Exploring Study Design Foibles in Randomized Controlled Trials on Convalescent Plasma in Hospitalized COVID-19 Patients
Abstract
1. Introduction
2. Material and Methods
3. Results
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Shen, C.; Wang, Z.; Zhao, F.; Yang, Y.; Li, J.; Yuan, J.; Wang, F.; Li, D.; Yang, M.; Xing, L.; et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA 2020, 323, 1582–1589. [Google Scholar] [CrossRef] [PubMed]
- Perotti, C.; Baldanti, F.; Bruno, R.; Del Fante, C.; Seminari, E.; Casari, S.; Percivalle, E.; Glingani, C.; Musella, V.; Belliato, M.; et al. Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial. Haematologica 2020, 105, 2834–2840. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Senefeld, J.W.; Johnson, P.W.; Kunze, K.L.; Bloch, E.M.; van Helmond, N.; Golafshar, M.A.; Klassen, S.A.; Klompas, A.M.; Sexton, M.A.; Diaz Soto, J.C.; et al. Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study. PLoS Med. 2021, 18, e1003872. [Google Scholar] [CrossRef] [PubMed]
- Joyner, M.J.; Carter, R.E.; Senefeld, J.W.; Klassen, S.A.; Mills, J.R.; Johnson, P.W.; Theel, E.S.; Wiggins, C.C.; Bruno, K.A.; Klompas, A.M.; et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N. Engl. J. Med. 2021, 384, 1015–1027. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bloch, E.M.; Shoham, S.; Casadevall, A.; Sachais, B.S.; Shaz, B.; Winters, J.L.; van Buskirk, C.; Grossman, B.J.; Joyner, M.; Henderson, J.P.; et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J. Clin. Investig. 2020, 130, 2757–2765. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- AlQahtani, M.; Abdulrahman, A.; Almadani, A.; Alali, S.Y.; Al Zamrooni, A.M.; Hejab, A.H.; Conroy, R.M.; Wasif, P.; Otoom, S.; Atkin, S.L.; et al. Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. Sci. Rep. 2021, 11, 9927. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Balcells, M.E.; Rojas, L.; Le Corre, N.; Martínez-Valdebenito, C.; Ceballos, M.E.; Ferrés, M.; Chang, M.; Vizcaya, C.; Mondaca, S.; Huete, Á.; et al. Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial. PLoS Med. 2021, 18, e1003415. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Baldeón, M.E.; Maldonado, A.; Ochoa-Andrade, M.; Largo, C.; Pesantez, M.; Herdoiza, M.; Granja, G.; Bonifaz, M.; Espejo, H.; Mora, F.; et al. Effect of convalescent plasma as complementary treatment in patients with moderate COVID-19 infection. Transfus. Med. 2022, 32, 153–161. [Google Scholar] [CrossRef] [PubMed]
- Beltran Gonzalez, J.L.; Gonzalez Gamez, M.; Mendoza Enciso, E.A.; Esparza Maldonado, R.J.; Hernandez Palacios, D.; Duenas Campos, S.; Ovalle Robles, I.; Macias Guzman, M.J.; Garcia Diaz, A.L.; Gutierrez-Pena, C.M.; et al. Efficacy and safety of convalescent plasma and intravenous immunoglobulin in critically ill COVID-19 patients. A controlled clinical trial. medRxiv 2021. [Google Scholar] [CrossRef]
- Bennett-Guerrero, E.; Romeiser, J.L.; Talbot, L.R.; Ahmed, T.; Mamone, L.J.; Singht, S.M.; Hearing, J.C.; Salman, H.; Holiprosad, D.D.; Freedenberg, A.T.; et al. Severe Acute Respiratory Syndrome Coronavirus 2 Convalescent Plasma Versus Standard Plasma in Coronavirus Disease 2019 Infected Hospitalized Patients in New York: A Double-Blind Randomized Trial. Crit. Care Med. 2021, 49, 1015–1025. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Korley, F.K.; Durkalski-Mauldin, V.; Yeatts, S.D.; Schulman, K.; Davenport, R.D.; Dumont, L.J.; El Kassar, N.; Foster, L.D.; Hah, J.M.; Jaiswal, S.; et al. Early Convalescent Plasma for High-Risk Outpatients with COVID-19. N. Engl. J. Med. 2021, 385, 1951–1960. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Körper, S.; Weiss, M.; Zickler, D.; Wiesmann, T.; Zacharowski, K.; Corman, V.M.; Grüner, B.; Ernst, L.; Spieth, P.; Lepper, P.M.; et al. Results of the CAPSID randomized trial for high-dose convalescent plasma in patients with severe COVID-19. J. Clin. Investig. 2021, 131, e152264. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Thorlacius-Ussing, L.; Brooks, P.T.; Nielsen, H.; Jensen, B.A.; Wiese, L.; Saekmose, S.G.; Johnsen, S.; Gybel-Brask, M.; Johansen, I.S.; Topholm Bruun, M.; et al. A randomized placebo-controlled trial of convalescent plasma for adults hospitalized with COVID-19 pneumonia. Sci. Rep. 2022, 12, 16385. [Google Scholar] [CrossRef] [PubMed]
