Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial
Prof Hugh Montgomery, F D Richard Hobbs, Francisco Padilla, Douglas Arbetter, Alison Templeton, Seth Seegobin, MD Kenneth Kim, Jesus Abraham Simón Campos, Rosalinda H Arends, Bryan H Brodek, Dennis Brooks, Pedro Garbes, Julieta Jimenez, Gavin C K W Koh, Kelly W Padilla, Katie Streicher, Rolando M Viani, Vijay Alagappan, Menelas N Pangalos, Mark T Esser, Wakana Abe, Tania Adan De Varona, Daria Adiatullina, Daniel Aguilar Zapata, Kevin Ahlers, Carolina Aimo, Ayoade Akere, Elena Akimova, Jorge Alatorre Alexander, Logan Aldrich, Ismael Ali Garcia, Karim Ali García, Lee Allison, Rosa Alonso Zuñiga, Ivan Aloysius, Javier Altclas, Andres Alvarisqueta, Martti Antila, Camila Anton, Elisabet Árboix Alamo, Samir Arora, Ramón Alejandro Avilés Felix, Natalya Bakhtina, Varenka Barbero-Becerra, Armando Barragan-Reyes, Alejandro Barreira, Mitchell Barrett, Jiri Beran, Nikolett Berki, Viktoria Berki, Richard Betten, Claudia Binelli, Lenka Brunzová, Cecilia Bussolari, Karianna Byargeon, Justyna Bytnar, Carlos Camberos, Pedro Campos Corzo, Grazia Cannon, Valentina Canovi, Simone Carla Da Rosa, Ana Caroline Moser, Luis Carrera Rivas, Marcelo Martin Casas, Paulo Castañeda-Méndez, Ana Cavalcante, Eugenia Cherepova, Alexei Chermenskii, Lauren Clark, Mauro Codeluppi, Flavia Coelho, Belinda Contreras, Alex Cran, Taylor Dao, Chrisette Dharma, Cosimo Di Castri, Victoria Diaz Balocchi, Omar Durán, Kara Earl, Adam Ellery, Tomoko Endo, Andrea Everding, Rainald Fischer, Benedito Fonseca, Chelsea C Franklin, Susan-Beatrice Franz, Anna Fumagalli, Mauricio Galindo-Amaya, Mariagiulia Galli, Laura Gerna, Karolly Gil Ureña, Henrikki Gomes Antila, Laura Ines Gomes Maricato, Gabriela Goncalvez, Martin Gonzalez, Jesús González-Lama, Stephen Granier, Jacob Granier, Stephan Grunwald, David Guardeño-Ropero, Monica Guberti, Sridhar Guduri, Carolina Guerrero García, Jehad Haggiagi, Kacie Hale, Toshimasa Hayashi, Maiara Hermes, Dante Hernandez Colin, Yuji Hirai, Masayuki Hojo, Tetsuya Homma, Billy Hour, Andreas Huber, Diego Iacovelli, Noriomi Ishibashi, Yutaro Iwabe, Shinyu Izumi, Arne Jessen, Heiko Jessen, Wilner Jeudy, Marta Jiménez Marcos, Rebecca Johnson, Eva Juárez-Hernández, Kiyomi Kabasawa, Katarzyna Kamińska, Megumi Kawabe, Angela Kemp, Oleg Khmelnitskiy, Carina Klassen, Olena Kobrynska, Pavel Koleckar, Stephanie Korn, Marc Kornmann, Viktor Kostenko, Evgenii Kovalchuk, Yana Kovalchuk, Tim Kümmerle, Ulrike Lachmund, Kerstin Lammersmann, Flávio Lastebasse, Ivana Lattuada, Felicitas Lauer, Kyrylo Lebed, Olga Lebed, Diego Lecona-Garcia, Maria Christina Leoni, Marina Lima, Raymond Little, Holly Little, Andrea Lizardi-Díaz, Michele Lobo-Becker, Francesco Luppi, Veronica Macias, Shigefumi Maesaki, Cristiano Magnaghi, Annalisa Mancini, Stanisław Mazur, Tatiana Melnikova, Sergio Menchaca, Ibrahim Menendez-Perez, Ewa Międlar, Shuuichi Mizunuma, Anastasiya Mochalova, Mihad Mohamed, Theresa Moll, Camila Montalvo, Amber Mottola, Birgit Mück, Rebeca Mussi Brugnolli, Akanksha Nanda, Dörthe Neuner, Agatha Ngwueke, Sebastian Noe, Martin Novacek, Laura Nuzzolo-Shihadeh, Emeka Obiekwe, Isaias G Ocampo Gaytán, Norio Ohmagari, Shin