.;Ursprung R.;Danioth S.;Werner R.;Dias S.;Schuster M.;Krause M.;Vuichard D.;Majer S.;Rescigno D.;Borer F.;Meyer A.;Kohler M.;Schenker G.;Vazquez P.;Gosmain Y.;Vallotton L.;Warpelin-Decrausaz L.;Sormani V.;Niksch D.;Voidey A.;Sommer I.;Grosjean M.;Garapo C.;Okeibunor J. P.;Hashish A.;Kodama C.;Mandil A.;Butu C.;Dara M.;Kuli A.;Mesi A.;Mamulashvili N.;Zurlyte I.;Reveiz L.;Azim T.;Gupta M.;Takahashi R.;Cawthorne A.;Lo Y. R.;Tonolette J. P.;Benitez S.;Borges A.;Bouquet T.;Chuffart S.;Egorova E.;Embaye R.;Kone S.;Merle C.;Molinaro P.;La Rotta R.;Mafunga N.;Mazur A.;Queyras G.
2022-01-01
Abstract
Background: The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date. Methods: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948. Findings: Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82-1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89-1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76-0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46-1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76-0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77-1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75-0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings. Interpretation: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both). Funding: WHO.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11379/634027
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simulazione ASN
Il report seguente simula gli indicatori relativi alla propria produzione scientifica in relazione alle soglie ASN 2023-2025 del proprio SC/SSD. Si ricorda che il superamento dei valori soglia (almeno 2 su 3) è requisito necessario ma non sufficiente al conseguimento dell'abilitazione. La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione può differire dall'esito di un’eventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilità dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.
La presente simulazione è stata realizzata sulla base delle specifiche raccolte sul tavolo ER del Focus Group IRIS coordinato dall’Università di Modena e Reggio Emilia e delle regole riportate nel DM 589/2018 e allegata Tabella A. Cineca, l’Università di Modena e Reggio Emilia e il Focus Group IRIS non si assumono alcuna responsabilità in merito all’uso che il diretto interessato o terzi faranno della simulazione. Si specifica inoltre che la simulazione contiene calcoli effettuati con dati e algoritmi di pubblico dominio e deve quindi essere considerata come un mero ausilio al calcolo svolgibile manualmente o con strumenti equivalenti.