- Bégin, P.; Callum, J.; Jamula, E.; Cook, R.; Heddle, N.M.; Tinmouth, A.; Zeller, M.P.; Beaudoin-Bussières, G.; Amorim, L.; Bazin, R.; et al. Convalescent plasma for hospitalized patients with COVID-19: An open-label, randomized controlled trial. Nat. Med. 2021, 27, 2012–2024, Erratum in Nat. Med. 2022, 28, 212. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Gharbharan, A.; Jordans, C.C.E.; GeurtsvanKessel, C.; den Hollander, J.G.; Karim, F.; Mollema, F.P.N.; Stalenhoef-Scukken, J.E.; Dofferhoff, A.; Ludwig, I.; Koster, A.; et al. Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection. Nat. Commun. 2021, 12, 3189. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Misset, B.; Piagnerelli, M.; Hoste, E.; Dardenne, N.; Grimaldi, D.; Michaux, I.; De Waele, E.; Dumoulin, A.; Jorens, P.G.; van der Hauwaert, E.; et al. Convalescent Plasma for Covid-19-Induced ARDS in Mechanically Ventilated Patients. N. Engl. J. Med. 2023, 389, 1590–1600. [Google Scholar] [CrossRef] [PubMed]
- Avendaño-Solá, C.; Ramos-Martínez, A.; Muñez-Rubio, E.; Ruiz-Antoran, B.; Malo de Molina, R.; Torres, F.; Fernandez-Cruz, A.; Calderon-Parra, J.; Payeares-Herrera, C.; Diaz De Santiago, A.; et al. A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia. J. Clin. Investig. 2021, 131, e152740. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Ortigoza, M.B.; Yoon, H.; Goldfeld, K.S.; Troxel, A.B.; Daily, J.P.; Wu, Y.; Li, Y.; Wu, D.; Cobb, G.F.; Baptiste, G.; et al. Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial. JAMA Intern. Med. 2022, 182, 115–126. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Alemany, A.; Millat-Martinez, P.; Corbacho-Monné, M.; Malchair, P.; Ouchi, D.; Ruiz-Comellas, A.; Ramírez-Morros, A.; Rodríguez Codina, J.; Amado Simon, R.; Videla, S.; et al. High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: A randomised, placebo-controlled trial. Lancet Respir. Med. 2022, 10, 278–288. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Holm, K.; Lundgren, M.N.; Kjeldsen-Kragh, J.; Ljungquist, O.; Böttiger, B.; Wikén, C.; Öberg, J.; Fernström, N.; Rosendal, E.; Överby, A.K.; et al. Convalescence plasma treatment of COVID-19: Results from a prematurely terminated randomized controlled open-label study in Southern Sweden. BMC Res. Notes 2021, 14, 440. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bajpai, M.; Maheshwari, A.; Dogra, V.; Kumar, S.; Gupta, E.; Kale, P.; Saluja, V.; Thomas, S.S.; Trehanpati, N.; Bihari, C.; et al. Efficacy of convalescent plasma therapy in the patient with COVID-19: A randomised control trial (COPLA-II trial). BMJ Open 2022, 12, e055189. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bargay-Lleonart, J.; Sarubbo, F.; Arrizabalaga, M.; Guerra, J.M.; Borras, J.; El Hajii, K.; Flexas, M.; Perales, J.; Fernandez-Baca, V.; Gallegos, C.; et al. Reinforcement of the Standard Therapy with Two Infusions of Convalescent Plasma for Patients with COVID-19: A Randomized Clinical Trial. J. Clin. Med. 2022, 11, 3039. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Lacombe, K.; Hueso, T.; Porcher, R.; Mekinian, A.; Chiarabini, T.; Georgin-Lavialle, S.; Ader, F.; Saison, J.; Martin-Blondel, G.; De Castro, N.; et al. Use of covid-19 convalescent plasma to treat patients admitted to hospital for covid-19 with or without underlying immunodeficiency: Open label, randomised clinical trial. BMJ Med. 2023, 2, e000427. