In a recent study published in the Lancet, researchers evaluated the safety and efficacy of tixagevimab–cilgavimab, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibody (mAb) combination in patients with mild to moderate coronavirus disease 2019 (COVID-19).
Study: 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. Image Credit: NIAID
The authors performed a comprehensive literature search on the PubMed database to identify five studies that reported the use of anti-SARS-CoV-2 mAbs in the outpatient treatment setting. However, none of these studies used an intramuscular route of mAb administration.
The United States (US) Food and Drug Administration (FDA) has given emergency use authorization (EUA) to several SARS-CoV-2-neutralizing mAbs. However, all those mAbs are administered intravenously or subcutaneously.
To date, tixagevimab–cilgavimab is the only mAb combination that protects against severe COVID-19 from a single intramuscular dose. Additionally, it is long-acting with a longer half-life compared to other currently used mAbs for COVID-19 treatment. The current clinical trial adds to the growing evidence supporting the use of tixagevimab–cilgavimab against SARS-CoV-2 in different clinical settings beyond the EUA.
About the study
Researchers recruited participants at 95 sites in the US, Latin America, Europe, and Japan for the ongoing phase III clinical trial, TACKLE. The study population comprised unvaccinated, non-hospitalized adults over 18 years with a positive reverse transcription-polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infection three days or less before enrolment. In addition, the eligible participants also fulfilled the World Health Organization (WHO) criteria of Clinical Progression Scale (CPS) score of more than one and less than four.
The researchers randomly assigned eligible participants to the test and control groups in a ratio of 1:1. to receive either a single 600 mg dose of tixagevimab–cilgavimab or a placebo. Notably, the eligible participants received the study drug seven days or less from the self-reported onset of COVID-19 symptoms.
Further, the team blinded the participants, investigators, and sponsor staff to treatment-group assignments. They also stratified the randomization process based on the time from symptom onset and high versus low risk of progression to severe COVID-19.
The researchers used a Cochran-Mantel-Haenszel (CMH) test to calculate the relative risk (RR) reduction in severe COVID-19 incidence or death from any cause in the tixagevimab–cilgavimab group compared to the placebo group. The test results indicated the primary efficacy of the mAb treatment.
The primary endpoints of the study were safety, severe COVID-19, or death from any cause by day 29. The primary data cutoff of the study was 29 days, while the follow-up continued for 457 days. The team assessed drug safety for 450 days, i.e., over five half-lives of tixagevimab– cilgavimab. Specifically, they assessed the presence of adverse events, serious adverse events, and adverse events of special interest, including anaphylaxis and hypersensitivity reactions, such as injection site reactions.
The secondary endpoints assessed whether treatment with tixagevimab–cilgavimab reduced the progression of self-reported COVID-19 symptoms and the differences in symptom duration between tixagevimab–cilgavimab and placebo groups, and the single-dose pharmacokinetics of tixagevimab–cilgavimab.
Of the 1,014 enrolled participants, 456 received tixagevimab–cilgavimab, and 454 received a placebo. Baseline characteristics, including age, sex, and race/ethnicity, were similar between all the groups.
In the primary efficacy analysis, 18/407 participants in the tixagevimab–cilgavimab group progressed to severe COVID-19 or died versus 37/415 participants in the placebo group, with an RR reduction of 50.5%. Likewise, the Cox Regression analysis showed a dip of 51% in the risk for severe COVID-19 or death from any cause for the tixagevimab–cilgavimab group.
Notably, the early administration of tixagevimab–cilgavimab drastically reduced the development of severe COVID-19 or death, as shown by the RR reductions at three, five, and seven days or less from symptom onset. Also, there was a significant reduction in respiratory failure in the tixagevimab–cilgavimab group compared with the placebo group.
The authors noted that 132 of 452 participants reported adverse events in the tixagevimab–cilgavimab group while only 163 of 451 in the placebo group, with most adverse events being mild or moderate in severity. The most common adverse event in both groups was COVID-19-associated pneumonia.
Overall, the tixagevimab–cilgavimab mAb combination offered clinically significant protection against severe COVID-19 or death in non-hospitalized unvaccinated adults. Secondary analyses showed that earlier treatment with tixagevimab– cilgavimab led to more favorable outcomes. Moreover, this mAb combination had a favorable safety profile and good tolerability.
- 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, Prof F D Richard Hobbs, Francisco Padilla, Douglas Arbetter, Alison Templeton, Seth Seegobin, 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, The Lancet Respiratory Medicine 2022, DOI: https://doi.org/10.1016/S2213-2600(22)00180-1, https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00180-1/fulltext