Ohta, Ptuonye Onyewuchi, Iurii Pankov, Maurício Pedrosa, Yael Peré, Alejandro Pereyra, Eliana Perez, Eduardo Perez-Alba, Paloma Perpiña Lozano, Tanya Perrei, Dena Peterson, Ligia Pierroti, Felipe Pineda-Cárdenas, Teresa Plascencia Sanchez, Camila Poletti, Chiara Pomaranzi, Lisette Portes, Nils Postel, Monica Ramirez, Isabel Ramírez, Miguel Ramirez-Baena, Mahadev Ramjee, Giovanna Ratti, Jackie Reeve, Petr Reichert, Petra Reichertová, Edgar Alejandro Reyes Garcia, Celso Ricardo, Nicomedes Rodríguez Rodríguez, Jaun Roldán Sánchez, Matilde Romero-Lopez, Tyrone Rosales, Harvey Rosales, Mohamed Roshan, Simran Roshan, Patrizia Rovere Querini, Heather Rutter, Sadaf Sachwani, Hironori Sagara, Jun Sakai, Nina Samson, José Héctor Sánchez Mijangos, Liliana Sánchez, Ana Sánchez-González, Micko Sandford, Laura Santana, Felipe Santos De Carvalho, Reiko Sasao, Lubna Sato, Elizabeth Scheuermann, Olaf Schmidt, Masafumi Seki, Safia Shaikh, Daishi Shimada, Masaharu Shinkai, Masahiro Shinoda, Jackie Smith, Fernando Solorzano, Silvia Soncini, Katalin Soregine, Erica Sosa, Olalekan Sowade, Veronika Špinková, Ruth Staniford, Iska Steigemann, Vivien Steiner, Vladimir Strelkov, Cintya R Suárez Pineda, Hiroki Suenaga, Shintaro Suzaki, Hannah Swayze, Yuji Tada
The Lancet Respiratory Medicine, doi:10.1016/s2213-2600(22)00180-1
Background Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab-cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab-cilgavimab in preventing progression to severe COVID-19 or death. Methods TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab-cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394.
placebo in the 7 days after symptom onset. The greatest reductions in development of severe COVID-19 or death were observed when tixagevimab-cilgavimab was administered as early as possible after symptom onset, as shown by the RR reductions at 3 days or less (prespecified subgroup), 5 days or less and, at 7 days or less (prespecified subgroup) from symptom onset (figure 2B ). For most participant subgroups, reductions in the risk of developing severe COVID-19 or death with tixagevimab-cilgavimab were consistent with the primary analysis (figure 2C ). Most events were observed in participants at high risk of progression to severe COVID-19 (figure 2C ). Although the number of events was low in participants at low risk of progression to severe COVID-19, a large but not statistically significant RR reduction with tixagevimab-cilgavimab was observed in this group. There was a low proportion of seropositive participants, those aged 75 years or older, and those on corticosteroids at baseline (table 1, figure 2C ) and concomitantly a small number of events in these subgroups, resulting in low RR reductions with wide 95% CIs. There was a significant reduction in respiratory failure in participants in the tixagevimab-cilgavimab group compared with the placebo group (table 2 ). Antidrug antibody data were available in a subset of participants up to 84 days after receiving the study drug. Treatment-emergent antidrug antibodies to tixagevimabcilgavimab occurred in six (5%) of 134..
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