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Gharbharan, A.; Jordans, C.; Zwaginga, L.; Papageorgiou, G.; van Geloven, N.; van Wijngaarden, P.; den Hollander, J.; Karim, F.; van Leeuwen-Segarceanu, E.; Soetekouw, R.; et al. Outpatient convalescent plasma therapy for high-risk patients with early COVID-19: A randomized placebo-controlled trial. Clin. Microbiol. Infect. 2023, 29, 208–214. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bartelt, L.A.; Markmann, A.J.; Nelson, B.; Keys, J.; Root, H.; Henderson, H.I.; Kuruc, J.A.; Baker, C.; Bhowmik, D.R.; Hou, Y.J.; et al. Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study. mBio 2022, 13, e0175122. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Devos, T.; Van Thillo, Q.; Compernolle, V.; Najdovski, T.; Romano, M.; Dauby, N.; Jadot, L.; Leys, M.; Maillart, E.; Loof, S.; et al. Early high antibody titre convalescent plasma for hospitalised COVID-19 patients: DAWn-plasma. Eur. Respir J. 2022, 59, 2101724. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Denkinger, C.M.; Janssen, M.; Schäkel, U.; Gall, J.; Leo, A.; Stelmach, P.; Weber, S.F.; Krisam, J.; Baumann, L.; Stermann, J.; et al. Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: A randomized clinical trial. Nat. Cancer 2023, 4, 96–107. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- De Santis, G.C.; Oliveira, L.C.; Garibaldi, P.M.M.; Almado, C.E.L.; Croda, J.; Arcanjo, G.G.A.; Oliveira, É.A.F.; Tonacio, A.C.; Langhi, D.M., Jr.; Bordin, J.O.; et al. High-Dose Convalescent Plasma for Treatment of Severe COVID-19. Emerg. Infect. Dis. 2022, 28, 548–555. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Hamdy Salman, O.; Ail Mohamed, H.S. Efficacy and safety of transfusing plasma from COVID-19 survivors to COVID-19 victims with severe illness. A double-blinded controlled preliminary study. Egypt. J. Anaesth. 2020, 36, 264–272. [Google Scholar] [CrossRef]
- Irawan, C.; Rumende, C.M.; Sukrisman, L.; Pitoyo, C.W.; Suwarto, S.; Susilo, A.; Mulansari, N.A.; Harahap, A.T.; Priantono, D.; Syafitri, R.; et al. Efficacy of COVID convalescent plasma therapy in hospitalized moderate coronavirus disease 2019 patients. J. Infect. Dev. Ctries 2023, 17, 43–51. [Google Scholar] [CrossRef] [PubMed]
- Kirenga, B.; Byakika-Kibwika, P.; Muttamba, W.; Kayongo, A.; Loryndah, N.O.; Mugenyi, L.; Kiwanuka, N.; Lusiba, J.; Atukunda, A.; Mugume, R.; et al. Efficacy of convalescent plasma for treatment of COVID-19 in Uganda. BMJ Open Respir. Res. 2021, 8, e001017. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Khawaja, T.; Kajova, M.; Levonen, I.; Pietilä, J.P.; Välimaa, H.; Paajanen, J.; Pakkanen, S.H.; Patjas, A.; Montonen, R.; Miettinen, S.; et al. Double-blinded, randomised, placebo-controlled trial of convalescent plasma for COVID-19: Analyses by neutralising antibodies homologous to donors’ variants. Infect. Dis. 2024, 56, 423–433. [Google Scholar] [CrossRef] [PubMed]
- Li, L.; Zhang, W.; Hu, Y.; Tong, X.; Zheng, S.; Yang, J.; Kong, Y.; Ren, L.; Wei, Q.; Mei, H.; et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA 2020, 324, 460–470. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Libster, R.; Pérez Marc, G.; Wappner, D.; Coviello, S.; Bianchi, A.; Braem, V.; Esteban, I.; Caballero, M.T.; Wood, C.; Berrueta, M.; et al. Early High-Titer Plasma Therapy to Prevent Severe COVID-19 in Older Adults. N. Engl. J. Med. 2021, 384, 610–618. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- O’Donnell, M.R.; Grinsztejn, B.; Cummings, M.J.; Justman, J.E.; Lamb, M.R.; Eckhardt, C.M.; Philip, N.M.; Cheung, Y.K.; Gupta, V.; João, E.; et al. A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19. J. Clin. Investig. 2021, 131, e150646. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Self, W.H.; Wheeler, A.P.; Stewart, T.G.; Schrager, H.; Mallada, J.; Thomas, C.B.; Cataldo, V.D.; O’Neal, H.R., Jr.; Shapiro, N.I.; Higgins, C.; et al. Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial. Chest 2022, 162, 982–994. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Bar, K.J.; Shaw, P.A.; Choi, G.H.; Aqui, N.; Fesnak, A.; Yang, J.B.; Soto-Calderon, H.; Grajales, L.; Starr, J.; Andronov, M.; et al. A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia. J. Clin. Investig. 