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

Montgomery, Hugh; Hobbs, F D Richard; Padilla, Francisco; Arbetter, Douglas; Templeton, Alison; Seegobin, Seth; Kim, Kenneth; Campos, Jesus Abraham Simón; Arends, Rosalinda H; Brodek, Bryan H; Brooks, Dennis; Garbes, Pedro; Jimenez, Julieta; Koh, Gavin; Padilla, Kelly; Streicher, Katie; Viani, Rolando M.; Alagappan, Vijay; Pangalos, Menelas N.; Esser, Mark T.; Abe, Wakana; Varona, Tania Adan De; Adiatullina, Daria; Zapata, Daniel; Ahlers, Kevin; Aimo, Carolina; Akere, Ayoade; Akimova, Elena N.; Alexander, J.A. Alatorre; Aldrich, Logan; García, Ismael Ali; García, Karim Ali; Allison, L. J.; Zuñiga, Rosa Alonso; Aloysius, Ivan; Altclas, Javier; Alvarisqueta, Andres; Antila, Martti; Anton, Camila; Alamo, Elisabet Árboix; Arora, Samir; Felix, Ramón Alejandro Avilés; Bakhtina, Natalya; Barbero-Becerra, Varenka J.; Barragan-Reyes, Armando; Barreira, Alejandro; Barrett, Mitchell; Beran, Jiřı́; Berki, Nikolett; Berki, Viktoria; Betten, Richard; Binelli, Claudia; Brunzová, Lenka; Bussolari, Cecilia; Byargeon, Karianna; Bytnar, Justyna; Camberos, Carlos; Corzo, Pedro Campos; Cannon, Grazia; Canovi, Valentina; Rosa, Simone Carla da; Moser, Ana Caroline; Rivas, Luis Carrera; Casas, Marcelo Martín; Castañeda-Méndez, Paulo; Cavalcante, Ana Amélia de Carvalho Melo; Cherepova, Eugenia; Chermenskii, Alexei; Clark, Lauren; Codeluppi, Mauro; Coelho, Flávia; Contreras, Belinda; Cran, Alex; Dao, Taylor; Dharma, Chrisette; Castri, Cosimo Di; Balocchi, Victoria Diaz; Durán, Omar; Earl, Kara; Ellery, Adam; Endo, Tokiko; Everding, Andrea; Fischer, Rainald; Fonseca, Benedito Antônio Lopes da; Franklin, Chelsea C.; Franz, Susan-Beatrice; Fumagalli, Anna; Galindo-Amaya, Mauricio; Galli, Mariagiulia; Gerna, Laura; Ureña, Karolly Gil; Antila, Henrikki Gomes; Maricato, Laura Ines Gomes; Goncalvez, Gabriela; González, Martín; González-Lama, Jesús; Granier, Stephen; Granier, Jacob; Grunwald, Stephan; Guardeño-Ropero, David; Guberti, Monica; Guduri, Sridhar; García, Carolina Guerrero; Haggiagi, Jehad; Hale, Kacie; Hayashi, Toshimasa; Hermes, Maiara; Colin, Dante Hernandez; Hirai, Yuji; Hojo, Masayuki; Homma, Tetsuya; Hour, Billy; Huber, Andreas; Iacovelli, Diego; Ishibashi, Noriomi; Iwabe, Yutaro; Izumi, Shinyu; Jessen, Arne; Jessen, Heiko; Jeudy, Wilner; Marcos, Marta Jiménez; Johnson, Rebecca A.; Juárez-Hernández, Eva; Kabasawa, Kiyomi; Kamińska, Katarzyna; Kawabe, Megumi; Kemp, Angela; Khmelnitskiy, Oleg; Klassen, Carina; Kobrynska, Olena; Koleckar, Pavel; Korn, Stephanie; Kornmann, Marc; Костенко, В. А.; Kovalchuk, Evgenii; Kovalchuk, Y.O.; Kümmerle, Tim; Lachmund, Ulrike; Lammersmann, Kerstin; Lastebasse, Flávio; Lattuada, Ivana; Lauer, Felicitas; Lebed, Kyrylo; Lebed, Olga; Lecona-Garcia, Diego; Leoni, Maria