2021, 131, e155114. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Agarwal, A.; Mukherjee, A.; Kumar, G.; Chatterjee, P.; Bhatnagar, T.; Malhotra, P.; PLACID Trial Collaborators. Convalescent plasma in the management of moderate COVID-19 in adults in India: Open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020, 371, m3939, Erratum in BMJ 2020, 371, m4232. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Manzini, P.M.; Ciccone, G.; De Rosa, F.G.; Cavallo, R.; Ghisetti, V.; D’Antico, S.; Galassi, C.; Saccona, F.; Castiglione, A.; Birocco, N.; et al. Convalescent or standard plasma versus standard of care in the treatment of COVID-19 patients with respiratory impairment: Short and long-term effects. A three-arm randomized controlled clinical trial. BMC Infect. Dis. 2022, 22, 879. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Sekine, L.; Arns, B.; Fabro, B.R.; Cipolatt, M.M.; Machado, R.R.G.; Durigon, E.L.; Parolo, E.; Pellegrini, J.A.S.; Viana, M.V.; Schwarz, P.; et al. Convalescent plasma for COVID-19 in hospitalised patients: An open-label, randomised clinical trial. Eur. Respir J. 2022, 59, 2101471. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Siripongboonsitti, T.; Nontawong, N.; Tawinprai, K.; Suptawiwat, O.; Soonklang, K.; Poovorawan, Y.; Mahanonda, N. Efficacy of combined COVID-19 convalescent plasma with oral RNA-dependent RNA polymerase inhibitor treatment versus neutralizing monoclonal antibody therapy in COVID-19 outpatients: A multi-center, non-inferiority, open-label randomized controlled trial (PlasMab). Microbiol Spectr. 2023, 11, e0325723. [Google Scholar] [CrossRef] [PubMed]
- Simonovich, V.A.; Burgos Pratx, L.D.; Scibona, P.; Beruto, M.V.; Vallone, M.G.; Vázquez, C.; Savoy, N.; Giunta, D.H.; Pérez, L.G.; Sánchez, M.D.L.; et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N. Engl. J. Med. 2021, 384, 619–629. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Pouladzadeh, M.; Safdarian, M.; Eshghi, P.; Abolghasemi, H.; Ghorbani Bavani, A.; Sheibani, B.; Mroadi Chogahakabodi, P.; Feghhi, A.; Ghafourian Boroujerdnia, M.; Forouzan, A.; et al. A randomized clinical trial evaluating the immunomodulatory effect of convalescent plasma on COVID-19-related cytokine storm. Intern. Emerg. Med. 2021, 16, 2181–2191. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- van den Berg, K.; Glatt, T.N.; Vermeulen, M.; Little, F.; Swanevelder, R.; Barrett, C.; Court, R.; Bremer, M.; Nyoni, C.; Swarts, A.; et al. Convalescent plasma in the treatment of moderate to severe COVID-19 pneumonia: A randomized controlled trial (PROTECT-Patient Trial). Sci. Rep. 2022, 12, 2552. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Rasheed, A.M.; Fatak, D.F.; Hashim, H.A.; Maulood, M.F.; Kabah, K.K.; Almusawi, Y.A.; Abdulamir, A.S. The therapeutic potential of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq. Infez. Med. 2020, 28, 357–366. [Google Scholar] [PubMed]
- Ray, Y.; Paul, S.R.; Bandopadhyay, P.; D’Rozario, R.; Sarif, J.; Raychaudhuri, D.; Bhowmik, D.; Lahiri, A.; Vasudevan, J.S.; Maurya, R.; et al. A phase 2 single center open label randomised control trial for convalescent plasma therapy in patients with severe COVID-19. Nat. Commun. 2022, 13, 383. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): A randomised controlled, open-label, platform trial. Lancet 2021, 397, 2049–2059. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Writing Committee for the REMAP-CAP Investigators; Estcourt, L.J.; Turgeon, A.F.; McQuilten, Z.K.; McVerry, B.J.; Al-Beidh, F.; Annane, D.; Arabi, Y.M.; Arnold, D.M.; Beane, A.; et al. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA 2021, 326, 1690–1702. [Google Scholar] [CrossRef] [PubMed]
- Rojas, M.; Rodríguez, Y.; Hernández, J.C.; Díaz-Coronado, J.C.; Vergara, J.A.D.; Vélez, V.P.; Mancilla, J.P.; Araujo, I.; Yepes, J.T.; Ricaurte, O.B.; et al. Safety and efficacy of convalescent plasma for severe COVID-19: A randomized, single blinded, parallel, controlled clinical study. BMC Infect. Dis. 2022, 22, 575. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Saito, S.; Kutsuna, S.; Akifumi, I.; Hase, R.; Oda, R.; Terada, J.; Shimizu, Y.; Uemura, Y.; Takamatsu, Y.; Yasuhara, A.; et al. Efficacy of convalescent plasma therapy for COVID-19 in Japan: An open-label, randomized, controlled trial. J. Infect. Chemother. 2023, 29, 869–874. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Sullivan, D.J.; Gebo, K.A.; Shoham, S.; Bloch, E.M.; Lau, B.; Shenoy, A.G.; Mosnaim, G.S.; Gniadek, T.J.; Fukuta, Y.; Patel, B.; et al. Early Outpatient Treatment for Covid-19 with Convalescent Plasma. N. Engl. J. Med. 2022, 386, 1700–1711. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Menichetti, F.; Popoli, P.; Puopolo, M.; Spila Alegiani, S.; Tiseo, G.; Bartoloni, A.; De Socio, G.V.; Luchi, S.; Blanc, P.; Puoti, M.; et al. Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Netw. Open 2021, 4, e2136246, Erratum in JAMA Netw. Open 2022, 5, e2146944. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Ventura-Enríquez, Y.; Cabello-Gutiérrez, C.; Pérez-Calatayud, Á.A.; Cortina-De La Rosa, E.; Fareli-Gonzale, C.J.; Castillo-Juarez, P.; Pena-Perez Carlos, A.; Zavaleta-Martinez, E.O.; Diaz-Padilla, E.; Murrieta, S.; et al. Convalescent Plasma to Treat COVID-19: A Two-Center, Randomized, Double-Blind Clinical Trial. Life 2022, 12, 1767. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Senefeld, J.W.; Franchini, M.; Mengoli, C.; Cruciani, M.; Zani, M.; Gorman, E.K.; Focosi, D.; Casadevall, A.; Joyner, M.J. COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis. JAMA Netw. Open 2023, 6, e2250647. [Google Scholar] [CrossRef] [PubMed]
- Sullivan, D.J.; Focosi, D.; Hanley, D.F.; Cruciani, M.; Franchini, M.; Ou, J.; Casadevall, A.; Paneth, N. Outpatient randomized controlled trials to reduce COVID-19 hospitalization: Systematic review and meta-analysis. J. Med. Virol. 2023, 95, e29310. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Focosi, D.; Franchini, M. COVID-19 convalescent plasma therapy: Hit fast, hit hard! Vox Sang 2021, 116, 935–942. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Senefeld, J.W.; Gorman, E.K.; Johnson, P.W.; Moir, M.E.; Klassen, S.A.; Carter, R.E.; Paneth, N.S.; Sullivan, D.J.; Morkeberg, O.H.; Wright, R.S.; et al. Rates Among Hospitalized Patients With COVID-19 Treated with Convalescent Plasma: A Systematic Review and Meta-Analysis. Mayo Clin. Proc. Innov. Qual. Outcomes 2023, 7, 499–513. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Iannizzi, C.; Chai, K.L.; Piechotta, V.; Valk, S.J.; Kimber, C.; Monsef, I.; Wood, E.M.; Lamikanra, A.A.; Roberts, D.J.; McQuilten, Z.; et al. Convalescent plasma for people with COVID-19: A living systematic review. Cochrane Database Syst. Rev. 2023, 5, CD013600. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Franchini, M.; Liumbruno, G.M.; Piacentini, G.; Glingani, C.; Zaffanello, M. The Three Pillars of COVID-19 Convalescent Plasma Therapy. Life 2021, 11, 354. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Zheng, K.; Liao, G.; Lalu, M.M.; Tinmouth, A.; Fergusson, D.A.; Allan, D.S. A Scoping Review of Registered Clinical Trials of Convalescent Plasma for COVID-19 and a Framework for Accelerated Synthesis of Trial Evidence (FAST Evidence). Transfus. Med. Rev. 2020, 34, 158–164. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Schünemann, H.J.; Oxman, A.D.; Higgins, J.P.; Vist, G.E.; Glasziou, P.; Guyatt, G.H. Chapter 11: Presenting results and ‘Summary of findings’ tables. In Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0; (updated March 2011); Higgins, J.P., Green, S., Eds.; The Cochrane Collaboration: London, UK, 2011; Available online: https://handbook-5-1.cochrane.org/ (accessed on 19 June 2024).