Christina; Lima, Marina de Deus Moura de; Little, Raymond; Little, Holly; Lizardi-Díaz, Andrea; Lobo-Becker, Michele; Luppi, F; Macias, Veronica; Maesaki, Shigefumi; Magnaghi, Cristiano; Mancini, Annalisa; Mazur, Stanisław; Melnikova, Tatiana; Menchaca, Sergio; Menendez-Perez, Ibrahim; Międlar, Ewa; Mizunuma, Shuuichi; Mochalova, Anastasiya; Mohamed, Mihad; Moll, Theresa; Montalvo, Camila; Mottola, Amber; Mück, Birgit; Brugnolli, Rebeca Mussi; Nanda, Akanksha; Neuner, Dörthe; Ngwueke, Agatha; Noe, Sebastian; Nováček, Martin; Nuzzolo-Shihadeh, Laura; Obiekwe, Emeka; Gaytán, Isaias G. Ocampo; Ohmagari, Norio; Ohta, Shin; Onyewuchi, Ptuonye; Pankov, Iurii; Pedrosa, Maurício; Peré, Yael; Pereyra, Alejandro; Perez, Eliana; Pérez-Alba, Eduardo; Lozano, Paloma Perpiña; Perrei, Tanya; Peterson, Dena; Pierroti, Ligia; Pineda-Cárdenas, Felipe; Sanchez, Teresa Plascencia; Poletti, Camila; Pomaranzi, Chiara; Portes, Lisette; Postel, Nils; Ramírez, Mónica Teresa González; Ramírez, Isabel de Torres; Ramirez-Baena, Miguel; Ramjee, Mahadev; Ratti, Giovanna; Reeve, Jackie; Reichert, Petr; Reichertová, Petra; Garcia, Edgar Alejandro Reyes; Ricardo, Celso; Rodríguez, Nicomedes Rodríguez; Sánchez, Jaun Roldán; Romero-Lopez, Matilde; Rosales, Tyrone; Rosales, Harvey; Roshan, Mohamed; Roshan, Simran; Querini, Patrizia Rovere; Rutter, Heather; Sachwani, Sadaf; Sagara, Hironori; Sakai, Jun; Samson, Nina; Mijangos, José Héctor Sánchez; Sánchez, Liliana; Sánchez-González, Ana; Sandford, Micko; Costa, Laura Emmanuela Lima; Carvalho, Felipe Santos de; Sasao, Reiko; Sato, Lubna; Scheuermann, Elizabeth A; Schmidt, Olaf; Seki, Masafumi; Shaikh, Safia; Shimada, Daishi; Shinkai, Masaharu; Shinoda, Masahiro; Smith, Jackie; Solorzano, Fernando; Soncini, Silvia; Soregine, Katalin; Sosa, Erica T.; Sowade, Olalekan; Špinková, Veronika; Staniford, Ruth; Steigemann, Iska; Steiner, Vivien; Стрелков, В. Д.; Pineda, Cintya R. Suárez; Suenaga, Hiroki; Suzaki, Shintaro; Swayze, Hannah; Tada, Yuji; Takeshita, Yuichiro; Takiguchi, Yasuo; Tanaka, Akihiko; Tarumoto, Norihito; Tatarintseva, Albina; Taubert, Michelle; Terenya, Elizaveta; Tinoco, César; Tomiyasu, Tomohiro; Torres-Vidal, Gladys; Trejo-Aguiar, Gabriela; Tsushima, Kenji; Tunstall, Emma; Turrà, Caterina; Valdes, Yoandy; Castro, Nelly Valencia; Visconti, Guilherme; Vitali, Giordano; Vutikullird, Apinya; Watti, Jezdancher; Werth, Doreen; Wilson, Cheyanne; Wilson, Philippe B.; Workman, Amy; Wörle, Pamela; Wyen, Christoph; Yamaguchi, Yoshiko; Yamamoto, Kei