- Nakagawa, S.; Lagisz, M.; Yang, Y.; Drobniak, S.M. Finding the right power balance: Better study design and collaboration can reduce dependence on statistical power. PLoS Biol. 2024, 22, e3002423. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Kadam, P.; Bhalerao, S. Sample size calculation. Int. J. Ayurveda Res. 2010, 1, 55–57. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Wang, X.; Ji, X. Sample Size Estimation in Clinical Research: From Randomized Controlled Trials to Observational Studies. Chest 2020, 158, S12–S20. [Google Scholar] [CrossRef] [PubMed]
- Janiaud, P.; Hemkens, L.G.; Ioannidis, J.P.A. Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently? Can. J. Cardiol. 2021, 37, 1353–1364. [Google Scholar] [CrossRef] [PubMed]
- Luke, T.C.; Kilbane, E.M.; Jackson, J.L.; Hoffman, S.L. Meta-analysis: Convalescent blood products for Spanish influenza pneumonia: A future H5N1 treatment? Ann. Intern. Med. 2006, 145, 599–609. [Google Scholar] [CrossRef] [PubMed]
- ACTIV-3–Therapeutics for Inpatients with COVID-19 (TICO) Study Group. Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: A randomised, double-blind, phase 3 trial. Lancet Respir. Med. 2022, 10, 972–984, Erratum in Lancet Respir. Med. 2022. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews Systematic reviews and Meta-Analyses. BMJ 2021, 372, n71. [Google Scholar] [CrossRef] [PubMed]
Study, Year [ref.] NCT | Study Design | Recruitment Start (mm/dd/yy) | Sample Size Estimation | Cases/Controls | Early Termination (Reason) | Primary Outcome | 28-Day Mortality | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
Effect Size 1 | Power | CL | Expected | Actual | Endpoint | Reached | |||||
Balcells, 2021 [7] | Open-label RCT including hospitalized COVID-19 patients | 05/10/2020 | AD: 35% | 80% | 95% | 29 early CCP + ST/29 late CCP + ST | 28 early CCP + ST/30 late CCP + ST | No | Composite of mechanical ventilation; hospitalization for >14 days or death | No | Early CCP: 5/28 (17.9%) Late CCP: 2/30 (6.7%) P = 0.25 |
Baldeon, 2021 [8] | Double-blind, placebo-controlled RCT including hospitalized pts. with moderate COVID-19 | 05/01/2020 | RD: 40% | 80% | 95% | 100 CCP/95 SP | 63 CCP/95 SP | No | Survival rate at 28 days | No | CCP: 11.1% SP: 12.6% P = NS |
Bennett-Guerrero, 2021 [10] | Double-blind RCT including hospitalized COVID-19 patients | 04/08/2020 | RD: 25% | 90% | 95% | 400 CCP/100 SP | 59 CCP/15 SP | Yes (EUA from FDA) | Number of ventilator-free days from randomization to day 28 | No | CCP: 14/59 (23.7%) SP: 4/15 P = 0.80 (26.7%) |
CAPSID, 2021 [12] NCT04433910 | Open-label RCT including hospitalized patients with severe COVID-19 | 08/30/2020 | AD: 30% | 80% | 95% | 48 CCP + ST/48 ST | 53 CCP + ST/52 ST | No | Composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21 | No | CCP + ST: 8/53 (15.1%) ST: 14/52 (26.9%) P = 0.16 |
CCAP-2, 2022 [13] NCT04345289 | Double-blind, placebo-controlled RCT including hospitalized COVID-19 pts. | 06/13/2020 | RD: 35% | 80% | 95% | 353 CCP/177 PL | 98 CCP/46 PL | Yes (futility) | Clinical status on day 14 | No | CCP: 12/98 (12.2%) PL: 3/46 (6.5%) P = NS |
CONCOR-1, 2021 [14] NCT04348656 | Open-label RCT including hospitalized patients with COVID-19 | 05/14/2020 | RD: 25% | 80% | 95% | 800 CCP/400 ST | 625 CCP/313 ST | Yes (futility) | Composite outcome of intubation or death by day 30 | No | CCP: 114/548 (20.8%) ST: 62/303 (20.5%) P = 0.90 |
ConCOVID, 2021 [15] | Open-label, RCT including hospitalized patients with severe COVID-19 | 04/08/2020 | AD: 50% | 80% | 95% | 213 CCP/213 ST | 43 CCP/43 ST | Yes (nAbs in recipients at admission) | Overall mortality until discharge | No | CCP: 6/43 (13.9%) ST: 11/43 (25.6%) P = NS |
CONFIDENT, 2023 [16] NCT04558476 | Open-label RCT including mechanically ventilated COVID-19 patients | 09/01/2020 | RD: 33% | 80% | 95% | 250 CCP/250 ST | 237 CCP/238 ST | No | 28-day mortality | Yes | CCP: 84/237 (35.4%) ST: 107/238 (45.0%) P = 0.03 |
ConPlas, 2021 [17] NCT04345523 | Open-label RCT including hospitalized patients with COVID-19 | 04/04/2020 | RD: 50% | 80% | 95% | 175 CCP/175 ST | 179 CP/171 ST | No | Clinical worsening at 14 days | Yes | CCP: 7/179 (3.9%) ST: 14/171 (8.2%) P = 0.11 |
CONTAIN COVID-19, [18] NCT04364737 | Open-label RCT including hospitalized patients with COVID-19 | 04/17/2020 | AD 18% | 80% | 95% | 463 CCP/463 PL | 468 CCP/473 PL | No | Clinical status on day 14 | No | CCP: 59/462 (12.8%) PL: 71/462 (15.4%) |
COPLA-II, 2022 [21] NCT04425915 | Open-label, phase III RCT including severe COVID-19 patients | 06/14/2020 | RD: 25% | 80% | 95% | 190 CCP + ST/190 ST | 200 CCP + ST/200 ST | No | Clinical improvement measured by a two-point reduction in the ordinal scale | Yes | CCP + ST: 42/200 (53.2%) ST: 37/200 (46.8%) P = 0.62 |
Coplasma-2020, 2022 [22] | RCT including hospitalized patients with COVID-19 | 07/01/2020 | AD: 20% | 80% | 95% | 126 CCP/63 ST | 37 CCP/17 ST | Yes (slow recruitment) | Time for clinical improvement within 21 days | Yes | CCP: 0/37 ST: 0/17 |
CORIPLASM, 2023 [23] NCT04345991 | Open-label RCT including hospitalized COVID-19 patients | 04/16/2020 | AD: 30% | 97.2% | NR | 60 CCP/60 ST | 60 CCP/60 ST | No | WHO score > 6 on day 4 and survival on day 14 | No | CCP: 7/60 (11.7%) ST: 12/60 (20.0%) P = NS |
DAWn-plasma, 2021 [26] | RCT including patients hospitalized for COVID-19 | NR | RD: 50% | 80% | 95% | 322 CCP/161 ST | 320 CCP/163 ST | No | Patient alive without mechanical ventilation at day 15 | No | CCP: 8.8% ST: 8.8% |
Denkinger, 2023 [27] | Open-label RCT including cancer patients hospitalized with severe COVID-19 | 09/03/2020 | RD: 35% | 80% | 95% | 87 CCP + ST/87 ST | 68 CCP + ST/66 ST | Yes (slow recruitment) | Time to clinical improvement of two points on a 7-point ordinal scale | Yes | CCP + ST: 14/68 (20.6%) ST: 19/66 (28.8%) P = NS |
Hamdy Salman, 2020 [29] | RCT including hospitalized COVID-19 pts. | 06/01/2020 | AD: 20% | 80% | 95% | 15 CCP + ST/15 ST | 15 CCP + ST/15 ST | No | Reduction in two or more of a four-category illness severity scale over 5 days | Yes | NR |
Kirenga, 2021 [31] NCT04542941 | RCT including hospitalized COVID-19 patients | 09/21/2020 | RD: 40% | 80% | 95% | 66 CCP + ST/66 ST | 69 CCP + ST/67 ST | No | Viral clearance by day 28 | No | CCP + ST: 10/69 (14.5%) ST: 8/67 (11.9%) P = 0.66 |
Khawaja, 2024 [32] | RCT including hospitalized COVID-19 pts. | 02/02/2021 | RD: 45% | 80% | 95% | 130 HT-CCP/130 LT-CCP/130 PL | 18 HT-CCP/19 LT-CCP/20 PL | Yes (slow recruitment) | Reduction in intubation and corticosteroid support, safety. | No | HT-CCP: 0/18 LT-CCP: 1/19 (5.2) PL: 0/20 |
Li, 2020 [33] ChiCTR2000029757 | Open-label RCT including patients with severe or life-threatening COVID-19 | 02/14/2020 | RD: 40% | 80% | 95% | 100 CCP + ST/100 ST | 52 CCP + ST/51 ST | Yes (slow recruitment) | Time to clinical improvement within 28 days | No | CCP + ST: 8/51 (15.7%) ST: 12/50 (24.0%) P = 0.30 |
O’Donnell, 2021 [35] | Double-blind RCT including hospitalized COVID-19 pts. | 04/21/2020 | OR: 1.5 | 82% | NR | 146 CCP/73 SP | 150 CCP/73 SP | No | Clinical status at 28 days | No | CCP 19/150 SP 18/73 P = 0.03 |
PassITON, 2022 [36] NCT04362176 | Double-blind, placebo-controlled RCT including hospitalized COVID-19 pts. | 04/28/2020 | OR: ≤0.73 | 80% | 95% | 500 CCP/500 PL | 487 CCP/473 PL | No | Clinical status at 14 days | No | CCP: 89/482 (18.5%) PL: 80/465 (17.2%) P = NS |
PLACID, 2020 [38] CTRI/2020/04/024775 | Open-label, parallel-arm, phase II RCT including hospitalized patients with moderate COVID-19 | 04/22/2020 | RD: 50% | 80% | 95% | 226 CCP + ST/226 ST | 235 CCP + ST/229 ST | No | Composite outcome of progression to sever disease or all-cause mortality at 28 days | No | CCP + ST: 44/235 (18.7%) ST: 41/229 (17.9%) P = NS |