doi:10.1016/s2213-2600(22)00180-1

Cited by 156 publications

(82 citation statements)

References 23 publications

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“…Tixagevimab plus cilgavimab does appear to remain active against BA.2 [ 175 ] but this combination therapy is currently only authorized for prophylactic use (as of April 2022) [ 175 ]. However, within a trial setting, the TACKLE study assessed the efficacy of tixagevimab plus cilgavimab versus placebo in >900 outpatients with symptomatic COVID-19 for ≤7 days and showed that active treatment reduced progression to severe COVID-19 or death (relative risk reduction 50.5%) [ 176 ]. In addition, Bebtelovimab is active in vitro against most circulating omicron subvariants [ 177 ], but at present there are no efficacy data from placebo-controlled clinical trials.…”

Section: Treatment Of Covid-19 In Patients With Chronic Liver Disease...mentioning

confidence: 99%

Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper

Marjot

Eberhardt

Böettler

et al. 2022

Journal of Hepatology

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Section: Treatment Of Covid-19 In Patients With Chronic Liver Disease...mentioning

confidence: 99%

Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper

Marjot

Eberhardt

Böettler

et al. 2022

Journal of Hepatology

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“…Severe COVID-19 or death occurred in 18 (4%) of 407 treated participants in the tixagevimab–cilgavimab group versus 37 (9%) of 415 treated participants in the placebo group. SARS-CoV-2 can be expected to cause severe disease most frequently in older patients with a variety of comorbidities 2 , 3 , 4 but the mean age of participants in this study was 46·1 years (SD 15·2). 2 Adverse events ascribed to tixagevimab–cilgavimab were mild, as has been the case for almost all the monoclonal antibodies directed against SARS-CoV-2.…”

mentioning

confidence: 84%

“…SARS-CoV-2 can be expected to cause severe disease most frequently in older patients with a variety of comorbidities 2 , 3 , 4 but the mean age of participants in this study was 46·1 years (SD 15·2). 2 Adverse events ascribed to tixagevimab–cilgavimab were mild, as has been the case for almost all the monoclonal antibodies directed against SARS-CoV-2. 2 …”

mentioning

confidence: 84%

“… 2 Adverse events ascribed to tixagevimab–cilgavimab were mild, as has been the case for almost all the monoclonal antibodies directed against SARS-CoV-2. 2 …”

mentioning

confidence: 88%

“…In The Lancet Respiratory Medicine , Hugh Montgomery and colleagues 2 report the use of a combination of monoclonal antibodies, tixagevimab and cilgavimab, to prevent the progression of SARS-CoV-2 infection. In a double-blind, randomised controlled trial, unvaccinated patients with documented SARS-CoV-2 infection were randomly assigned to receive 600 mg tixagevimab–cilgavimab intramuscularly within 7 days of onset of COVID-19 symptoms (n=456) or a placebo injection (n=454).…”

mentioning

confidence: 99%

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Early treatment to prevent progression of SARS-CoV-2 infection

Cohen¹

2022

The Lancet Respiratory Medicine

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Safety and Efficacy of Combined Tixagevimab and Cilgavimab Administered Intramuscularly or Intravenously in Nonhospitalized Patients With COVID-19

et al. 2023

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ImportanceDevelopment of effective, scalable therapeutics for SARS-CoV-2 is a priority.ObjectiveTo test the efficacy of combined tixagevimab and cilgavimab monoclonal antibodies for early COVID-19 treatment.Design, Setting, and ParticipantsTwo phase 2 randomized blinded placebo-controlled clinical trials within the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)–2/A5401 platform were performed at US ambulatory sites. Nonhospitalized adults 18 years or older within 10 days of positive SARS-CoV-2 test and symptom onset were eligible and were enrolled from February 1 to May 31, 2021.InterventionsTixagevimab-cilgavimab, 300 mg (150 mg of each component) given intravenously (IV) or 600 mg (300 mg of each component) given intramuscularly (IM) in the lateral thigh, or pooled placebo.Main Outcomes and MeasuresCoprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLOQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events through 28 days.ResultsA total of 229 participants were randomized for the IM study and 119 were randomized for the IV study. The primary modified intention-to-treat population included 223 participants who initiated IM tixagevimab-cilgavimab (n = 106) or placebo treatment (n = 117) (median age, 39 [IQR, 30-48] years; 113 [50.7%] were men) and 114 who initiated IV tixagevimab-cilgavimab (n = 58) or placebo treatment (n = 56) (median age, 44 [IQR, 35-54] years; 67 [58.8%] were women). Enrollment in the IV study was stopped early based on a decision to focus on IM product development. Participants were enrolled at a median of 6 (IQR, 4-7) days from COVID-19 symptom onset. Significant differences in time to symptom improvement were not observed for IM tixagevimab-cilgavimab vs placebo or IV tixagevimab-cilgavimab vs placebo. A greater proportion in the IM tixagevimab-cilgavimab arm (69 of 86 [80.2%]) than placebo (62 of 96 [64.6%]) had nasopharyngeal SARS-CoV-2 RNA below LLOQ at day 7 (adjusted risk ratio, 1.33 [95% CI, 1.12-1.57]) but not days 3 and 14; the joint test across time points favored treatment (P = .003). Differences in the proportion below LLOQ were not observed for IV tixagevimab-cilgavimab vs placebo at any of the specified time points. There were no safety signals with either administration route.ConclusionsIn these 2 phase 2 randomized clinical trials, IM or IV tixagevimab-cilgavimab was safe but did not change time to symptom improvement. Antiviral activity was more evident in the larger IM trial.Trial RegistrationClinicalTrials.gov Identifier: NCT04518410

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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

Cited by 156 publications

References 23 publications

Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper

Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper

Early treatment to prevent progression of SARS-CoV-2 infection

Safety and Efficacy of Combined Tixagevimab and Cilgavimab Administered Intramuscularly or Intravenously in Nonhospitalized Patients With COVID-19

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