PLACO COVID, 2022 [39] NCT04428021 | Three-arm blinded RCT on hospitalized COVID-19 patients; power 80% | 06/01/2020 | AD: 15% | 80% | 95% | 60 CCP + ST/60 ST/60 SP + ST | 60 CCP + ST/60 ST/60 SP + ST | No | 30-day mortality | No | CCP + ST: 14/60 (23.3%) ST: 12/60 (20.0%) P = 0.69 |
PLACOVID, 2022 [40] NCT04547660 | Open-label RCT including hospitalized COVID-19 patients | 07/15/2020 | AD: 20% | 80% | 95% | 80 CCP + ST/80 ST | 80 CCP + ST/80 ST | No | Proportion of patients with clinical improvement at day + 28 | No | CCP + ST: 18/80 (22.5%) ST: 13/80 (16.3%) P = 0.32 |
PlasmAr, 2021 [42] NCT04383535 | Double-blind, placebo-controlled RCT including severe COVID-19 patients | 05/28/2020 | OR: 1.8 | 80% | 95% | 222 CCP/111 PL | 228 CCP/105 PL | No | Patient’s clinical status at 30 days | No | CCP: 25/228 (11.0%) PL: 12/105 (11.4%) P = NS |
PROTECT, 2022 [44] NCT04516811 | Double-blind, phase III RCT including patients with moderate to severe COVID-19 | 09/30/2020 | RD: 33% | 80% | 95% | 300 CCP/300 PL | 52 CCP/51 PL | Yes (futility) | Clinical improvement at day 28 | No | CCP: 11/52 (21.5%) PL: 13/51 (25.5%) P = NS |
Ray, 2022 [46] CTRI/2020/05/025209 | Open-label, phase II RCT including hospitalized COVID-19 patients | 05/31/2020 | AD: 23% | NR | NR | 40 CCP/40 ST | 40 CCP/40 ST | No | All-cause mortality by day 30 | No | CCP: 10/40 (25.0%) ST: 14/40 (35.0%) P = NS |
RECOVERY, 2021 [47] NCT04381936 | Open-label RCT including hospitalized COVID-19 patients | 05/28/2020 | AD: 20% | 90% | 99% | 5500 CCP + ST/550 ST | 5795 CCP + ST/5763 ST | No | 28-day mortality | No | CCP + ST: 1399/5795 (24.1%) ST: 1408/5763 (24.4%) P = 0.95 |
REMAP-CAP, 2021 [48] NCT02735707 | Open-label RCT including critically ill COVID-19 pts. | 03/09/2020 | OR: 1.2 | NR | NR | NR | 1075 CCP/904 PL | No | Median number of organ support-free days | No | CCP: 352/1074 (32.8%) PL: 300/904 (33.2%) P = NS |
Rojas, 2022 [49] NCT04332835 | Single-blinded, parallel-controlled RCT in including hospitalized COVID-19 patients | 08/08/2020 | RD: 30% | 90% | 95% | 46 CCP + ST/46 ST | 40 CCP + ST/43 ST | No | Reduction in viral load at day 28 | No | CCP + ST: 6/46 (13.0%) ST: 2/45 (4.4%) P = 0.15 |
Saito, 2023 [50] | Open-label RCT including hospitalized patients with mild COVID-19 | 02/24/2021 | RD: 50% | 90% | 95% | 96 CCP/96 ST | 10 CCP/11 ST | Yes (vaccination coverage and mAB availability) | Time-weighted average change in the SARS-CoV-2 viral load | No | No deaths recorded |
TSUNAMI, 2021 [52] NCT04716556 | Open-label RCT including hospitalized COVID-19 patients | 07/15/2020 | RD:40% | 80% | 95% | 237 CCP + ST/237 ST | 231 CCP + ST/239 ST | No | Composite of worsening respiratory failure or death < 30 days | No | CCP + ST: 14/231 (6.1%) ST: 19/239 (7.9%) P = 0.43 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Franchini, M.; Mengoli, C.; Casadevall, A.; Focosi, D. Exploring Study Design Foibles in Randomized Controlled Trials on Convalescent Plasma in Hospitalized COVID-19 Patients. Life 2024, 14, 792. https://doi.org/10.3390/life14070792
Franchini M, Mengoli C, Casadevall A, Focosi D. Exploring Study Design Foibles in Randomized Controlled Trials on Convalescent Plasma in Hospitalized COVID-19 Patients. Life. 2024; 14(7):792. https://doi.org/10.3390/life14070792
Chicago/Turabian StyleFranchini, Massimo, Carlo Mengoli, Arturo Casadevall, and Daniele Focosi. 2024. "Exploring Study Design Foibles in Randomized Controlled Trials on Convalescent Plasma in Hospitalized COVID-19 Patients" Life 14, no. 7: 792. https://doi.org/10.3390/life14070792
APA StyleFranchini, M., Mengoli, C., Casadevall, A., & Focosi, D. (2024). Exploring Study Design Foibles in Randomized Controlled Trials on Convalescent Plasma in Hospitalized COVID-19 Patients. Life, 14(7), 792. https://doi.org/10.3390/life14070792